Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9]CC)([O:6][CH2:7][CH3:8])(OCC)[CH3:2].[CH3:12][C:13]1([CH3:24])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15](=[CH:21][CH2:22]O)[CH2:14]1.C(O)(=O)CC>>[CH3:19][C:17]1([CH3:20])[CH2:18][C:13]([CH3:24])([CH3:12])[CH2:14][C:15]([CH2:2][C:1]([O:6][CH2:7][CH3:8])=[O:9])([CH:21]=[CH2:22])[CH2:16]1
Reactant: CCOC(C)(OCC)OCC
Reactant: CC1(C)CC(=CCO)CC(C)(C)C1
Solvent: CCC(=O)O
Product: C=CC1(CC(=O)OCC)CC(C)(C)CC(C)(C)C1
Temperature: 145 °C
Yield: 72.4 %

Procedure:
A mixture of triethyl orthoacetate (18.6 ml, 102 mmol), 2-(3,3,5,5-tetramethyl-cyclohexylidene)ethanol (3) (4.63 g, 25.4 mmol) and propionic acid (0.19 ml, 2.5 mmol) was heated at 145° C. for 10 h. Ethanol was distilled off from the mixture in the course of reaction. The reaction mixture was cooled and poured into water (100 ml). The aqueous phase was extracted with hexane (250 ml) and the combined organic phases were washed with 5% aqueous KHSO4 (50 ml) and brine (50 ml). The extract was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether and light petroleum ether-ethyl acetate, 100:2) to give 16 (4.64 g, 73%) as an oil. 1H-NMR (CDCl3, TMS): 0.91 (6H, s, 3,5-CH3); 1.01 (6H, s, 3,5-CH3); 1.23 (3H, t, 7 Hz, ethyl CH3) 1.00-1.30 (4H, m, 4-CH2 and 2,6-CH); 1.86 (2H, d, 13 Hz, 2,6-CH); 2.22 (2H, s, CH2C═O); 4.08 (2H, q, 7 Hz, ethyl CH2); 5.06 and 5.07 (total 2H, both d, 11 and 17.5 Hz, ═CH2) and 5.95 ppm (1H, dd, 11 and 17.5 Hz, —CH═).
Reaction SMILES: [F:1][C:2]([F:20])([O:10][C:11]1[CH:19]=[CH:18][C:14]([CH:15](Br)[CH3:16])=[CH:13][CH:12]=1)[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6].[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28]([SH:33])[CH:27]=[N:26]1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28]([S:33][CH:15]([CH3:16])[C:14]2[CH:18]=[CH:19][C:11]([O:10][C:2]([F:20])([F:1])[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6])=[CH:12][CH:13]=2)[CH:27]=[N:26]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: CC(Br)c1ccc(OC(F)(F)C(F)OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(Sc1cnn(C(C)(C)C)c(=O)c1Cl)c1ccc(OC(F)(F)C(F)OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
1.4 g of 4-(1,1,2-trifluoro-2-trifluoromethoxy-ethoxy)-α-methyl-benzyl bromide (Example 2) and 1 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone are added to a suspension of 0.8 g of potassium carbonate in 10 cc of dimethylformamide. The resulting reaction mixture is stirred for 1 hour at room temperature, is diluted with ether, is washed with diluted HCl and brine; the washed solution is thoroughly dehydrated, the solvent is evaporated off and the so obtained raw reaction product is chromatographed on silica gel with 9/1 hexane/ethyl acetate. 0.58 g of pure product is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[NH:33][C:34]3[CH:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][C:35]=3[N:36]=2)[CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:26]4[CH2:27][CH2:28][CH:29]([C:32]5[NH:33][C:34]6[CH:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][C:35]=6[N:36]=5)[CH2:30][CH2:31]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: N#Cc1ccc2nc(C3CCNCC3)[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5nc6ccc(C#N)cc6[nH]5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 36 %

Procedure:
200 mg (0.64 mmol) 4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 200 mg (0.64 mmol) 2-piperidine-4-yl-3H-benzimidazole-5-carbonitrile hydrochloride salt were treated as described in example 2.0. Additional NaBH(OAc)3 has been added after 24 and 26 hours (two equivalents each). After five days stirring at room temperature the solvents have been evaporated and the residue was purified via chromatography. 121 mg of the desired compound were obtained.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:25]1([CH3:33])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][NH2:32]>>[C:25]1([CH3:33])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:32]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Reactant: Cc1ccccc1NN
Product: Cc1ccccc1-n1nccc1-c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-22) and o-tolylhydrazine according to the method described for example 1. MS: M=397.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)(Cl)Cl>[C:36]([NH:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1)(=[O:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc3c2CCCc2ccccc2-3)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(c(N3CCN(C(=O)OC(C)(C)C)CC3)n1)CCCc1ccccc1-2
Temperature: 60 °C

Procedure:
The product from Example 83A (20 mg, 0.051 mmol) was treated with CHCl3 (0.080 mL), pyridine (0.020 mL, 0.25 mmol), and acetic anhydride (0.006 mL, 0.061 mmol), then heated at 60° C. overnight, cooled and purified by chromatography (eluting with 9:1, 4:1 and 2:1 CH2Cl2:EtOAc) to provide the title compound. MS (M+H)+ m/z 438.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]=1[O:32][CH3:33])[CH:8]1[CH2:34][C:35]3[C:40]([CH:7]21)=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[NH:3])[NH2:2].[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([NH:48][C:29]([C:26]1[CH:27]=[CH:28][C:23]([C:15]2[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=2[CH:9]2[CH:8]3[CH2:34][C:35]4[C:40]([CH:7]3[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=3)[NH:10]2)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[C:24]([O:32][CH3:33])[CH:25]=1)=[O:30])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Reactant: NCc1ccccc1
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NCc3ccccc3)cc2OC)cc1O

Procedure:
Example 236 was prepared according to the protocol described for example 235 from 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-2,4′-dimethoxy-biphenyl-4-carboxylic acid (example 235 step a) and benzylamine. Mass Spectrum: 625 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: CCOC(=O)CCCN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
2,4-Dichloro-5,6-dimethyl-3-nitropyridine (135.0 g, 0.488 mol) and ethyl 4-aminobutyrate hydrochloride (114.0 g, 0.683 mol) were triturated in N,N-dimethylformamide (675 mL) (DMF) at 0° C. Triethylamine (272.6 mL, 1.95 mol) was added to generate a brown slurry. After 15 minutes, the reaction mixture was allowed to warm to ambient temperature and the reaction was stirred overnight. Analysis by 1H NMR indicated the reaction was incomplete. An additional amount of triethylamine (102.2 mL, 0.73 mol) and ethyl 4-aminobutyrate hydrochloride (35.28 g, 0.159 mol) in DMF (200 mL) were added to the reaction mixture and allowed to stir over an additional 24 hours. Half of the reaction mixture was added to separate flasks and deionized water (3 L) was added to each flask and were stirred for 1 hour. The resulting precipitate in each flask was harvested by filtration and dried under reduced pressure. The crude product was recrystallized from ethyl acetate and filtered to yield 86.20 g of ethyl 4-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butyrate as a yellow granular solid.
Reaction SMILES: [CH2:1]([NH:11][C:12]([C@@H:14]1[CH2:17][CH2:16][N:15]1C(OC(C)(C)C)=O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:11][C:12]([C@@H:14]1[CH2:17][CH2:16][NH:15]1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)[C@@H]1CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)[C@@H]1CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(tert-Butoxycarbonyl)-(S)-(−)-2-azetidinecarboxylic acid n-decyl amide (285) (160 mg; 0.470 mmol) is dissolved in methylene chloride (4 mL) at ambient temperature. Trifluoroacetic acid (2 mL) is added and the solution is stirred for 2 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (20 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3 times, 5 mL each). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (289) as a solid. ISMS: MH+ 241.2
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:19][C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C(OC(C)(C)C)=O)=[N:9][CH:10]=1)=[O:4].C(O)=O>C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:19][C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(N(Cc2cc([N+](=O)[O-])ccc2OCc2ccccc2)C(=O)OC(C)(C)C)nc1
Solvent: CCOCC
Solvent: O=CO
Product: COC(=O)c1ccc(NCc2cc([N+](=O)[O-])ccc2OCc2ccccc2)nc1

Procedure:
A mixture of methyl-2-[N-(2-benzyloxy-5-nitrobenzyl)-N-t-butoxycarbonylamino]pyridine-5-carboxylate (5.2 g) and formic acid (20 ml) was heated on a steam bath to give a clear solution. The mixture was evaporated to dryness and the residue obtained was dissolved in diethylether (100 ml) and washed with saturated sodium bicarbonate. The organic layer was dried and evaporated to give methyl-2-[N-(2-benzyloxy-5-nitrobenzyl)-amino]pyridine-5-carboxylate, yield 3.3 g. This same procedure was used to prepare ethyl-2-[N-(2-benzyloxy-5-bromobenzyl)-amino]thiophene-5-carboxylate.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:32][O:33][C:34](=[O:39])[C:35]([NH2:38])([CH3:37])[CH3:36].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>>[CH3:32][O:33][C:34](=[O:39])[C:35]([NH:38][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]3([OH:19])[CH2:15][CH2:16][CH2:17][CH2:18]3)=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:30])([CH3:37])[CH3:36]
Reactant: COC(=O)C(C)(C)N
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)O)c(C)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)NC(C)(C)C(=O)OC)c(C)c1
Yield: 82.1 %

Procedure:
4-{1-Ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (389 mg, 0.962 mmol), α-aminoisobutyric acid methyl ester hydrochloride (221 mg, 1.44 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (276 mg, 1.44 mmol), 1-hydroxybenzotriazole hydrate (195 mg, 1.44 mmol) and triethylamine (536 μL, 3.85 mmol) are stirred overnight. The reaction is concentrated and partitioned between EtOAc (150 ml) and 1N HCl (50 ml). The aqueous layer is extracted with EtOAc (100 ml). The combined organic layers are washed with, water (50 ml), NaHCO3 (50 ml), brine (50 ml), dried (anhydrous MgSO4), concentrated and chromatographed (12 g SiO2, 15% EtOAc/Hexanes) to yield the title compound (398 mg, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][C:4]=1[CH3:13].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:28]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[NH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([Li])CCC>O1CCCC1>[CH2:28]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[N:36]1[C:10](=[O:12])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:13])[CH:5]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(CC(=O)O)cc1C
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of (4-methoxy-3-methyl-phenyl)-acetic acid (5.04 g, 27.97 mmol) and triethylamine (3.9 mL, 27.97 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen at −78° C. was added trimethylacetyl chloride (3.44 mL, 27.97 mmol). The reaction mixture was stirred at −78° C. for 10 minutes, 0° C. for 1 hour, then re-cooled to −78° C. At the same time, to a separate flask charged with a solution of (R)-(+)-4-benzyl-2-oxazolidinone (4.96 g, 27.97 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen at −78° C. was added dropwise a solution of n-butyllithium (14 mL, 28 mmol, 2 M in hexanes). The second reaction mixture was stirred at −78° C. for 20 minutes, then transferred via cannula into the first reaction flask containing the mixed anhydride at −78° C. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to room temperature and stirred for 18 hours. The mixture was quenched with saturated aqueous ammonium chloride solution (200 mL), concentrated to about half of its original volume under reduced pressure to remove tetrahydrofuran. The remaining mixture was extracted with ethyl acetate (2×250 mL). The organic layers were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography over silica gel eluted with 1:1 ethyl acetate/hexanes to give (R)-4-benzyl-3-[2-(4-methoxy-3-methyl-phenyl)-acetyl]-oxazolidin-2-one as a pale yellow oil (8.5 g, 89%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
Into a stirred solution of 5.00 g (16.0 mmol) of tert-butyl 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine-1-carboxylate in 100 ml of 1,4-dioxane at 0° C. was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCl gas was continued for an additional 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3×80 mL of dichloromethane and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9:1, dichloromethane:methanol+1% isopropyl amine) to afford 2.85 g (87.5% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.09 (d, 1H, J=8.4 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.49 (t, 1H, J=8.0 Hz), 6.35-6.25 (m, 1H), 3.58 (apparent q, 2H, J=3.0 Hz), 3.14 (t, 2H, J=5.6 Hz), 2.54-2.46 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:42])[CH2:23][N:24]1[C:33](=[O:34])[C:32]2[N:31]([CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])[C:30](Cl)=[N:29][C:28]=2[N:27]([CH3:41])[C:25]1=[O:26].C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:42])[CH2:23][N:24]1[C:33](=[O:34])[C:32]2[N:31]([CH2:35][CH:36]=[C:37]([CH3:38])[CH3:39])[C:30]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]3)=[N:29][C:28]=2[N:27]([CH3:41])[C:25]1=[O:26]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1.30 g of 3-tert.-butyloxycarbonylamino-piperidine are added to a mixture of 2.51 g of 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine and 880 mg of sodium carbonate in 8 ml of dimethylsulphoxide. The reaction mixture is stirred for 18 hours at 60° C. For working up it is combined with water and the precipitate formed is suction filtered. The solid crude product is dissolved in ethyl acetate, the solution is dried over magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (10:1 to 1:1) as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([OH:22])[C:13]([NH:19][CH:20]=[O:21])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][CH2:34][CH2:35]Br>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[CH:15]=[CH:14][C:13]4[N:19]([CH:20]=[O:21])[CH2:35][CH2:34][CH2:33][O:22][C:12]=4[C:11]=3[O:10][C:9]=2[CH:23]([CH3:25])[CH3:24])=[CH:6][CH:7]=1
Reactant: CC(C)c1oc2c(O)c(NC=O)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)c1oc2c3c(ccc2c(=O)c1-c1ccc(Cl)cc1)N(C=O)CCCO3
Temperature: 60 °C

Procedure:
A stirred mixture of N-[3-(4-chlorophenyl)-8-hydroxy-2-isopropyl-4-oxo-4H-chromen-7-yl]formamide (0.122 g, 0.34 mmol), cesium carbonate (0.444 g, 1.36 mmol, 4 eq.) and 1,3-dibromopropane (0.069 g, 0.34 mmol) in anhydrous N,N-dimethylformamide (3 ml) is heated at 60° C. under a nitrogen atmosphere for 2 h. The mixture is cooled to room temperature and filtered through Celite filter aid. The pad of Celite is washed with ethyl acetate and methylene chloride, and the combined filtrates are evaporated in vacuo to afford a brown solid. This is purified by flash chromatography (cyclohexane/ethyl acetate=9:1 to 4:1) to furnish the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[C:4]([OH:13])[C:3]=1[F:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C)C=O>[C:26]([O:25][C:23](=[O:24])[CH2:22][O:13][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=[C:2]([Cl:1])[C:3]=1[F:14])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C1CCCc2c1cc(Cl)c(F)c2O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a stirred solution of 7-chloro-6-fluoro-5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.90 g, 4.18 mmol) in dry N,N-dimethylformamide (10 mL) was added potassium carbonate (1.16 g, 8.36 mmol) and tert-butyl bromoacetate (1.22 g, 6.27 mmol) at room temperature and the resulting mixture was stirred for 2 hours, then extracted with ethyl acetate (25 mL×3), washed with water (25 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford (3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (1.32 g, 96%), which was used in the next step without further purification. MS cald. for C16H18ClFO4 328, obsd. 329 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([O:17]CC)=[O:16])=[O:12])[C:4]=2[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To the product of Example 3 (5.1 g, 14.2 mmol) dissolved in 100 mL of methanol (MeOH) was added 25 mL (25.0 mmol) of 1N sodium hydroxide. (NaOH). This reaction was stirred at room temperature overnight before all solvent was removed under reduced pressure. The residue was dissolved in 250 mL of water and the solution was brought to pH 3 with 1N HCl. The product was extracted from the aqueous phase with 3×250 mL of Et2O. The Et2O layer was then dried (Na2SO4), filtered, and stripped of all solvent under reduced pressure to provide 4.7 g of the title compound after drying in a vacuum oven.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12](=[O:35])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2I)[C:21](=[O:27])[C:22]#[C:23][CH:24]([CH3:26])[CH3:25])[CH:14]=1>>[CH3:10][O:11][C:12](=[O:35])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)/[C:22](=[C:23](\[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)/[CH:24]([CH3:26])[CH3:25])/[C:21]2=[O:27])[CH:14]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)C)c2ccccc2I)c1
Reactant: OB(O)c1ccccc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccccc3)C(C)C)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from phenylboronic acid (commercially available) and 3-{[(2-iodo phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.04 (s, 1H), 7.94 (d, 1H), 7.48-7.53 (m, 3H), 7.39 (t, 1H), 7.15 (dd, 2H), 6.99 (t, 1H), 6.59-6.61 (d, 1H), 6.55 (t, 1H), 5.59 (d, 2H), 5.00-5.05 (m, 3H), 3.97 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([CH2:10][C:11]([OH:13])=[O:12])[CH:8]=[CH:9][C:3]=2[O:2]1.[CH3:14]C1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc2c(c1)OCO2

Procedure:
A solution of 3,4-(methylenedioxy)phenylacetic acid (28.0 g, 155 mmol), catalytic TsOH, and MeOH (125 mL) was stirred over 60 h. Saturated aqueous NaHCO3 was added and the product was extracted into CH2 Cl2. The organic solution was dried (MgSO4), filtered, and concentrated. Distillation (120 -1° C., 1 mmHg) provided the title compound as a clear and colorless oil (27.6 g). 1H NMR (250 MHz, CDCl3): δ6.74 (m, 3H), 5.94 (s, 2H), 3.69 (s, 3H), 3.54 (s, 2H).