Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[NH:16][S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])=[O:5])C.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([NH:16][S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:19])=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2
Reactant: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.7 %

Procedure:
To a mixed solution of ethyl-4-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.88 g) in tetrahydrofuran (20 mL)-methanol (10 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.56 g), and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (777 mg, yield 96%) as colorless crystals. melting point>280° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=[CH:3]1.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(CC)CC)C.Cl.[NH2:30][CH2:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[C:34](=[O:50])[N:35]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:36]2=[O:41]>CN(C=O)C>[O:49]=[C:43]1[CH:42]([N:35]2[C:34](=[O:50])[C:33]3[C:37](=[CH:38][CH:39]=[CH:40][C:32]=3[CH2:31][NH:30][C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)=[O:9])[C:36]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: Cn1cncc1C(=O)O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cncc1C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
A mixture of 1-methyl-1H-imidazole-5-carboxylic acid (0.3 g, 2.6 mmol) and carbonyl diimidazole (0.5 g, 3.0 mmol) in DMF (30 mL) was stirred at room temperature for 3 hours. Triethylamine (0.8 g, 6.0 mmol) was added, followed by 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol). The mixture was stirred at 75° C. (oil bath) for 3 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with water (2×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give 3-methyl-3H-imidazole-4-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.2 g. 28%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.50-2.64 (m, 2H), 2.84-2.97 (m, 1H), 3.81 (s, 3H), 4.89 (d, J=5.6 Hz, 2H), 5.13-5.20 (dd, J=5.2 and 12.5 Hz, 1H), 7.68-7.84 (m, 5H), 8.94 (t, J=5.5 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.98, 30.93, 33.51, 37.44, 48.88, 121.88, 125.45, 127.05, 131.52, 132.29, 133.09, 134.83, 139.42, 142.08, 160.25, 166.94, 167.53, 169.82, 172.74; Anal. calcd. for C19H17N5O5+0.13H2O+0.1Et2O: C, 57.52; H, 4.54; N, 17.29. Found: C, 57.23; H, 4.27; N, 16.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:33])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:33])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([OH:30])=[O:29])[CH2:25][N:26]=1)=[CH:18]2)(=[O:10])=[O:11]
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4OC)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 7 h
Yield: 77.5 %

Procedure:
Ethyl (2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (1.0 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-methanol (10 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (0.50 g) in water (5 mL)) was added to this solution, and the mixture was stirred at room temperature for 7 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-brown oil was crystallized from ethyl acetate-hexane to give the title compound (730 mg, yield: 78%) as pale-yellow crystals.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([CH:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:10]1.O>C(#N)C>[Br:1][C:10]1[S:9][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]=1[CH:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(OC(C)(C)C)c1csc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(Br)sc2ccccc12
Reaction time: 20 h
Yield: 44 %

Procedure:
N-bromosuccinimide (67 mg, 0.37 mmol) was added at room temperature to a stirred solution of methyl 2-(1-benzothiophen-3-yl)-2-(tert-butoxy)acetate (4b) (70 mg, 0.25 mmol) in acetonitrile (2 mL) under a nitrogen atmosphere. After 20 hours, water (10 mL) was added and the reaction mixture was extracted with dichloromethane (2×10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product (4c) as a pale oil (40 mg, 0.11 mmol, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37]CBr>CN(C)C=O>[Br:35][CH2:36][CH2:37][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:20][CH3:21])[N:12]=[CH:11][N:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=1
Reactant: BrCCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(O)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCBr)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
N-{2-Chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (500 mg), potassium carbonate (857 mg), and 1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium kp sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 451 mg (yield 71%) of N-(4-{[6-(2-bromoethoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propyl-urea. N-(4-{[6-(2-Bromoethoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea (50 mg), (3 potassium carbonate (40 mg), and N-methylpiperazine (50 μl) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 20 mg (yield 44%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH:22]([CH3:28])[NH:21][CH2:20][CH2:19]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH:22]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Product: COc1cc2c(cc1OC)C(C)N(C(=O)c1cc3ncc(Cl)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4](C(O)=O)[C:3]=1[C:14]([OH:16])=[O:15].[OH-].[Ca+2].[OH-]>O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(F)c1F

Procedure:
Decarboxylation of 3,4,5,6-tetrafluorophthalic acid was carried out by following the procedure of Example 1, except that 238 g of 3,4,5,6-tetrafluorophthalic acid, 11.1 g (0.15 mole) of calcium hydroxide, and 480 g of water were used [pH 1.52 at 30° C. at the time of charging]. This example was found to have produced 2,3,4,5-tetrafluorobenzoic acid in a yield of 86.5 mole %.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:45]1[CH2:48][CH:47]([C:49]([N:51]2[CH2:57][CH2:56][CH2:55][N:54]([CH:58]3[CH2:61][CH2:60][CH2:59]3)[CH2:53][CH2:52]2)=[O:50])[CH2:46]1>C(Cl)Cl>[CH:58]1([N:54]2[CH2:55][CH2:56][CH2:57][N:51]([C:49]([CH:47]3[CH2:46][N:45]([C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[N:3][CH:4]=4)=[O:10])[CH2:48]3)=[O:50])[CH2:52][CH2:53]2)[CH2:61][CH2:60][CH2:59]1
Reactant: Cc1ncc(C(=O)O)cn1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1ncc(C(=O)N2CC(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Reaction time: 3 h
Yield: 28.6 %

Procedure:
To a stirred solution of 2-methylpyrimidine-5-carboxylic acid (23 mg, 0.17 mmol) in DCM (3 ml) was added HOBt (23 mg, 0.17 mmol) and HBTU (64 mg, 0.17 mmol). After 3 hours, a solution of 1-(Azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (48 mg, 0.17 mmol), in DCM (1 ml) was added and the yellow suspension gradually dissolved to give a yellow solution. The reaction mixture was quenched with saturated NaHCO3 (1 ml) and the aqueous layer extracted with DCM (3×5 ml). The combined organic layers were dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with 99:1 to 95:5 gradient of DCM/2M NH3 in MeOH) gave the title compound (17.4 mg, 29% yield) as pale yellow oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([C:18](Cl)=[O:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:39]([Li])[CH2:40][CH2:41][CH3:42].O1CCCC1.Cl>C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([C:18](=[O:19])[CH2:39][CH2:40][CH2:41][CH3:42])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(=O)Cl)CS[C@H]12
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The reaction of these carbanionic reagents with activated 3-carboxycephem intermediates (acid chlorides and mixed anhydrides) is carried out under the same conditions as discussed hereinabove for the process of this invention. A typical procedure is illustrated by reaction of benzhydryl 7-phenylacetamido-3-chlorocarbonyl-3-cephem-4-carboxylate with n-butyllithium. A ethereal solution of 3 equivalents of n-butyllithium is added to a solution of 1 mmole of benzhydryl 7-phenylacetamido-3-chlorocarbonyl-3-cephem-4-carboxylate in 30 ml. of tetrahydrofuran at -73° C. After approximately 5 minutes 10 ml. of 1N. hydrochloric acid is added, and the acidified mixture is then allowed to warm to about 0° C. Ethyl acetate is added, and the resulting mixture is washed with dilute hydrochloric acid and brine and dried over anhydrous sodium sulfate. Chromatographic purification provides benzhydryl 7-phenylacetamido-3-valeroyl-3-cephem-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([CH2:51][N:52]([CH:54]2[CH2:59][CH2:58][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][CH2:55]2)[CH3:53])[CH2:47][CH2:46]1>C(#N)C.C(N(CC)CC)C>[C:63]([O:62][C:60]([N:57]1[CH2:58][CH2:59][CH:54]([N:52]([CH2:51][C@H:48]2[CH2:49][CH2:50][C@H:45]([NH:44][C:18]([C:14]3[CH2:15][CH2:16][O:17][C:11]4[CH:10]=[CH:9][C:8]([C:5]5[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=5)=[CH:21][C:12]=4[CH:13]=3)=[O:19])[CH2:46][CH2:47]2)[CH3:53])[CH2:55][CH2:56]1)=[O:61])([CH3:66])([CH3:65])[CH3:64]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N[C@H]2CC[C@H](CN(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC2)CCO3)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (400 mg) and 1-hydroxybenzotriazole (289 mg) in acetonitrile (20 ml) was added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.41 g), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of tert-butyl trans-4-[N-(4-aminocyclohexylmethyl)-N-methylamino]piperidine-1-carboxylate (698 mg) and triethylamine (0.4 ml) in acetonitrile (30 ml), and the resulting mixture was stirred for 20 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:3→1:2) and to recrystallization (ethyl acetate/hexane) to obtain trans-N-[4-[N-(1-tert-butoxycarbonylpiperidin-4-yl)-N-methylaminomethyl]cyclohexyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 65) (560 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:16][CH3:17])[N:5]=[C:4]([CH3:18])[C:3]=1[CH2:19][N:20]1[CH2:25][CH2:24][O:23][C:22]([CH3:27])([CH3:26])[CH2:21]1.[OH:28][C:29]1[CH:37]=[C:36]([OH:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH2:33])=[O:32].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN1CCCC1=O.[Cu].O>[CH2:16]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][CH3:15])[C:8]=1[C:6]1[N:5]=[C:4]([CH3:18])[C:3]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][C:22]([CH3:27])([CH3:26])[CH2:21]2)=[C:2]([O:38][C:36]2[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[C:29]([OH:28])[CH:37]=2)[CH:7]=1)[CH3:17]
Reactant: NC(=O)c1ccc(O)cc1O
Reactant: CCc1cccc(CC)c1-c1cc(Cl)c(CN2CCOC(C)(C)C2)c(C)n1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1cc(Oc2ccc(C(N)=O)c(O)c2)c(CN2CCOC(C)(C)C2)c(C)n1
Temperature: 150 °C

Procedure:
A mixture of 4-[4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-pyridin-3-ylmethyl]-2,2-dimethyl-morpholine (30 mg, 0.08 mmol), 2,4-dihydroxy-benzamide (24 mg, 0.16 mmol), copper powder (10 mg) and K2CO3 (22 mg, 0.16 mmol) in 1-methyl-2-pyrrolidinone (1 mL) is heated at 150° C. overnight. After cooling, EtOAc (10 mL) and water (10 mL) are added to the mixture. The organic layer is separated, washed with brine (3×), dried (Na2SO4) and concentrated. The crude is purified by PTLC (1:1 Hexane/EtOAc) to give to give the title compound. 1H NMR (CDCl3) 12.41 (s, 1H), 7.35 (d, 2H), 7.23 (m, 1H), 7.10 (m, 2H), 6.63 (s, 1H), 6.51 (m, 2H), 5.85 (br, 2H), 3.72 (m, 2H), 3.56 (s, 2H), 2.74 (s, 3H), 2.41-2.30 (m, 6H), 1.20 (s, 6H), 1.76 (m, 2H), 1.01 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CO[CH:19](OC)[N:20](C)C.[C:25]([O-])(=O)C.[NH4+]>CN(C=O)C.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:25]=[N:15][CH:14]=[C:13]([C:12]=2[OH:16])[C:19]#[N:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)[O-]
Reactant: COc1ccc(CC(=O)CC#N)cc1OC
Reactant: COC(OC)N(C)C
Agent: [NH4+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(-c2cncc(C#N)c2O)cc1OC
Temperature: 122 °C
Yield: 69 %

Procedure:
To a solution of 4-(3,4-dimethoxyphenyl)-3-oxo-butyronitrile (5.0 g, 23 mmol) in DMF (12 mL) was added dimethylformamide-dimethylacetal (DMF-DMA, 13.5 mL, 101 mmol) and the solution heated at 122° C. overnight. Concentration on a rotary evaporator under high vacuum gave an orange-red solid. This solid was dissolved in EtOH (100 mL) and excess ammonium acetate was added and the reaction mixture was heated at 85° C. for 1 h. The reaction mixture was allowed to cool to room temperature (r.t.) for 1 h then the solids were collected by filtration and washed with EtOH (cold) to give 5-(3,4-dimethoxyphenyl)-4-hydroxynicotinonitrile (4.1 g, 69%) as a brown solid. The filtrate was concentrated on a rotary evaporator and the residue purified on silica gel with 0-25% MeOH in CH2Cl2 to give an additional amount of 5-(3,4-dimethoxyphenyl)-4-hydroxynicotinonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][CH2:20][N:19]([CH2:24][C:25]([OH:27])=O)[C:18]=3[CH:28]=1)=[O:12])=[CH:5]2.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[O:27]=[C:25]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:24][N:19]1[C:18]2[CH:28]=[C:14]([NH:13][C:11]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)=[O:12])[CH:15]=[CH:16][C:17]=2[O:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNC1
Reactant: O=C(O)CN1CCCOc2ccc(NC(=O)c3cc4cc(Cl)ccc4[nH]3)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)N(CC(=O)N1CCCC1)CCCO2)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-acetic acid (80 mg) and pyrrolidine (14.2 mg) were dissolved in anhydrous THF. To that solution was added BOP and the resulting mixture treated with triethylamine (40.5 mg). The reaction was stirred overnight at room temperature. The reaction was evaportated and the crude product purified by TLC using EtOAc as solvent to yield 68 mg of the product. LCMS: AP+ 453/455.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+].O>C(O)C.CO>[OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: NC(=O)NC1CCC(O)c2sccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 2.5 liters of ethanol, 34.85 grams of (-)-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea is stirred and 9.8 grams of NaBH4 is added. The mixture is stirred overnight at room temperature, 1400 ml. of water is added, and after stirring for 0.5 hour the ethanol is evaporated in vacuo. The mixture is cooled and 25-30 ml. of acetic acid is added until no more foaming occurs. The mixture is stirred for 0.75 hour, filtered to collect the first crop and this solid is washed with water and air dried. This solid is recrystallized from acetone and then from acetone/methanol to give 6.75 g. of isomer B of the title compound, m.p. 211°-213° C. (dec.), [α]D25.5 =-23.23° (c, 3.11 in methanol). This material contains 92% isomer B and 8% isomer A when assayed by high pressure liquid chromatography.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][NH:7][CH:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25]C(C#N)=[CH:21][CH:20]=1)[CH2:12]2.[CH3:27][C:28]#[N:29].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:28]([C:27]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][N:11]2[CH2:12][CH:13]3[CH:8]([N:7]([CH3:6])[C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:9]([CH2:15][CH2:14]3)[CH2:10]2)=[CH:26][CH:25]=1)#[N:29]
Reactant: CNC1C2CCC1CN(CCOc1ccc(C#N)cc1)C2
Reactant: CC#N
Reactant: CCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCNC(=O)N(C)C1C2CCC1CN(CCOc1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl isocyanate (0.8 mL, 9.66 mmol) in DCM (3 mL) was added dropwise, at 0° C., to a mixture of 4-{2-[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]ethoxy}benzonitrile (Preparation K; 2.5 g, 8.76 mmol) and MeCN (50 mL). The mixture was stirred at rt for 3 h, K2CO3 (2 g, 14.4 mmol) was added and the mixture was stirred for a further 2 h. Filtration and evaporation gave 2.96 g of crude product. This was purified twice by chromatography on silica gel, the first time eluting with a gradient of EtOAc:MeOH:ammoniacal methanol (10:1:0 to 10:0:1), and the second time eluting with DCM:MeOH:TEA (190:10:1). This gave 2.3 g (71.4%) of the title compound.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[C:15]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([Cl:28])=[C:23]([O:29][CH3:30])[CH:22]=2)([CH3:18])([CH3:17])[CH3:16].[CH:31]([C:33]1[N:38]=[C:37]([C:39]([O:41][CH3:42])=[O:40])[CH:36]=[CH:35][CH:34]=1)=O.C(=O)([O-])O.[Na+]>ClCCl.O>[C:15]([C:19]1[NH:20][C:21]2[C:26]([C:27]=1[CH2:31][C:33]1[N:38]=[C:37]([C:39]([O:41][CH3:42])=[O:40])[CH:36]=[CH:35][CH:34]=1)=[CH:25][C:24]([Cl:28])=[C:23]([O:29][CH3:30])[CH:22]=2)([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1cc2[nH]c(C(C)(C)C)cc2cc1Cl
Reactant: COC(=O)c1cccc(C=O)n1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cccc(Cc2c(C(C)(C)C)[nH]c3cc(OC)c(Cl)cc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a solution of triethylsilane (0.202 mL) and trifluoroacetic acid (0.049 mL) in dichloromethane (2 mL) was added a suspension of 2-tert-butyl-5-chloro-6-methoxy-1H-indole (100 mg) and methyl 6-formylpyridine-2-carboxylate (76.2 mg) in dichloromethane (1.5 mL) under ice-cooling, and this mixture was stirred at room temperature overnight. To the reaction mixture was added water, and then the resulting mixture was alkalified by the addition of sodium hydrogen carbonate. The organic layer was separated and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (152 mg). 1H-NMR (CDCl3) δ ppm: 1.39 (9H, s), 3.90 (3H, s), 4.05 (3H, s), 4.52 (2H, s), 6.91 (1H, s), 6.95-7.05 (1H, m), 7.28 (1H, s), 7.60 (1H, t, J=7.8 Hz), 7.80-8.20 (2H, m).