Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]([O:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])=[O:13])[O:5][C@@H:4]([N:21]2[C:31]3[N:30]=[C:28]([NH2:29])[NH:27][C:25](=[O:26])[C:24]=3[N:23]=[CH:22]2)[CH2:3]1.[C:32]([NH:42][C@H:43]([C:47](O)=[O:48])[CH:44]([CH3:46])[CH3:45])([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]([O:14][CH:15]([CH2:16][OH:17])[CH2:18][O:19][C:47](=[O:48])[C@H:43]([CH:44]([CH3:45])[CH3:46])[NH:42][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[O:13])[O:5][C@@H:4]([N:21]2[C:31]3[N:30]=[C:28]([NH2:29])[NH:27][C:25](=[O:26])[C:24]=3[N:23]=[CH:22]2)[CH2:3]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](COC(=O)CCC(=O)OC(CO)CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(CO)OC(=O)CCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2′,3′-dideoxy-3′-fluoro-5′-O-[3-(1,3-dihydroxy-2-propyloxy carbonyl)-propanoyl]guanosine (1.3 g, 2.93 mmole), N-CBZ-L-valine (1.00 g, 4 mmole), HOBT (0.54 g, 4 mmole) and DMAP (48.8 mg, 0.4 mmole) was coevaporated two times with DMF and reduced to about 60 ml. DCC (0.91 g, 4.4 mmole) was added and the mixture was stirred for 72 hours at room temperature. The mixture was filtered and the solution evaporated under reduced pressure. Ethyl acetate (150 ml) was added and the organic phase washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 0.99 g
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13](=[O:24])[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[F:23])[N:9]1[C:25](=[O:39])[NH:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([C:36](=[O:38])[NH2:37])[CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40](O)([C:42](F)(F)F)=[O:41].C(OC([N:54]1[CH2:58][CH2:57][C@H:56]([C:59](=[O:70])[NH:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([Cl:68])[C:63]=2[F:69])[NH:55]1)=O)(C)(C)C>>[Cl:68][C:64]1[C:63]([F:69])=[C:62]([CH:67]=[CH:66][CH:65]=1)[CH2:61][NH:60][C:59]([C@@H:56]1[N:55]([C:40](=[O:41])[CH2:42][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([C:36]([NH2:37])=[O:38])[CH:28]=2)[NH:54][CH2:58][CH2:57]1)=[O:70].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13](=[O:24])[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[F:23])[N:9]1[C:25](=[O:39])[NH:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([C:36](=[O:38])[NH2:37])[CH:28]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)NCc2cccc(Cl)c2F)N1
Agent: CC(C)(C)OC(=O)N1CC[C@H](C(=O)NCc2cccc(Cl)c2F)N1C(=O)Nc1cn(C(N)=O)c2ccccc12
Product: NC(=O)n1cc(CC(=O)N2NCC[C@@H]2C(=O)NCc2cccc(Cl)c2F)c2ccccc21

Procedure:
The title compound was prepared from (R)-2-(1-carbamoyl-1H-indol-3-ylcarbamoyl)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-pyrazolidine-1-carboxylic acid tert-butyl ester according to the procedure described for the preparation of Example 432 using 10 equivalents of TFA for the Boc deprotection. MS: 459 [M+H]+; tR (HPLC conditions b): 3.73 min. (R)-2-(1-Carbamoyl-1H-indol-3-ylcarbamoyl)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-pyrazolidine-1-carboxylic acid tert-butyl ester was prepared as described in Scheme D5 step C using (R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-pyrazolidine-1-carboxylic acid tert-butyl ester (prepared as described in Scheme B5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].[C:13](Cl)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([O:8][CH3:13])=[O:7]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(=O)O)ccc1C
Solvent: CO
Product: COC(=O)c1ccc(C)c(OC)c1
Reaction time: 36 h
Yield: 98 %

Procedure:
A solution of 3-methoxy-4-methylbenzoic acid (6.0 g.) in methanol (120 ml.) was treated with acetyl chloride (6 ml.) and stirred for 36 hours. The solution was evaporated. The residue was dissolved in methanol (100 ml.) and the solution evaporated. This procedure was repeated to give methyl 3-methoxy-4-methylbenzoate (6.34 g., 98%) as a colorless oil; NMR: 2.2(s,3H, CH3), 3.9(2s,6H, 2×OCH3), 7.1(d,1H), 7.5 (m,2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1([C:36](Cl)=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:36]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)=[O:37])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Reactant: O=C(Cl)c1cccc2ccccc12
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)c1cccc2ccccc12
Yield: 42 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (120 mg) with 1-naphthoyl chloride (71 uL) provided 66 mg (42%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][CH3:20])[CH:14]=2)[C:3]=1[CH3:21].[OH2:22].C1C[O:26]CC1>[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:20])(=[O:26])=[O:22])[CH:14]=2)[C:3]=1[CH3:21]
Reactant: C1CCOC1
Reactant: CSc1cccc(-c2nc3cc(F)ccc3c(Cl)c2C)c1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Product: Cc1c(-c2cccc(S(C)(=O)=O)c2)nc2cc(F)ccc2c1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirring solution of 4-chloro-7-fluoro-3-methyl-2-(3-(methylthio)phenyl)-quinoline (130 mg, 0.41 mmol) (described herein) in THF (5.0 mL) and water (1.0 mL) were sequentially added 4-methylmorpholine n-oxide (144 mg, 1.2 mmol) and osmium tetroxide (1.1 μL, 0.020 mmol). The reaction was stirred at rt for 6 h, then an additional 0.05 eq. osmium tetroxide was added and the reaction stirred for 18 more h. The reaction was then quenched with 10% aqueous sodium thiosulfate solution, concentrated, and partitioned between EtOAc and 10% aqueous sodium thiosulfate solution. The organic layer was washed with brine, dried (MgSO4), and concentrated, affording 4-chloro-7-fluoro-3-methyl-2-(3-(methylsulfonyl)phenyl)quinoline. Mass Spectrum (ESI) m/e=350 (M+1).
Reaction SMILES: O=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].C(O)(=O)C>C1(C)C=CC=CC=1>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:13]=[C:14]([NH:15]/[C:2](/[CH3:9])=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C(\C)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
4.0 g (31 mmol) Ethyl 3-oxobutanoate, 5.0 g (31 mmol) 3-trifluoromethylaniline, and 1.86 g (31 mmol) acetic acid are dissolved in 50 ml toluene. The reaction mixture is refluxed overnight with a Dean-Stark trap to remove water. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethylacetate mixtures as eluent.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[S:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH3:24])[S:21][N:20]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C)sn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a solution of 157a (60 mg, 0.10 mmol) in THF/i-propanol/water (4 mL/4 mL/1 mL) was added lithium hydroxide (24 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 0.5 h and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was dried with Na2SO4 and concentrated to afford a yellow solid, which was purified by reverse-phase prep-HPLC to afford 157 as a yellow solid (27 mg, 50%). MS-ESI: [M+H]+ 546.7. 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.60-8.54 (m, 3H), 7.90 (s, 1H), 7.78 (d, J=16.0 Hz, 1H), 7.55-7.50 (m, 2H), 7.04 (s, 1H), 4.89 (t, J=6.5 Hz, 1H), 4.43-4.41 (m, 2H), 3.61 (s, 3H), 2.48 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][NH:7]1)=[O:5])[CH3:2].[C:16]([N:19]([CH2:21][C:22](O)=[O:23])[CH3:20])(=[O:18])[CH3:17]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][N:7]1[C:22](=[O:23])[CH2:21][N:19]([C:16](=[O:18])[CH3:17])[CH3:20])=[O:5])[CH3:2]
Reactant: CC(=O)N(C)CC(=O)O
Reactant: CCOC(=O)C1Cc2ccccc2CN1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: CCOC(=O)C1Cc2ccccc2CN1C(=O)CN(C)C(C)=O

Procedure:
This compound can be prepared by condensing 1,2,3,4-tetrahydroisoquinoline-3-carboxylic ethyl ester with N-acetylsarcosine according to the above-described methods; the corresponding acid can be prepared via catalytic hydrogenation of the product ester using Lindlar's catalyst or via base hydrolysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:45][CH2:46][CH2:47][N:48]4[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])[CH2:50][CH2:49]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 19 h
Yield: 85 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, and being stirred for 19 h to obtain the title compound (85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH2:12]=O.[ClH:14]>O>[ClH:14].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:12][NH:8][CH2:7][CH2:6]2
Reactant: COc1cccc(CCN)c1
Reactant: C=O
Agent: Cl
Solvent: O
Product: COc1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a stirred suspension of 3-methoxyphenethylamine (50.4 g, 0.33 mol. 1.0 eq) in water (40 mL) was added 37% aqueous formaldehyde solution (27.5 mL, 1.1 eq) and stirring continued for 20 min. Concentrated HCl (80 mL) was added and the mixture heated at reflux for 1 h. After cooling to room temperature the mixture was evaporated to dryness. The residue was recrystallised from acetone, affording the desired product as a white solid (60.1 g, 90%) which was used without further purification for the next step. MH+ 164.
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:20])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[CH:16][O:15][C:14]=1[CH3:19])=[CH:3]\[C:4](Cl)=[O:5].[O-:21]CC.[Na+:24]>CO>[CH3:1]/[C:2](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:20])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[CH:16][O:15][C:14]=1[CH3:19])=[CH:3]\[C:4]([O-:21])=[O:5].[Na+:24]
Reactant: CC(/C=C/c1c(C)coc1C)=C\C=C\C(C)=C\C(=O)Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CO
Product: CC(/C=C/c1c(C)coc1C)=C\C=C\C(C)=C\C(=O)[O-]

Procedure:
(E,E,E,E)-3,7-dimethyl-9-(2,4-dimethyl-3-furyl)-2,4,6,8-nonatetraenoic acid chloride (1.5 g.) was dissolved in a solution of methanol and sodium ethoxide (0.3 g.) and the resulting mixture was then concentrated to dryness to give sodium (E,E,E,E)-3,7-dimethyl-9-(2,4-dimethyl-3-furyl)-2,4,6,8-nonatetraenoate m.p.~280° with decomposition as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:17][O:16][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:11][C:2]3[N:3]2[CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:1]=3)=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1ccc2c(OC(C)C)cc(N)nc2c1
Product: CCOC(=O)c1cn2c(cc(OC(C)C)c3ccc(OC)cc32)n1

Procedure:
1.5 g of 2-amino-7-methoxy-4-isopropoxy-quinoline and 1.5 g of ethyl bromopyruvate were reacted by the method of Example 11 to obtain ethyl 8-methoxy-5-isopropoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 117°-118° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][CH2:12][CH2:13]O.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>C(Cl)Cl>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:13][CH2:12][Cl:11])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: OCCCl
Reactant: Oc1cccc2[nH]ccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50.1 %

Procedure:
To a solution of 4-hydroxyindole (4 g, 30 mmol), 2-chloroethanol (4.83 g, 60 mmol), triphenylphosphine (15.7 g, 60 mmol) in anhydrous tetrahydroufuran (40 ml) was slowly added diisopropyl azodicarboxylate (12.1 g, 60 mmol). The reaction was allowed to stir for 2.5 hours at room temperature, then poured into methylene chloride (250 ml), washed with water (3×100 ml) and dried over anhydrous sodium sulfate. This material was filtered and the solvent was removed under vacuum. Chromatography (20% hexanes-ethyl acetate) to remove triphenylphosphine, (20% methylene chloride-hexanes) afforded 2.94 g (50%) of product as a white solid: mp 69.5-72° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>Cl>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: Clc1ccnc2c(Cl)cccc12
Reactant: COC(=O)c1cc(F)ccc1N
Agent: Cl
Product: COC(=O)c1cc(F)ccc1Nc1ccnc2c(Cl)cccc12
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A mixture of 11.88 g of 4,8 dichloroquinoline, 10.4 g of methyl 2-amino-5-fluoro-benzoate and 60 ml of 2 N hydrochloric acid was refluxed for 21/2 hours and was then cooled to ≃0° C. and vacuum filtered. The moist residue was dissolved in 125 ml of lukewarm methanol and triethylamine was added to the resulting solution to make the pH alkaline. The mixture stood overnight at room temperature and was vacuum filtered and the recovered product was washed with water and dried to obtain 8.3 g of raw product which was crystallized from methanol to obtain 7.39 g of methyl 2-(8-chloro-4-quinolinylamino)-5-fluoro-benzoate melting at 196° C.
Reaction SMILES: [CH2:1]1[C@:7]([OH:10])([CH2:8][OH:9])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@@H:4]([OH:13])[C:2]1=O.[NH2:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17].Cl>CN(C=O)C.CO>[CH2:1]1[C@:7]([OH:10])([CH2:8][OH:9])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@@H:4]([OH:13])[C@H:2]1[NH:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17]
Reactant: O=C1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: NC(CO)CO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5 mmol of valiolone and 5 mmol of 2-amino-1,3-propanediol in 25 mL DMF or methanol is added a catalytic amount of HCl. After 1 hour at room temperature, 2.5 mmol of solid Na(CN)BH3 is added and the reaction mixture is stirred over night at room temperature. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in water and applied to a Dowex 50 (H+) column. The column is washed with water and the product is eluted with 0.5 N NH4OH. After concentrating the eluate, the residue is dissolved in water and applied successively first to a Amberlite CG-50 (NH4+) or Diaion WK-100 (NH4+) and then a Dowex 1 (OH-) column and each time the product is eluted with water to give voglibose.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH3:31][N:32]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25]
Reactant: CCCCCNC
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: CCCCCN(C)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and methyl-pentyl-amine. MS (ESI): 442.4 (MH+).
Reaction SMILES: BrBr.[C:3]([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([C:30]4[CH:29]=[C:28]([C:31](=[O:33])C)[CH:27]=[CH:26][C:25]=4[C:24]4[C:19]3=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:8]=2[CH:7]=1)(=[O:5])C.[OH-:34].[Na+].S([O-])(O)=[O:37].[Na+].Cl>O.O1CCOCC1>[CH:29]1[C:30]2[C:9]3([C:8]4[CH:7]=[C:6]([C:3]([OH:5])=[O:34])[CH:18]=[CH:17][C:16]=4[C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[CH:26]=[CH:27][C:28]=1[C:31]([OH:33])=[O:37]
Reactant: CC(=O)c1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(C(C)=O)cc21
Reactant: [OH-]
Reactant: O=S([O-])O
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., first 7.2 g of bromine and then a solution of 3.0 g of 2,2′-diacetyl-9,9′-spirobifluorene in a small amount of dioxane were added dropwise with stirring to a solution of 6.0 g of sodium hydroxide in 30 ml of water. After the mixture had been stirred for a further 1 hour at room temperature, 1 g of sodium hydrogensulfite, dissolved in 20 ml of water, was added to the clear yellow solution. Following acidification with conc. hydrochloric acid, the colorless product which had precipitated out was filtered off and washed with a small amount of water. Recrystallization from ethanol produced 9,9′-spirobifluorene-2,2′-dicarboxylic acid as water-clear prisms (m.p. 352° C.).
Reaction SMILES: I[C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:28][C:29]1(C)[C:33](C)(C)OB(C(C)=C)O1>CN(C=O)C.O>[CH3:33][C:29]([C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[CH2:28]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1C#N
Temperature: 110 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
To a solution of 2-iodo-4-[(5-nitro-2-pyridinyl)oxy]benzonitrile (Intermediate 129, 5.0 g) in DMF (50 mL) were added K3PO4 (5.77 g, 27.24 mmol), Pd(tBu3)2 (696 mg, 1.36 mmol) and 4,4,5,5-tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (3.84 mL, 20.43 mmol) and the reaction mixture was stirred for 4 hours at 110° C. After cooling the reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with ice cold brine (3×50 mL), dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 100 g) eluting from 100:0 to 80:20 cyclohexane/ethyl acetate to afford the title compound (1.8 g) as white solid.
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH3:2].[C:12]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:39])=[C:25]([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[NH2:37])[CH:26]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:39])=[C:25]([N:27]2[C:28](=[O:38])[C:29]3[C:30](=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[N:37]=[C:1]2[CH3:2])[CH:26]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3)ccc2Cl)c(N)c1
Product: COc1ccc2c(=O)n(-c3cc(NC(=O)c4ccccc4)ccc3Cl)c(C)nc2c1
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 1, triethyl orthoacetate was reacted with N-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide. The material so obtained was purified by column chromatography on an isolute SCX ion exchange column using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound in 27% yield; NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 3.91 (s, 3H), 7.09-7.14 (m, 2H), 7.46-7.6 (m, 3H), 7.71 (d, 1H), 7.87-8.06 (m, 5H), 10.57 (s, 1H); Mass Spectrum: M+H+ 420 and 422.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O-:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:8]([CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:10])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C(C)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(C)C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 10 %

Procedure:
Monoethyl methylmalonate (5.0 grams, 0.03 mole), 3,5-dichloroaniline (5.54 grams, 0.03 mole) and 1,3-dicyclohexylcarbodiimide (7.06 grams, 0.03 mole) were reacted in a manner similar to that described in Example LVII to give 1.0 gram (0.003 mole) of ethyl 2-(3,5-dichlorophenylaminocarbonyl)propanoate having a melting point of 89° C.-90° C. Elemental analysis of the product indicated the following: