Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.[CH3:41][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[OH:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([O:31][CH3:41])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (4.23 g, 10 mmol) in a mixture of CH2Cl2 (50 ml) and MeOH (5 ml) was added (trimethylsilyl)diazomethane (5.00 ml, 10.00 mmol). The solution was stirred at rt for 2 h under nitrogen. LC/MS showed no SM left. The reaction mixture was concentrated to afford methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (4.37 g, 100%). The compound was used in the next step without further purification. LCMS: m/e 559.4 (MH+), 3.29 min (method 2). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.95 (m, J=8.3 Hz, 2H), 7.22 (m, J=8.6 Hz, 2H), 5.22-5.39 (m, 1H), 4.72 (d, J=2.0 Hz, 1H), 4.49-4.67 (m, 1H), 3.94 (s, 3H), 3.87 (s, 1H), 3.38 (d, J=10.6 Hz, 1H), 2.37-2.60 (m, 1H), 2.05-2.21 (m, 1H), 1.96 (d, J=11.1 Hz, 2H), 1.90 (d, J=13.1 Hz, 1H), 1.61-1.82 (m, 7H), 1.55 (br. s., 8H), 1.37-1.52 (m, 2H), 1.18-1.37 (m, 4H), 1.08-1.18 (m, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.95 (s, 6H).
Reaction SMILES: COC(=O)[C@H](CC1C=CC=CC=1)NC(=O)[C@H](CC(=O)O)N.[NH2:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][C:25]([OH:27])=[O:26].[CH2:31]=[C:32]1[O:36][C:34](=[O:35])[CH2:33]1>>[C:34]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][C:25]([OH:27])=[O:26])(=[O:35])[CH2:33][C:32]([CH3:31])=[O:36]
Reactant: C=C1CC(=O)O1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Product: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
This invention encompasses a method and intermediates for preparing a commercial sweetening agent, α-L-aspartyl-L-phenylalanine methyl ester. The process involves reacting L-aspartic acid with diketene to form N-acetoacetyl-L-aspartic acid which is converted to N-acetoacetyl-L-aspartic anhydride by reaction with acetic anhydride. N-acetoacetyl-L-aspartic anhydride is reacted with L-phenylalanine methyl ester to provide N-acetoacetyl-α-L-aspartyl-L-phenylalanine methyl ester which is converted to α-L-aspartyl-L-phenylalanine methyl ester by reaction with hydroxylamine hydrochloride.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[OH-].[Na+].[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>C(Cl)Cl.C(Cl)Cl.O.O>[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:2]2[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: O=C(O)C1CNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)C1CN(S(=O)(=O)c2ccc(I)cc2)C1
Yield: 43.8 %

Procedure:
To a stirred solution of azetidine-3-carboxylic acid hydrochloride (1.0 g, 7.27 mmol) in DCM (25 mL) is added 5N aqueous NaOH (10 mL) and water (10 mL). p-Iodobenzenesulfonyl chloride (2.41 g, 7.98 mmol) is added portionwise. After 18 h the reaction mixture is diluted with DCM/water. The basic aqueous layer is acidified with 5N aqueous HCl. The resultant precipitate is filtered, washed with water and MeCN. Drying in air gives 1.17 g (44%) of 1-[(4-iodophenyl)sulfonyl]azetidine-3-carboxylic acid. m/z=368 [M++H].
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH2:21][CH3:22])[CH2:4][C@H:5]([CH2:9][N:10]([CH:18]=[O:19])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[C:6]([OH:8])=O)C.[Cl:23][C:24]1[N:29]=[C:28]([N:30]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)[CH2:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:27]([F:44])=[C:26]([NH:45][NH2:46])[N:25]=1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:23][C:24]1[N:25]=[C:26]([NH:45][NH:46][C:6](=[O:8])[C@H:5]([CH2:4][CH:3]2[CH2:1][CH2:22][CH2:21][CH2:20]2)[CH2:9][N:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:18]=[O:19])[C:27]([F:44])=[C:28]([N:30]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)[CH2:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[N:29]=1
Reactant: CCCC(CC)C[C@H](CN(C=O)OC1CCCCO1)C(=O)O
Reactant: CN1CCN(N(Cc2nccs2)c2nc(Cl)nc(NN)c2F)CC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CN1CCN(N(Cc2nccs2)c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)CC1
Reaction time: 8 h
Yield: 57.2 %

Procedure:
(2R)-4-Ethyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}heptanoic acid (0.3764 g, 1.257 mmol), 2-chloro-5-fluoro-6-hydrazino-N-(4-methyl-1-piperazinyl)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine (0.1683 g), NMM (0.298 mL, 2.71 mmol), HOAt (0.074 g, 0.542 mmol), and EDC (0.104 g, 0.542 mmol) were dissolved in DMF (10 mL). The reaction was left to stir overnight. Purification by RP-HPLC provided [(2R)-3-(2-{2-chloro-5-fluoro-6-[(4-methyl-1-piperazinyl)(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a brown oily solid (0.1688 g). LCMS: (M+H)+=655.4.
Reaction SMILES: [I:1][C:2]1[S:6][C:5]([CH:7]=O)=[C:4]([CH:9]=O)[CH:3]=1.[C:11]1(=[O:18])[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.[OH-].[K+]>>[I:1][C:2]1[S:6][C:5]2[CH:7]=[C:15]3[C:14](=[O:17])[C:13]4[C:12](=[CH:9][C:4]5[CH:3]=[C:2]([I:1])[S:6][C:5]=5[CH:7]=4)[C:11](=[O:18])[C:16]3=[CH:9][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)CC1
Reactant: O=Cc1cc(I)sc1C=O
Agent: [K+]
Agent: [OH-]
Product: O=C1c2cc3cc(I)sc3cc2C(=O)c2cc3sc(I)cc3cc21
Temperature: 20 °C
Yield: 86.6 %

Procedure:
5-Iodo-2,3-thiophenedicarboxaldehyde (20.00 g, 75.15 mmol) and 1,4-cyclohexandione (4.25 g, 37.12 mmol) were dissoved in IMS (industrial methylated spirits) (600 cm3) by warming and stirring, and then cooled to 20° C. with a water bath. 5% KOH solution (7.5 cm3) was added in one portion under nitrogen with vigorous stirring. The reaction mixture was stirred at 20° C. for 30 minutes and the precipitate formed was collected by suction filtration, washed with IMS, water, IMS, then acetone, and dried in the vacuum oven at 40° C. overnight to yield 2,8-diiodo-anthra[2,3-b:7,6-b′]dithiophene-5,11-dione (18.39 g, 87%). The solid was directly used for the following reactions without further purification.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([NH2:23])=O)[S:19][CH:20]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>CC(N(C)C)=O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]#[N:23])[S:19][CH:20]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC(=O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (25 mg) obtained in Example 13 in DMA (5 mL) was added trifluoroacetic anhydride (240 mg) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hr. To the reaction mixture was added water, the precipitate was collected by filtration, and the obtained solid was crystallized from ethyl acetate and hexane to give the title compound (16.7 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)O1.Br[C:35]1[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:14]([N:12]1[CH:13]=[C:9]([C:35]2[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:10]=[N:11]1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC1(C)OB(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)OC1(C)C
Reactant: Nc1ncccc1Br
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: CCO
Solvent: Cc1ccccc1
Product: Nc1ncccc1-c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
4-(4,4,5,5-Tetramethyl-(1,3,2)dioxaborolan-2-yl)-1-trityl-1H-pyrazole (3.2 g, 7.33 mmol) described in Manufacturing Example 32-1-2, 3-bromo-pyridine-2-ylamine (1.14 g, 6.60 mmol), tetrakis(triphenylphosphine)palladium (0) (424 mg, 0.37 mmol), toluene (40 mL), 2 M aqueous sodium carbonate solution (10 mL) and ethanol (20 mL) were stirred for 1 hour at 95° C. The reaction solution was allowed to room temperature, and partitioned into water and ethyl acetate. The ethyl acetate layer was washed with water once, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (2.3 g, 78.0%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][N:19]=[C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][C:43]2[N:46]([CH2:59][CH:60]3[CH2:62][O:61]3)[N:47]=[C:48]([C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=3)[C:42]=2[CH2:41]1)(=[O:39])=[O:38]>C(Cl)Cl>[NH3:8].[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][C:43]2[N:46]([CH2:59][CH:60]([OH:61])[CH2:62][N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:22]5[C:17](=[CH:18][N:19]=[C:20]([N:23]6[CH2:24][CH2:25][O:26][CH2:27][CH2:28]6)[CH:21]=5)[NH:16][CH:15]=4)[CH2:12][CH2:13]3)[N:47]=[C:48]([C:49]3[CH:50]=[CH:51][C:52]([C:55]([F:56])([F:57])[F:58])=[CH:53][CH:54]=3)[C:42]=2[CH2:41]1)(=[O:39])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3cnc(N4CCOCC4)cc23)CC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(c3c[nH]c4cnc(N5CCOCC5)cc34)CC2)C1
Product: N
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
4-(5-Morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.47 mmol) was dissolved in 3.0 mL of CH2Cl2 and treated with 2.5 mL of trifluoroacetic acid. The reaction mixture was stirred at 25° C. for 1 h before all volatiles were removed. The solid was dissolved in MeOH (20 mL) and neutralized with DOWEX 550A OH anion exchange resin to pH 8. The resin was then filtered off and MeOH was removed under reduced pressure. The residue was dissolved in 2.5 mL of iPrOH and treated with 187 mg (0.47 mmol, 1 eq) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction was stirred at 85° C. for 3 h before solvent was removed. Column chromatography (silica, 5-10% MeOH/CH2Cl2 then 5-10% (2 N NH3 in MeOH)/CH2Cl2) provided 97 mg (30%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.25. MS (electrospray): exact mass calculated for C33H40F3N7O4S, 687.28; m/z found, 688.3 [M+H]+. 1H NMR (400 MHz, CDCl3); 8.47 (br s,1H), 8.44 (d, J=1.0 Hz, 1H), 7.70 and 7.65 (AB pattern, J=8.4 Hz, 4H), 7.03 (d, J=2.1 Hz, 1H), 6.76 (s, 1H), 4.58-4.50 (m, 2H), 4.21-4.00 (m, 3H), 3.90 (t, J=4.5 Hz, 4H), 3.72-3.58 (m, 2H), 3.40 (t, J=4.5 Hz, 4H), 3.10-2.85 (m, 4H), 2.88 (s, 3H), 2.80-2.70 (m, 1H), 2.52-2.41 (m, 3H), 2.20-2.00 (m, 3H), 1.80-1.60 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])[CH3:3].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:42][C:43]1[C:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[CH3:57])=[N:45][O:46][C:47]=1[CH:48]1[CH2:50][CH2:49]1>O1CCCC1.O.C(OCC)(=O)C>[CH:48]1([C:47]2[O:46][N:45]=[C:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=3[CH3:57])[C:43]=2[CH2:42][O:16][CH:14]2[CH2:15][CH:9]3[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)[CH2:50][CH2:49]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reactant: Cc1ccccc1-c1noc(C2CC2)c1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A flask was purged with nitrogen and then charged with N-Boc-nortropine (1.64 g, 7.20 mmol), 18-crown-6 (1.59 g, 6.00 mmol), and anhydrous tetrahydrofuran (60 mL). Potassium tert-butoxide (1.34 g, 12.0 mmol) was added portion-wise, and the mixture was stirred vigorously under nitrogen for 1 hour. 4-(Bromomethyl)-5-cyclopropyl-3-(o-tolyl)isoxazole (1.75 g, 6.00 mmol) in tetrahydrofuran (20 mL, anhydrous) was added dropwise, and the reaction mixture was stirred for 1 hour under nitrogen. The solvent was reduced in vacuo and the mixture diluted with water (100 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The crude residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate/hexanes to yield the desired product as a yellow oil. MS m/z 439.2 (M+1).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].I[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[O:18][C:17]2=[O:24].C#C.[C:27]([C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[C:45](=[O:49])[O:44][C:43]2=[O:50])#[C:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:38])[O:33][C:32]2=[O:39]>>[C:27]([C:21]1[CH:22]=[CH:14][CH:15]=[C:16]2[C:20]=1[C:19](=[O:23])[O:18][C:17]2=[O:24])#[C:28][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].[C:28]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:38])[O:33][C:32]2=[O:39])#[C:27][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[C:45](=[O:49])[O:44][C:43]2=[O:50]
Reactant: O=C1OC(=O)c2cc(I)ccc21
Reactant: O=C1OC(=O)c2c(I)cccc21
Agent: C#C
Agent: O=C1OC(=O)c2cc(C#Cc3ccc4c(c3)C(=O)OC4=O)ccc21
Product: O=C1OC(=O)c2c(C#Cc3cccc4c3C(=O)OC4=O)cccc21

Procedure:
The present inventors have found that (ethyne-1,2-diyl)bis(isobenzofuran-1,3-diones), such as 5,5′-(ethyne-1,2-diyl)bis(isobenzofuran-1,3-dione), may be obtained in a high yield in a one-step procedure by employing a Sonogashira coupling to react a chloro-, bromo-, or iodoisobenzofuran-1,3-dione, such as 5-chloro-, 5-bromo-, or 5-iodoisobenzofuran-1,3-dione, with acetylene, i.e. ethyne. By employing a one step procedure and by avoiding aqueous work-up, causing hydrolysis of the anhydride moieties, a (ethyne-1,2-diyl)bis(isobenzofuran-1,3-dione), such as 5,5′-(ethyne-1,2-diyl)bis(isobenzofuran-1,3-dione), may be obtained in significantly higher yield and shorter process time compared to known processes.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1.[C:25](#[N:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+].[O-][Cl:39].[Na+]>>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][C:25](=[N:32][Cl:39])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1
Reactant: [O-]Cl
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: N#Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(OC)c(NC(=NCl)c2ccccc2)c1
Temperature: 180 °C
Reaction time: 5 h
Yield: 66.7 %

Procedure:
Anhydrous p-toluene sulfonic acid (41.99 g, 220.8 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38 mmol) obtained in step 1 and benzonitrile (22.77 g, 220.8 mmol) were added thereto and stirred at 180° C. for 5 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO3 thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The concentrate was dissolved in 50% methanol and 5% NaOCl (56 Ml, 37.65 mmol) was added dropwise thereto. After 5 min, the resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent—MeOH/CDCl3=5:95, Merck, Silicagel 60) to obtain the title compound (31 g, 25.10 mmol) in a yield of 88%;
Reaction SMILES: BrBr.CCOCC.[Cl:8][C:9]1[CH:10]=[C:11]([C:14](=O)[CH3:15])[S:12][CH:13]=1.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[NH2:20][C:18]1[S:19][CH:15]=[C:14]([C:11]2[S:12][CH:13]=[C:9]([Cl:8])[CH:10]=2)[N:17]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1cc(Cl)cs1
Agent: BrBr
Solvent: CCO
Solvent: CCOCC
Product: Nc1nc(-c2cc(Cl)cs2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine was added to an ether solution of 4-chloro-2-acetylthiophene under ice cooling, and the mixture was stirred at room temperature for 2 hours to obtain a brominated compound. Thiourea was added to an EtOH solution of the brominated compound at room temperature, and the mixture was stirred overnight at 80° C. to obtain 2-amino-4-(4-chlorothiophen-2-yl)thiazole.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]([CH2:18][CH2:19][C:20](Cl)=[S:21])(=[O:17])[CH3:16]>>[C:15]([CH2:18][CH2:19][C:20]([N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH2:11][C:12]([OH:14])=[O:13])=[S:21])(=[O:17])[CH3:16]
Reactant: O=C(O)CNC1Cc2ccccc2C1
Reactant: CC(=O)CCC(=S)Cl
Product: CC(=O)CCC(=S)N(CC(=O)O)C1Cc2ccccc2C1

Procedure:
By reacting N-(2-indanyl)glycine with 3-acetylthiopropionyl chloride in a similar manner to that of Example 1, there is obtained N-(3-acetylthiopropionyl)-N-(2-indanyl)glycine as colorless scales.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.BrP(Br)Br>C(Cl)Cl.C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC(c1ccc2occc2c1)c1ccccn1
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: c1ccc(Cc2ccc3occc3c2)nc1
Reaction time: 1.5 h

Procedure:
A solution of benzofuran-5-yl(pyridin-2-yl)methanol (500 mg, 2220 μmol) in DCM (10 mL) at 0° C. was treated with tribromophosphine (314 μL, 3330 μmol) and stirred for 1.5 h. The mixture was diluted with CHCl3, washed with sat. aqueous KHCO3, dried over MgSO4, and evaporated. A suspension of the crude material and 10% Pd—C (50 mg) in EtOAc (5 mL) and MeOH (3 mL) was stirred under 1 atm H2 at 24° C. for 1 h. The solids were filtered off (Celite) and washed with EtOAc. The filtrate was evaporated and purified by flash chromatography (hexanes to EtOAc to 5% MeOH in DCM) to give 2-(benzofuran-5-ylmethyl)pyridine as a yellow foam. 1H NMR (400 MHz, CD3OD) δ ppm 8.71 (br. s, 1H), 8.17 (t, J=7.6 Hz, 1H), 7.70-7.64 (m, 3H), 7.50-7.48 (m, 2H), 7.29 (d, J=8.1 Hz, 1H), 6.76 (s, 1H), 4.71 (s, 2H). MS (ESI) m/z: Calculated: 209.1; Observed: 210.0 (M++1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[S:8][C:7]([SH:9])=[N:6][N:5]=1.[C:10]([O:14][C:15](N=[N+]=[N-])=[O:16])([CH3:13])([CH3:12])[CH3:11]>O.O1CCOCC1.C(N(CC)CC)C>[C:10]([O:14][C:15]([NH:2][CH2:3][C:4]1[S:8][C:7]([SH:9])=[N:6][N:5]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: NCc1nnc(S)s1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1nnc(S)s1
Reaction time: 24 h
Yield: 65.2 %

Procedure:
To a mixture of 5-aminomethyl-1,3,4-thiadiazole-2-thiol hydrochloride (5.5 g) in water (50 ml), dioxane (50 ml) and triethylamine (15 ml) was added t-butoxycarbonyl azide (5.6 g) and the mixture was stirred for 24 hours at 40° to 45° C. After the reaction was over, the dioxane was distilled off under reduced pressure. The residue was adjusted to pH2 with 10% hydrochloric acid and extracted twice with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate and then evaporated to dryness to give 5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazole-2-thiol (4.83 g). m.p. 144° to 146° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][C:6]([C:14]1[O:15][CH2:16][C@@H:17]([CH2:19][C:20](O)=O)[N:18]=1)=[CH:5]2.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:10]=1)[NH:7][C:6]([C:14]1[O:15][CH2:16][C@@H:17]([CH2:19][CH2:20][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:18]=1)=[CH:5]2
Reactant: O=C1CCOCC1
Reactant: C1COCCN1
Reactant: Cc1cc([N+](=O)[O-])c2[nH]c(C3=N[C@H](CC(=O)O)CO3)cc2c1
Product: Cc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@H](CCN4CCOCC4)CO3)cc2c1

Procedure:
2-[(R)-2-(5-methyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-oxazol-4-yl]acetic acid prepared in Example 104, tetrahydropyran-4-one and morpholine were consecutively reacted according to the same procedures as Example 1, Step A of Preparation 29, and Example 156 to give the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:26]4[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1COCC1.CCCCCCC.[BH4-].[Na+]>O>[C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:26]4[CH:27]=[CH:28][C:29]([CH2:30][OH:31])=[CH:32][CH:33]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COCCOCOc1ccc(C#Cc2ccc(C=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COCCOCOc1ccc(C#Cc2ccc(CO)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
740 mg (1.6 mmol) of 4-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl]benzaldehyde were introduced into 40 ml of a mixture of THF and methanol (50/50) in a round-bottomed flask. 32 mg (0.8 mmol) of sodium borohydride were introduced in small amounts at 5° C. and the temperature was permitted to increase to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.