Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CN(C)C)C=C2)C(O)=O)(C)(C)C.[C:32]([O:36][C@@H:37]([C:43]1[C:44]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)=[C:45]2[C:50](=[CH:51][C:52]=1[CH3:53])[N:49]=[C:48]([CH2:54][OH:55])[CH:47]=[CH:46]2)[C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C@@H:37]([C:43]1[C:44]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)=[C:45]2[C:50](=[CH:51][C:52]=1[CH3:53])[N:49]=[C:48]([C:54]([OH:5])=[O:55])[CH:47]=[CH:46]2)[C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH3:33])([CH3:34])[CH3:35]
Reactant: Cc1cc2nc(CN(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CO)ccc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C(=O)O)ccc2c1-c1ccc(Cl)cc1

Procedure:
(S)-6-(1-tert-Butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-7-methylquinoline-2-carboxylic acid was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)acetic acid of Example 9, except that (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(hydroxymethyl)-7-methylquinolin-6-yl)acetate was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)ethanol. LCMS-ESI+ (m/z): 456.2, 458.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1.O>ClCCl>[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:27][CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:10]3[N:9]([CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)[CH2:20][CH2:21]2)=[O:42])=[CH:39][CH:38]=1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)OCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a stirred mixture of 4.5 parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol, 2 parts of N,N-diethylethanamine and 195 parts of dichloromethane is added dropwise a solution of 1.7 parts of 4-methoxybenzoyl chloride in dichloromethane. Upon completion, stirring is continued overnight at room temperature. Water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanone. The salt is filtered off and dried, yielding 2.5 parts (43.5%) of [2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl] 4-methoxybenzoate; dihydrochloride. hemihydrate; mp. 189.2° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH2:14]1CCN2C(=NCCC2)CC1.CI.O>CN(C=O)C>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
To a solution of 4-bromo-2-nitrobenzoic acid (25.3 g, 103 mmol) in DMF (200 mL) at 0° C. were added DBU (79.1 mL, 514.8 mmol) and MeI (32.2 mL, 515 mmol). The reaction mixture was stirred for 15 min at this temperature and for 72 h at r.t. The mixture was poured into water and extracted with EtOAc (2×). The combined organic layers were washed with water (2×), dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, 7:3 hexanes:EtOAc) to provide the title compound (26.24 g, 98%) as a yellow oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:12]=[C:13]([NH2:20])[C:14](=[CH:18][CH:19]=1)[C:15]([OH:17])=[O:16]>C1(C)C=CC=CC=1>[F:10][C:11]1[CH:12]=[C:13]([NH:20][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:14](=[CH:18][CH:19]=1)[C:15]([OH:17])=[O:16]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)Nc1cc(F)ccc1C(=O)O
Reaction time: 2 h

Procedure:
A solution of phenyl isocyanate (2.98 g) in toluene (30 ml) was added dropwise to a stirred suspension of 4-fluoroanthranilic acid (3.88 g) in toluene (80 ml) at 50°. The mixture was stirred at 90° for 2 hours and the toluene evaporated under reduced pressure (30 ml). The residue was recrystallised from hexane/ethyl acetate to give 4-fluoro-N-phenylcarbamoylanthranilic acid, m.p. 163°-166°. (Compound 5).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:23]=3)[CH2:20][C:19](=[O:35])[NH:18][C:9]=2[CH:10]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-ethoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M163) (111 mg, 0.22 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (62 mg, 72%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:23][CH:24]=[CH2:25])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=O)C.O1C2C=CC=CC=2OCC1CN1CCCC(CO)(C)C1>>[CH2:23]([C:6]1([CH2:4][OH:3])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)[CH:24]=[CH2:25]
Reactant: C=CCC1(C(=O)OCC)CCCN(CC2COc3ccccc3O2)C1
Agent: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Product: C=CCC1(CO)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared from 3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylic acid ethyl ester using the procedure described for [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([N:18]2[CH2:22][C@@H:21]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH2:20][C@H:19]2[C:29]([NH:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)=[O:30])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[N-:42]=[C:43]=[O:44].[K+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([N:18]2[CH2:22][C@@H:21]([N:23]3[CH2:28][CH2:27][N:26]([C:43](=[O:44])[NH2:42])[CH2:25][CH2:24]3)[CH2:20][C@H:19]2[C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][CH:41]=2)=[O:30])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: [N-]=C=O
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCNCC3)CN2C(=O)[C@H]2CC[C@@H](CNC(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(C(N)=O)CC3)CN2C(=O)C2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.5 %

Procedure:
To a solution of the compound prepared in Example 50 (150 mg) in acetic acid (2 mL) and water (2 mL) was added potassium isocyanate (105 mg) and the mixture stirred at room temperature for 4 days. The reaction mixture was then treated with saturated aqueous sodium bicarbonate (10 mL) and extracted into dichloromethane (3×10 mL). The combined organic phases were washed with brine, dried and concentrated. Purification by flash chromatography (silica gel, 5-10% methanol/dichloromethane) gave methyl 4-[(2S,4S)-1-{[4-({[(tert-butoxy)carbonyl]amino}methyl)cyclohexyl]carbonyl}-4-(4-carbamoylpiperazin-1-yl)pyrrolidine-2-amido]benzoate (54 mg) as a colourless oil.
Reaction SMILES: O1CCCC1.C(O)C.CN(C)/[CH:11]=[CH:12]/[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[N+:23]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:20][O:19][C:17]([C:16]1[CH:15]=[C:14]2[C:13]([CH:12]=[CH:11][NH:23]2)=[CH:22][CH:21]=1)=[O:18]
Reactant: COC(=O)c1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a mixed solvent of tetrahydrofuran (30 ml), ethanol (30 ml) and water (100 ml), added are methyl E-4-(2-dimethylaminovinyl)-3-nitrobenzoate (10.0 g) and sodium hydrosulfite (104.5 g), and stirred at 70° C. for 1 hours. After this is cooled to room temperature, a saturated saline solution is added thereto. Then, this is extracted with chloroform. The organic layer is dried, and the solvent is evaporated away. The resulting residue is purified through silica gel column chromatography (eluent: hexane/ethyl acetate=2/1 to 1/1) to obtain 6-methoxycarbonylindole (2.79 g).
Reaction SMILES: [F:1][C:2]([F:19])([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C@H:4]([N:9]=[C:10]=[O:11])[C:5]([O:7][CH3:8])=[O:6].[CH2:20]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>ClCCl>[CH2:23]1[C:24]2([CH2:29][CH2:28][N:27]([C:10]([NH:9][C@@H:4]([CH2:3][C:2]([F:19])([F:1])[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:5]([O:7][CH3:8])=[O:6])=[O:11])[CH2:26][CH2:25]2)[CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)N=C=O
Reactant: C1CCC2(C1)CCNCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (S)-4,4-difluoro-2-isocyanato-5-phenylpentanoate (425 mg, 1.58 mmol) were dissolved in 25 ml of dichloromethane. 8-Azaspiro[4.5]decane (220 mg, 1.58 mmol, 1 eq.) and DIPEA (269 μl, 204 mg, 1.58 mmol, 1 eq.) were added to this solution which was stirred at RT overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). The product-containing fractions were combined and freed from the solvent under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[CH:24][C:25](I)=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)[C:30]#[CH:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[CH:24][C:25]([C:31]#[C:30][CH2:29][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2cc(I)ccc2NC(=O)C3)cc1OC
Reactant: C#CCN1CCCC1
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(C#CCN4CCCC4)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to Method O, 2-(3,4-dimethoxy-phenylamino)-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-26) and 1-(prop-2-ynyl)pyrrolidine were converted to I-31 (29%): HRMS Calcd. for C27H27N5O3: 470.2192, Found 470.2185.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:12]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>C(O)C>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[C:12]([O:20][CH3:21])=[CH:13][CH:14]=[CH:15][C:16]=1[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc([N+](=O)[O-])c1NC(=O)OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1cccc(N)c1NC(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of (2-methoxy-6-nitrophenyl) carbamic acid benzyl ester (17.5 g; 0.058 mol) and SnCl2·2H2O (65.3 g; 0.29 mol) in anhydrous ethanol, was heated at 70° C. for 2 hours. The solvent was then removed under vacuum and the residue was acidified with 10% aqueous HCl. The title compound was extracted with ethyl acetate and washed with diluted aqueous K2CO3. The precipitated solid was filtered off, the organic layer was dried over MgSO4 and evaporated under vacuum to give the title compound after crystallization with n-hexane. The compound was used without further purification. Yellow solid; 9.6 g.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[C:15]([O:19][C:20]([NH:22][C@H:23]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28](O)=[O:29])=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([C:49]2[N:50]=[N:51][S:52][CH:53]=2)=[C:45]([CH2:47][NH2:48])[CH:46]=1>CN(C=O)C>[C:15]([O:19][C:20]([NH:22][C@H:23]([CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([NH:48][CH2:47][C:45]1[CH:46]=[C:41]([Cl:40])[CH:42]=[CH:43][C:44]=1[C:49]1[N:50]=[N:51][S:52][CH:53]=1)=[O:29])=[O:25])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Reactant: NCc1cc(Cl)ccc1-c1csnn1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-c1csnn1)C1CCCCC1

Procedure:
EDC (0.388 g, 2.02 mmol), HOAt (0.275 g, 2.02 mmol), and 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-proline (prepared by standard peptide coupling protocols, 0.551 g, 1.55 mol) were added to a stirred solution of 1-[5-Chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]methanamine (0.351 g, 1.555 mmol) in DMF (7.8 mL). After 16 h the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by flash chromatography on silica (eluting with an EtOAc/hexanes gradient, 1–100% EtOAc). 1-{(2R)-2-[(tert-Butoxycarbonyl)amino]-2-cyclohexylethanoyl}-N-[5-chloro-2-(1,2,3-thiadiazol-4-yl)benzyl]-L-prolinamide was obtained as a solid. MS m/z=562.6.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]=1[C:15]1[C:16]2[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=2[N:18]=[CH:19][N:20]=1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:35][CH2:36][C@H:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:38][CH2:39]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A72) and commercially available trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=O)[CH3:2].Br[CH:14](C(OCC)=O)[C:15]([O:17]CC)=[O:16].[OH-].[K+]>C(O)C>[CH3:2][C:1]1[C:4]2[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[O:8][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CC(=O)c1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)oc(=O)c2ccccc12
Reaction time: 2 h

Procedure:
A mixture of 2-acetylbenzoic acid (6.21g), diethyl bromomalonate (9.0g.) and potassium hydroxide (2.12g.) in ethanol (50ml.) was heated under reflux for 6 hours. The cooled mixture was evaporated to dryness, water (100ml.) added and extracted with ether. The combined ethereal extracts were washed with water, dried and evaporated to dryness. The residue was heated under reflux with a mixture of concentrated hydrochloric acid (160ml.) -- acetic acid (100ml.) for two hours, cooled and poured into iced water (1 litre). Filtration gave the product as a white solid, mp. 250°-2°, (lit mp. 248°-9°) (Found: C, 64.59; H, 4.01. C11H8O4 requires C, 64.70; H, 3.95).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH3:14])=[CH:5][C:6](=[O:13])[NH:7]2.[N+](C1C=CC=CC=1)([O-])=O.[Al+3].[Cl-].[Cl-].[Cl-].[C:28](Cl)(=[O:33])/[C:29](=[CH:31]/[CH3:32])/[CH3:30].C(N(CC)CC)C>C(Cl)(Cl)Cl.CO.C(=S)=S>[OH:1][C:2]1[CH:11]=[C:10]2[O:12][CH:31]([CH3:32])[CH:29]([CH3:30])[C:28](=[O:33])[C:9]2=[C:8]2[C:3]=1[C:4]([CH3:14])=[CH:5][C:6](=[O:13])[NH:7]2
Reactant: Cc1cc(=O)[nH]c2cc(O)cc(O)c12
Reactant: C/C=C(\C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)[nH]c2c3c(cc(O)c12)OC(C)C(C)C3=O
Yield: 11.9 %

Procedure:
A mixture of compound 13 (11.2 g, 58.6 mmol), carbon disulfide (220 mL) and nitrobenzene (80 mL) in a RBF was treated with AlCl3 (38.93 g, 293 mmol) followed by tigloyl chloride (8.33 g, 70.3 mmol). After completion of reaction (TLC chloroform:methanol, 9:1, Rf=0.4) the reaction was worked up as described for preparation of compound 4 and further treatment with triethylamine (8.2 mL, 64.4 mmol) in chloroform (200 mL) as described for 4 gave a residue after work up. The residue on purification by column chromatography (silica gel, 60-120 mesh, chloroform : methanol, 19:1) furnished (±) 5-hydroxy4,8,9-trimethyl-1,8,9,10-tetrahydro-2H-pyrano[2,3-h]-quinoline-2,10-dione (15, 1.9 g) in 21% yield as a solid. M.P. 300° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.CCN(C(C)C)C(C)C.[NH2:34][CH2:35][CH:36]([CH3:39])[C:37]#[N:38].C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:38][CH2:37][CH:36]([CH3:39])[C:35]#[N:34])[N:8]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Reactant: CC(C#N)CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C#N)CNc1nccc(-c2c(Br)nc(C3CC3)n2COCC[Si](C)(C)C)n1
Temperature: 90 °C
Yield: 100 %

Procedure:
A solution of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (2.5 g, 5.8 mmol), DIEA (2.0 mL, 11.6 mmol), and 3-amino-2-methylpropanenitrile (1.49 g, 17.7 mmol) in NMP (10 mL) was treated with Na2CO3 (1.23 g, 11.6 mmol) and the resulting reaction mixture heated at 90° C. overnight. The reaction was allowed to cool to room temperature and was partitioned between EtOAc (75 mL) and water (100 mL). The layers were separated and the organic portion was washed with saturated aqueous NaHCO3 solution (100 mL), brine (150 mL), dried (Na2SO4) and concentrated to a brown residue. Purification by flash chromatography (0-50% EtOAc-heptane) afforded 3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)-2-methylpropanenitrile (2.79 g, 5.8 mmol) as a white solid: LCMS (m/z) 477.1 (MH+), tR=0.98 minute.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:13]2[O:12][CH2:11][CH2:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>[O-2].[Mn+4].[O-2]>[CH:2]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:1]
Reactant: CCOC(=O)C1=Cc2cccc(CO)c2OCC1
Agent: [Mn+4]
Agent: [O-2]
Product: CCOC(=O)C1=Cc2cccc(C=O)c2OCC1
Yield: 96.3 %

Procedure:
A mixture of ethyl 2,3-dihydro-9-hydroxymethyl-1-benzoxepin-4-carboxylate (0.45 g) and manganese (IV) oxide (4.5 g) was stirred under reflux for 1 hour and filtered off. The filtrate was evaporated in vacuo to give a solid of ethyl 2,3-dihydro-9-formyl-1-benzoxepin-4-carboxylate (0.43 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=2.[OH-].[Na+]>CO.O>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[C:10]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2
Reactant: COC[C@H]1CCCN1c1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (R)-methyl 3-(2-(methoxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (66 mg, 0.18 mmol, 1.00 equiv) in methanol (15 mL). A solution of sodium hydroxide (35 mg, 0.88 mmol, 5.00 equiv) in water (2 mL) was added. The resulting solution was stirred for 2 hrs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted in 20 mL of water. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 25 mg (39%) of (R)-3-(2-(methoxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O>NCCCN>[NH2:6][CH2:7][CH2:8][CH2:9][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Agent: NCCCN
Product: Cc1ccc(Cc2cnc(NCCCN)[nH]c2=O)cn1

Procedure:
1,3-Diaminopropane (60 ml) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (5.22 g) were heated together under reflux for 2.5 hr. Excess amine was stripped off and the residue recrystallised from ethanol to give 2-(3-aminopropylamino)-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone, (4.3 g; 79%) m.p. 162°-164° C.
Reaction SMILES: [CH3:1][C:2]1[O:17][C:7]2[CH:8]=[C:9]3[O:16][CH:15]=[CH:14][C:10]3=[C:11]([O:12][CH3:13])[C:6]=2[C:4](=[O:5])[CH:3]=1.[CH2:18](OCC)C.C[Al](C)C.[K].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2].O1CCCC1>[CH3:13][O:12][C:11]1[C:10]2[CH:14]=[CH:15][O:16][C:9]=2[CH:8]=[C:7]2[C:6]=1[C:4](=[O:5])[CH2:3][C:2]([CH3:18])([CH3:1])[O:17]2
Reactant: CCOCC
Reactant: COc1c2ccoc2cc2oc(C)cc(=O)c12
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c2c(cc3occc13)OC(C)(C)CC2=O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Under argon, 25 g of visnagin (108.6 mmol) are suspended in 500 ml of abs. diethyl ether and 50 ml of abs. tetrahydrofuran, 2.23 g (8.7 mmol) of nickel(II) acetylacetonate are added and the mixture is cooled to −20° C. At this temperature, 81.44 ml (162.9 mmol) of trimethylaluminum (2 M solution in hexane) are added slowly, and the mixture is then slowly warmed to 0° C. and stirring is continued. After one hour, 500 ml of saturated potassium/sodium tartrate solution are added (vigorous evolution of gas), and the mixture is then diluted with 500 ml of ethyl acetate. The organic phase is separated off and the aqueous phase is extracted once more with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The residue is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). This gives 23.28 g (86% of theory) of the title compound.