Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:3]=1[CH2:16][C:17]([OH:19])=O>O>[F:15][C:12]1[CH:11]=[CH:10][C:9]2[S:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[CH2:16][C:17](=[O:19])[C:14]=2[CH:13]=1
Reactant: O=C(O)Cc1c(Cl)cccc1Sc1ccc(F)cc1
Solvent: O
Product: O=C1Cc2c(Cl)cccc2Sc2ccc(F)cc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 585.5 %

Procedure:
To 0.1g of 2-chloro-6-(p-fluorophenylthio)phenyl-acetic acid was added 10g of polyphosphoric acid and the resulting mixture was stirred at 150° C for 2 hours. After cooling, to the mixture was added water and the mixture was extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and freed of solvent under reduced pressure. The residue obtained was recrystallized from benzene-n-hexane to afford 0.55g (58.8%) of 2-fluoro-9-chloro-10,11-dihydrodibenzo[b,f]thiepin-11-one as colorless crystals having a melting point of 135°-137° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.F[P-](F)(F)(F)(F)F.Cl.[CH:64]1[C:76]2[CH:75]([CH2:77][O:78][C:79](=[O:87])[NH:80][CH:81]3[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]3)[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:68]=2[CH:67]=[CH:66][CH:65]=1>C(OCC)(=O)C.CN(C)C=O>[CH:64]1[C:76]2[CH:75]([CH2:77][O:78][C:79](=[O:87])[NH:80][CH:81]3[CH2:82][CH2:83][N:84]([C:25](=[O:26])[C:24]4[CH:28]=[CH:29][C:21]([NH:20][C:18]5[N:17]=[CH:16][C:7]6[N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:12])([F:13])[CH2:11][N:5]([CH:1]7[CH2:4][CH2:3][CH2:2]7)[C:6]=6[N:19]=5)=[C:22]([O:30][CH3:31])[CH:23]=4)[CH2:85][CH2:86]3)[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:68]=2[CH:67]=[CH:66][CH:65]=1
Reactant: O=C(NC1CCNCC1)OCC1c2ccccc2-c2ccccc21
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
A mixture of 0.200 g (0.46 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1), 0.186 g (1.84 mmole) of triethylamine, 0.220 g (0.51 mmole) of N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-methanaminium, hexafluorophosphate(1-) (1:1) and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.182 g (0.51 mmole) of 4-piperidinyl-carbamic acid 9H-fluoren-9-ylmethyl ester monohydrochloride was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.210 g of {1-[4-(9-Cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoyl]-piperidin-4-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester.
Reaction SMILES: [F:1][C:2]([F:13])([CH3:12])[CH2:3][C@H:4]([N:9]=[C:10]=[O:11])[C:5]([O:7]C)=[O:6].C(=O)([O-])O.[Na+].[CH2:19]1[C:24]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][NH:21][CH2:20]1.[Li+].[OH-].Cl>C1COCC1.C(OCC)(=O)C>[CH2:19]1[C:24]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][N:21]([C:10]([NH:9][C@@H:4]([CH2:3][C:2]([F:13])([F:1])[CH3:12])[C:5]([OH:7])=[O:6])=[O:11])[CH2:20]1
Reactant: COC(=O)[C@H](CC(C)(F)F)N=C=O
Reactant: C1CCC2(CC1)CCNCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(F)(F)C[C@H](NC(=O)N1CCC2(CCCCC2)CC1)C(=O)O
Reaction time: 8 h

Procedure:
252 mg (1.3 mmol) of the isocyanate from example 7 were dissolved at 0° C. in 5 ml of THF and admixed with 109 mg (3.25 mmol, 2.5 eq.) of sodium hydrogencarbonate and 209 mg (1.37 mmol, 1.05 eq.) of 3-azaspiro[5.5]undecane. The mixture was stirred overnight, precipitated salts were removed and the reaction mixture was treated directly with 2.5 ml of 1 M LiOH solution (2.5 mmol, 1.9 eq.). The reaction was monitored by HPLC-MS. When the mass peak of the reactant had disappeared completely, the mixture was acidified cautiously with dilute HCl and the product was isolated by extraction with ethyl acetate, drying of the organic phase over sodium sulfate and concentration under reduced pressure. Yield: 440 mg (quantitative). The crude product was used directly in the amide coupling which follows.
Reaction SMILES: [O:1]1[CH2:6][CH:5](O)[CH2:4][O:3][CH2:2]1.[N+](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH:5]1[CH2:6][O:1][CH2:2][O:3][CH2:4]1)[CH3:15]
Reactant: OC1COCOC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CCCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CC1COCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
To a solution of 1,3-dioxan-5-ol (1.04 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.03 mmol). The reaction mixture is stirred at rt for 4 h. The reaction mixture is diluted with heptane and filtered. The filtrate is evaporated, and the residue is purified by chromatography on silica gel; elution with EtOAc:heptane (1:4) gives 0.65 g of the product 454. 1H NMR (CDCl3) δ 5.04 (s, 1 H), 4.89 (s, 1 H), 4.25-4.20 (m, 5 H), 3.98 (dd, 1 H), 3.78 (dd, 1 H), 3.65 (d, 1 H), 1.29 (t, 3 H).
Reaction SMILES: C([O:4][C@@H:5]1[C@:9]([CH2:18][CH:19]=[CH2:20])([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:7][C@H:6]1[N:30]1[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]1=[O:32])(=O)C.C[O-].[Na+].Cl>CO>[CH2:18]([C@@:9]1([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:7][C@@H:6]([N:30]2[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[C@@H:5]1[OH:4])[CH:19]=[CH2:20]
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O

Procedure:
To a stirred solution of nucleoside 1 (11.6 g, 22.3 mmol) in methanol (110 cm3) was added sodium methoxide (3.03 g, 55.5 mmol). The reaction mixture was stirred at room temperature for 16 h and neutralised with dilute hydrochloric acid. The solvent was partly evaporated and the residue was dissolved in dichloromethane (2×400 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogen-carbonate (3×250 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure to give 2 as a white solid material (10.1 g, 95%). δH (CDCl3) 8.77 (1 H, br s, NH), 7.58 (1 H, d, J 1.2, 6-H), 7.41-7.25 (10 H, m, Bn), 6.14 (1H, m, 2-H), 6.12 (1 H, d, J 7.8, 1′-H), 5.23 (1 H, m, 3″-Ha), 5.17 (1 H, br s, 3″-Hb), 4.68 (1 H, d, J 10.8, Bn), 4.59 (2 H, s, Bn), 4.55 (1 H, d, J 10.9, Bn), 4.39 (1 H, br s, 4′-H), 4.26 (1 H, dd J 7.8, 10.7, 2′-H), 3.84 (1 H, dd, J 3.1, 11.0, 5′-Ha), 3.58 (1 H, dd, J 1.4, 11.0, 5′-Hb), 3.04 (1 H, d, J 10.8, 2′-OH), 2.82-2.78 (2 H, m, 1″-Ha, 1″-Hb), 1.51 (3 H, d, J 1.0, CH3). δC (CDCl3) 163.5 (C-4), 151.1 (C-2), 137.3, 136.7 (Bn), 136.0 (C-6), 132.1 (C-2″), 128.8, 128.5, 128.3, 127.9, 127.6 (Bn), 118.4 (C-3″), 111.1 (C-5), 87.4, 82.6, 81.1, 79.3 (C-1′, C-2′, C-3′, C-4′), 73.7, 69.8 (Bn), 64.7 (C-5′), 35.1 (C-1″), 11.9 (CH3). (Found: C, 67.8; H, 6.1; N, 5.5. C27H30N2O5 requires C, 67.8; H, 6.3; N, 5.9%).
Reaction SMILES: Br.[NH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4].C1COCC1.C([O-])(O)=O.[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>O>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:3]([NH:2][C:23](=[O:24])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:4])=[CH:6][CH:7]=1
Reactant: CC(N)c1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.00 g (22.9 mmol) 4-(1-amino-ethyl)-phenol hydrobromide are added to 10 mL THF and 10 mL H2O before 13.5 g (160 mmol) NaHCO3 are added. Then 3.60 mL (25.2 mmol) benzyl chloroformate are added dropwise and the reaction mixture is stirred at r.t. for 3 h. Afterwards the reaction mixture is quenched by the addition of water and is set to a gentle acidic pH value using citric acid (10% in water). Then the product is extracted with EtOAc, the combined organic layers are dried over MgSO4, filtered and the solvent is removed in vacuo. The crude product is purified by flash chromatography (silica gel, PE/EtOAc).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH2:13]2)[C:3]=1[C:4]#[N:5].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>CC(N(C)C)=O>[S:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH2:13]2)[C:3]=1[C:4]#[N:5])(=[O:26])(=[O:25])[NH2:24]
Reactant: CCCC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Product: CCCC(=O)N1CCC[C@H](COc2cccc(NS(N)(=O)=O)c2C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of (S)-2-amino-6-((1-butyrylpiperidin-3-yl)methoxy)benzonitrile (Example 1b, 9.2 g, 30.53 mmol) in DMA (60 mL) was added sulfamoyl chloride (Example 1f, 10.54 g, 91.58 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature under nitrogen overnight then concentrated under reduced pressure, diluted with EtOAc, successively washed with NaHCO3, water and brine, dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound as colorless gel (9.5 g) in 82% yield. MS 381 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)C>CS(C)=O>[CH:27]1([C:26]2[N:15]3[CH2:14][C@@H:13]([CH2:12][O:11][C:10]4[CH:19]=[CH:20][C:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:8][CH:9]=4)[O:17][C:16]3=[N:18][C:24](=[O:23])[CH:25]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)C#CC1CCCCC1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Solvent: CS(C)=O
Product: O=c1cc(C2CCCCC2)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and cyclohexyl-propynoic acid ethyl ester (see Example 103) employing the procedure described in Example 100. [α]D25 +17.80 (c 0.5, DMSO)
Reaction SMILES: O.O.Cl.[NH2:4][C:5]([CH3:41])([CH3:40])[CH2:6][C:7]([NH:9][C@@H:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:11]1=[O:39])=[O:8].[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH:47]=O>>[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][NH:4][C:5]([CH3:41])([CH3:40])[CH2:6][C:7]([NH:9][C@@H:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:11]1=[O:39])=[O:8]
Reactant: CC(C)(N)CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Reactant: O=Cc1ncc[nH]1
Agent: Cl
Solvent: O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O)NCc1ncc[nH]1

Procedure:
The title compound was prepared from 3-amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]butanamide hydrochloride dihydrate and 2-imidazolecarboxaldehyde by the procedure described in Example 1. Final purification carried was out by reverse phase HPLC on C18, eluting with methanol/0.1% aqueous trifluoroacetic acid using a linear gradient of 65% methanol to 80% methanol over ten minutes; retention time approximately 5.5 min. 1H NMR (200 MHz, CD3OD): δ1.41 (s, 3H), 1.45 (s, 3H), 2.0-2.7 (m, 6H), 4.37 (dd; 8, 12 Hz; 1H), 4.51 (s, 2H), 4.83 (d, 15 Hz, 1H), 5.23 (d, 15 Hz, 1H), 6.98 (d, 8 Hz, 2H), 7.1-7.4 (m, 7H), 7.4- 7.7 (m, 5H). FAB-MS: calculated for C33H35N9O2 589; found 590 (M+H, 83%).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[C:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23]([C:41]([O:43]C)=[O:42])[CH2:24][C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:27]([CH3:40])[CH:26]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[C:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23]([C:41]([OH:43])=[O:42])[CH2:24][C:25]3[CH:26]=[C:27]([CH3:40])[C:28]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:29]([CH3:31])[CH:30]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(OCc2ccccc2)c(C)c1)OC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 38 mg (1.60 mmol) LiOH in 50 mL water was added to a solution of 600 mg (1.06 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2-dihydro-quinolin-3-yl)-piperidine-1-carboxylate in 30 mL THF and the reaction mixture was stirred for 1 h at RT. The organic solvent was eliminated i.vac., the aqueous residue was diluted with 50 mL water and acidified with 1 M HCL. The precipitate formed was filtered off, washed with 10 mL water and dried at 50° C.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]2[O:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:12][C:7]2=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[N:9]=[C:8]2[O:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:12][C:7]2=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccccc3)oc2n1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2nc(-c3ccccc3)oc2n1

Procedure:
A solution of 361 mg. of 5-nitro-2-phenyloxazolo[ 5,4-b]pyridine in 30 ml. of methanol was hydrogenated over 0.2 g. of 5% palladium-on-carbon catalyst. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. The residue was recrystallized from methanol to give 5-amino-2-phenyoxazolo[ 5,4-b]pyridine, m.p. 210° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.Cl.[CH3:22][NH:23][CH3:24].C(N(CC)CC)C>O1CCOCC1.O.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:23]([CH3:24])[CH3:22])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCN(c2cccc(Br)c2)CC1
Reactant: CNC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)C(=O)C1CCN(c2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
To a solution of 1-(3-bromophenyl)piperidine-4-carboxylic acid (2 g, 7.0 mmol) in dioxane (70 mL), was added thionyl chloride (2.6 mL, 35 mmol) at 0° C. The mixture was kept at rt for 1 h and evaporated. The residue was co-evaporated with dichloromethane and dissolved in dichloromethane (5 mL). To this mixture, were added the mixture of dimethylamine HCl salt (1.7 g, 21 mmol), triethylamine (4.9 mL, 35 mmol) and dichloromethane (20 mL) at 0° C. The mixture was stirred at rt for 1 h and diluted with water and separated. The organic phase was dried and evaporated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate 10:0 to 1:9) to give the titled compound (2.2 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Yield: 62.4 %

Procedure:
Ethyl 4-hydroxybenzoate (4.15 g, 25.0 mmol), tert-butyl 4-hydroxytetrahydro-1(2H)-pyridinecarboxylate (5.0 g, 25.0 mmol) and triphenyl phosphine (7.87 g, 30.0 mmol) were dissolved in tetrahydrofuran (50 mL), and with stirring at 0° C., diisopropyl azodicarboxylate (6.06 g, 30.0 mmol) was added thereto and stirred for 24 hours. The reaction solution was concentrated, and the precipitated white solid was taken out through filtration and washed with ethyl acetate. The mother liquid was washed with aqueous 1 N sodium hydroxide solution and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain the intended compound (5.45 g, 62%) as a colorless solid.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17](Cl)=[O:18]>[OH-].[Na+]>[O:18]=[C:17]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][CH2:16]1
Reactant: O=C(Cl)CCl
Reactant: O=C(O)[C@H](CO)NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 18.5 %

Procedure:
To a 0° C. solution of N-benzylserine (19.15 g, 105.7 mmol) in 2 N aq. NaOH (100 mL) was added chloroacetyl chloride (10.2 mL, 126.4 mmol) dropwise, and the solution was stirred for 45 min. To the solution was added 30% aq. NaOH (40 mL) dropwise, and the reaction was stirred for 1 h, and then stirred and warmed to room temperature for 72 h. The reaction was adjusted to pH 1 and extracted with three portions of EtOAc. The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was washed with EtOAc/hexane to give (3S)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (4.61 g, 19% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11]Br)=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>O.C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: BrCCc1coc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: NC1CCN(CCc2coc3ccccc23)CC1

Procedure:
10 mmol of 2-(benzofuran-3-yl)-1-bromoethane, 9.62 mmol of tert-butyl 4-piperidyl-carbamate, 2.65 g of potassium carbonate and 0.65 g of tetrabutylammonium sulphate are added to 10 ml of toluene. After refluxing for 12 hours, the mixture is taken up in water. The organic phase is then washed with water, dried and then filtered. Evaporation under reduced pressure allows the expected product to be isolated.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2cc(OC)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2oc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
The above prepared 5-methoxy-benzofuran-2-carboxylic acid ethyl ester (0.500 g, 2.27 mmol) was dissolved in 4.6 mL of THF/ethanol=1/1 and treated with 2.27 mL of aq. NaOH (3M, 3 eq.). The mixture was stirred for 2 h at ambient temperature and was then poured onto crashed ice/AcOEt/HCl dil.; the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave 0.428 g of the title acid as off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+].O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:24]1(/[CH:23]=[CH:22]/[C:2]2[CH:3]=[C:4]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=Cc1ccccc1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(OCc2cccc(/C=C/c3ccccc3)c2)cc1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
Methyl 4-[(3-bromophenyl)methoxy]benzenepropanoate (1.0 g, 2.9 mmol), styrene (0.45 g, 4.3 mmol), sodium hydrogencarbonate (0.60 g, 7.2 mmol), tetrabutylammonium chloride (1.6 g, 5.7 mmol) were dissolved in N,N-dimethylformamide (25 mL) and, after argon substitution, palladium acetate (19 mg, 0.086 mmol) was added. The reaction mixture was heated under an argon atmosphere at 100° C. for 18 hrs. The reaction mixture was cooled, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=15:1) to give the title compound (0.63 g, yield 59%) as a white powder.
Reaction SMILES: [CH:1]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6]O[C:3](=[O:4])[CH:2]=1.[NH3:11]>>[OH:4][C:3]1[CH:2]=[CH:1][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:11]=1
Reactant: O=C(O)c1ccc(=O)oc1
Reactant: N
Product: O=C(O)c1ccc(O)nc1

Procedure:
2-Hydroxypyridine or quinoline carboxylic acids and esters are useful as herbicide and pharmaceutical intermediates. One method for their preparation involves oxidizing quinolinic acid to obtain 2 3-bis(methoxycarbonyl)pyridine N-oxide, treating the N-oxide with acetic anhydride to give the 2-acetoxy compound, and hydrolyzing to give 6-hydroxy-2,3-dimethoxycarboxylpyridine in 27.5% overall yield; see E. Spinner et al., J. Chem. Soc. (B), 289 (1971). Another method involves reacting an ester of coumalic acid with ammonia to yield 2-hydroxy-5-pyridinecarboxylic acid; see W. T. Caldwell et al. J. Am. Chem. Soc. 66, 1479 (1944). Another method involves converting alpha-pyrone-6-carboxylic acid with ammonium acetate and glacial acetic acid into 2-pyridine-6-carboxylic acid; see J. Fried et al., J. Org. Chem. 6, 566 (1941).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:9]N1C(=O)CCC1=O>CN(C)C=O>[Br:9][C:6]1[O:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccco1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Br)o1

Procedure:
2-Acetylfuran is dissolved in N,N-dimethylformamide (5 g, 1.1 mol/L), and N-bromosuccinimide (1 eq.) is added.