Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[Cl:10][C:11]1[C:15]2=[N:16][C:17]3[C:23](=[O:24])[O:22][C:20](=[O:21])[C:18]=3[CH:19]=[C:14]2[S:13][CH:12]=1>C1COCC1>[C:3]([C:2]([NH:1][C:23]([C:17]1[N:16]=[C:15]2[C:11]([Cl:10])=[CH:12][S:13][C:14]2=[CH:19][C:18]=1[C:20]([OH:22])=[O:21])=[O:24])([CH3:9])[CH:6]([CH3:8])[CH3:7])(=[O:4])[NH2:5]
Reactant: O=C1OC(=O)c2nc3c(Cl)csc3cc21
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2c(Cl)csc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.6 %

Procedure:
2-Amino-2,3-dimethylbutyramide (0.71 g) all in one portion is added to a stirred solution of 3-chlorothieno[3,2-b]pyridine-5,6-dicarboxylic acid anhydride, (1.2 g) in THF (1.0 mL). After standing for five minutes, the ice bath is removed and the reaction stirred at room temperature for 28 hours. THF (5 mL) is added and the mixture heated at reflux for two hours and then set aside overnight. The cooled mixture is filtered and the collected solid washed with ether to give 1.4 g of the desired 5-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-3-chlorothieno[3,2-b]pyridine-6-carboxylic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C.FC(F)(F)S(O[CH2:44][CH:45]([F:47])[F:46])(=O)=O>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([CH2:44][CH:45]([F:47])[F:46])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1
Reactant: Cc1nc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(CC(F)F)C4)CC2)no1
Reaction time: 16 h

Procedure:
To a mixture of trans-8-chloro-1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.100 g, 0.237 mmol) and N-ethyldiisopropylamine (0.122 ml, 0.712 mmol) in dichloromethane (2.4 ml) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.061 g, 0.29 mmol). After stirring for 16 h the reaction mixture was partitioned between ethyl acetate (50 ml) and 0.5 M aqueous sodium hydroxide solution (50 ml). The layers were separated. The aqueous layer was extracted with one 50 ml-portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.031 g, 33%) as colorless solid. MS m/e: 449 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.C([O:14][C:15](=[O:17])[CH3:16])(=O)C.[C:18](O)(=[O:20])[CH3:19]>>[CH3:19][C:18]([CH2:16][C:15]([OH:14])=[O:17])=[O:20].[CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: C=C(C)[C@H]1CC=C(C)CC1
Product: CC(=O)CC(=O)O

Procedure:
This patent discloses a process in which the 1,2 epoxide of limonene is refluxed with acetic acid and acetic anhydride to yield the 1,2 diacetate of limonene and the excess of these esterification reagents is removed. The diester product of pyrolysed by heating at atmospheric pressure at an elevated temperature. The carvyl acetate is obtained by fractional distillation of the resulting mixture.
Reaction SMILES: CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([OH:30])=O.Cl.[CH3:32][NH:33][O:34][CH3:35]>CN(C)C=O.C(N(CC)CC)C>[CH3:35][O:34][N:33]([CH3:32])[C:28](=[O:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1
Reactant: CNOC
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccccn1
Reaction time: 0.25 h

Procedure:
EDCI (2.30 g, 0.012 mol) and 1-hydroxy benztriazole (1.36 g, 0.009 mol) were added o a stirred solution of pyridine-2-carboxylic acid (1.0 g, 0.008 mol) in N,N-dimethyl formamide (16 mL) at 0° C. The reaction mixture was allowed to stir for 15 min then triethyl amine was added followed by addition of N,O-dimethyl hydroxyl amine hydrochloride at 0° C. The resulting mixture was stirred at RT overnight. The reaction mixture was partitioned between water (30 mL) and ethyl acetate (2×30 mL). The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using 100-200 mesh silica gel and 0-20% EtOAc: Hexane as eluant to obtain product.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:16][C:17]1[N:18]([CH2:25][C@:26]2([CH3:29])[CH2:28][O:27]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1.CN(C=O)C>O>[Cl:16][C:17]1[N:18]([CH2:25][C@@:26]([CH3:29])([OH:27])[CH2:28][N:11]2[CH2:10][CH2:9][CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCC(c2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
4-Phenylpiperidine hydrochloride (0.522 g, 2.64 mmol) was added to a sodium hydroxide solution, and extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.5 g, 2.29 mmol) and DMF (5 ml) were added followed by stirring at 70° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl) -2-methyl-3-(4-phenylpiperidin-1-yl)propan-2-ol (0.703 g, yield 81%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:38]=[N+:39]=[N-])(=O)=O)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[N+:38](=[C:13]([C:5]1[CH:4]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1)[C:14]([O:16][CH3:17])=[O:15])=[N-:39]
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To methyl 3,5-bis(trifluoromethyl)phenylacetate (43.5 g, 160 mmol), in dry acetonitrile (250 ml), cooled to -5° C., was added 2,4,6-triisopropyl benzenesulfonyl azide (52.7 g). To the resulting solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (25.5 ml), and the mixture was stirred at -5° C. for 1 hour. The mixture was warmed to room temperature, and then stirred for 0.5 hour. The solvents were evaporated at reduced pressure and the residue purified by chromatography on silica gel (eluant 5% diethyl ether/petroleum ether), to afford the the title compound as yellow prisms. I.R (film, NaCl) 1740, 2140 cm-1.
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[CH:14]=[C:15]([OH:24])[N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].S(OC)(O[CH3:31])(=O)=O>C1COCC1.CN(C=O)C>[C:1]12([O:11][CH2:12][C:13]3[CH:14]=[C:15]([O:24][CH3:31])[N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COS(=O)(=O)OC
Reactant: Oc1cc(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(Adamantan-1-yloxymethyl)-2-cyclohexyl-2H-pyrazol-3-ol (0.29 g, 0.88 mmol) and sodium hydride (50 mg, 1.25 mmol of a 40% suspension in mineral oil) were stirred in THF-DMF (1:1) (10 mL) at 0° C. for 0.5 h, then allowed to warm to room temperature. Dimethyl sulphate (0.1 mL, 1 mmol) was added and the mixture stirred overnight. After concentration in vacuo, the mixture was poured into water (10 mL) and extracted with EtOAc (20 mL). The organic layer was separated washed with water (2×10 mL) and dried (MgSO4). Filtration and evaporation of the solvent afforded a yellow oil, which was purified by chromatography with EtOAc-hexane (1:1) as eluant. (0.24 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][CH:28]([F:37])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[F:36])[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][C:35]([F:36])=[C:29]([CH:28]([F:37])[F:27])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1ccc(F)c(C(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)F)c1
Yield: 18.6 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-27, 0.100 g, 0.268 mmol), 3-(difluoromethyl)-4-fluoroaniline (Intermediate-28, 0.065 g, 0.403 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.025 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.32 (s, 3H), 3.94 (s, 3H), 7.05-7.41 (m, 3H), 7.50 (s, 2H), 7.68-7.88 (m, 4H), 8.11 (m, 1H), 10.27 (s, 1H), 12.53 (s, 1H); MS (m/z): 503.10 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]([CH3:17])[C:10]1=[O:18].Cl[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:28])[F:29])=[CH:22][N:21]=2)=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]([CH3:17])[C:10]1=[O:18]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cn1c(=O)[nH]c(=O)n(-c2cc(O)ccc2Br)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ncc(C(F)(F)F)cc3Cl)ccc2Br)c1=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(2-bromo-5-hydroxyphenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (5.29 g, 0.0168 mol), 2,3-dichloro-5-trifluoromethylpyridine (5.44 g, 0.025 mol) and potassium carbonate (3.45 g, 0.025 mol) in N,N-dimethylformamide is stirred at 80° C. for 18 hours, cooled to room temperature and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. The solid is recrystallized from an ether/hexanes solution to give the title product as a yellow solid, mp 97°-110° C.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.N12CCCN=C1CCCCC2.[C:22]([O:26][C:27](=[O:49])[CH2:28][C@H:29]([C:39]1[O:40][CH2:41][C@@H:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:43]=1)[CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]>ClCCl.[Cu](Br)Br>[C:22]([O:26][C:27](=[O:49])[CH2:28][C@H:29]([C:39]1[O:40][CH:41]=[C:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:43]=1)[CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)[C@@H]1COC([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
A suspension of copper (II) bromide (2.08 g, 9.31 mmol) and hexamethylenetetramine (1.30 g, 9.31 mmol) in degassed dichloromethane (25 ml) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.39 ml, 9.31 mmol) and then cooled in a cold water bath and stirred for 5 minutes. This suspension was then treated dropwise with a solution of ethyl (4S)-2-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-4,5-dihydro-1,3-oxazole-4-carboxylate (Preparation 61) (0.92 g, 2.33 mmol) in dichloromethane (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and a solution of 0.88 ammonia:saturated aqueous solution of ammonium chloride (1:1, 100 mls). The layers were separated and the aqueous layer was extracted with ethyl acetate (×2). The organic layers were combined, washed sequentially with hydrochloric acid (2M), saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate:pentane (10:90) to afford the title compound as a pale yellow oil (0.59 g).
Reaction SMILES: [OH:1][CH:2]([CH2:36][C:37]1[CH:42]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:40]([OH:47])=[C:39]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:38]=1)[CH2:3][N:4]1[C:11](=[O:12])[C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:8](=[O:9])[N:7]([CH2:17][CH:18]([OH:35])[CH2:19][C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=2)[C:5]1=[O:6].[C:52](Cl)(=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69].Cl>>[C:52]([O:35][CH:18]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:32])([CH3:33])[CH3:34])[CH:21]=1)[CH2:17][N:7]1[C:8](=[O:9])[C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:11](=[O:12])[N:4]([CH2:3][CH:2]([O:1][C:52](=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:36][C:37]2[CH:42]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:40]([OH:47])=[C:39]([C:48]([CH3:49])([CH3:50])[CH3:51])[CH:38]=2)[C:5]1=[O:6])(=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCC1(CC)C(=O)N(CC(O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)N(CC(O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Agent: Cl
Product: CCCCCCCCCCCCCCCCCC(=O)OC(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CN1C(=O)N(CC(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC(=O)CCCCCCCCCCCCCCCCC)C(=O)C(CC)(CC)C1=O
Yield: 52.3 %

Procedure:
7.0 g (0.01 mol) of 1,3-bis-[2-hydroxy-3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propyl]-5,5-diethylbarbiturate and 6 g (0.02 mol) of stearic acid chloride in 50 ml of ligroin are brought to the reflux temperature and the resulting clear solution is kept at this temperature until the evolution of hydrochloric acid has ceased. After evaporating the solvent in vacuo, a syrupy residue is obtained which when chromatographed on a silica gel column gives 6.5 g (53% of theory) of 1,3-bis-[2-stearoyloxy-3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propyl]-5,5-diethylbarbiturate as an almost colourless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>>[Br:1][C:2]1[C:3]([C:12]([F:13])([F:15])[F:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[C:6]([CH3:11])=[CH:5]2
Reactant: Cc1cc2c(C(F)(F)F)c(Br)ccc2[nH]1
Reactant: BrCC1CC1
Product: Cc1cc2c(C(F)(F)F)c(Br)ccc2n1CC1CC1

Procedure:
Synthesized as described in Example 4 using 5-bromo-2-methyl-4-(trifluoromethyl)-1H-indole and (bromomethyl)cyclopropane: 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 6.49 (s, 1H), 3.99 (d, J=6.4 Hz, 2H), 2.46 (s, 3H), 1.14 (m, 1H), 0.56 (m, 2H), 0.32 (m, 2H); MS (ES) m/z 332 (M+1, isotope for Br) and 334 (M+1, isotope for Br).
Reaction SMILES: [CH2:1]([C@H:4]([C@H:11]([OH:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3].Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:18][C@@H:11]([C@@H:4]([CH2:1]/[CH:2]=[CH:3]/[C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=1)[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13]
Reactant: C=CC[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Product: CC(C)OC(=O)[C@@H](O)[C@@H](C/C=C/c1ccc(OC(F)(F)F)cc1)C(=O)OC(C)C
Temperature: 80 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
To a solution of diisopropyl (2R,3S)-2-allyl-3-hydroxybutanedioate (Intermediate 2a, 5.0 g; 19.4 mmol; 1.0 eq.), TEA (6.23 mL; 46.5 mmol; 2.4 eq.) in CH3CN (50.0 mL) was added 1-bromo-4-(trifluoromethoxy)benzene (5.13 g; 21.3 mmol; 1.1 eq.). To this solution was added a sonicated mixture of tri-o-tolylphosphine (0.59 g; 1.94 mmol; 0.10 eq.) and palladium(II) acetate (43.46 mg; 0.19 mmol; 0.01 eq.) in CH3CN (4 mL). The reaction was stirred at 80° C. for 14 h, cooled to RT and the solvents were evaporated (rotavap). The residue was taken up in EtOAc and washed with an aqueous saturated solution of NH4Cl, an aqueous saturated solution of NaHCO3 and then with an aqueous saturated solution of NaCl and dried over MgSO4. Evaporation of the solvent gave an oil. Purification by chromatography (SiO2, gradient from 10/90 EtOAc/c-hex to 100/0 EtOAc/c-hex in 30 min.) gave a colorless oil (6.98 g, 86.2%). M+(ESI): 419.2; M−(ESI): 417.0.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([OH:33])[N:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[N:30]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7.00 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 45 ml DMF were added 2.1 ml benzyl bromoacetate and 8.2 g cesium carbonate. After stirring at RT for 12 h the reaction mixture was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was not further purified. Yield: 7.02 g yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:13][NH:14][C:15](=[O:16])[C:11]=2[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[H-].[Na+].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[CH2:33]Cl.[I-].[Na+]>CN(C)C=O.C(O)(=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[CH2:33][N:14]1[C:15](=[O:16])[C:11]2[C:10]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:9]3[C:4]([CH:5]=[CH:6][CH:7]=[N:8]3)=[C:3]([O:2][CH3:1])[C:12]=2[CH2:13]1
Reactant: COc1ccc(COc2c3c(c(OC)c4cccnc24)CNC3=O)cc1
Reactant: ClCc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(COc2c3c(c(OC)c4cccnc24)CN(Cc2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 28 %

Procedure:
5-Methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 304 (17 mg, 0.049 mmol) was dissolved in dimethylformamide (0.3 ml) and cooled to 0° C. After adding sodium hydride (2.5 mg, 0.064 mmol), the reaction was stirred for 5 minutes at 0° C. 3,5-Dichlorobenzylchloride (11.5 mg, 0.059 mmol) and a catalytic amount of sodium iodide were then added. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. It was then cooled to 0° C., acidified with acetic acid (0.030 ml), and concentrated in vacuo. The resulting residue was diluted with ethyl acetate, washed twice with water, once with brine, and concentrated in vacuo. The residue was purified by silica gel chromatography (99/1-ethyl acetate/acetic acid) to afford 7-(3,5-dichloro-benzyl)-5-methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 307 (7 mg, 40%). 1H NMR (CDCl3) δ 9.0 (dd, 1H), 8.40 (dd, 1H), 7.60 (d, 2H), 7.55 (m, 1H), 7.20 (m, 3H), 6.80 (d, 2H), 5.60 (s, 2H), 4.75(s, 2H), 4.40 (s, 2H), 3.95 (s, 3H), 3.75 (s, 3H). MS: 509.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:14]([O-])=O.[Na+].C[Si](OP(=O)=O)(C)C.O>CCOC(C)=O>[F:24][C:13]([F:12])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:14]1[N:6]=[C:4]([OH:5])[C:3]2[C:2](=[CH:10][C:9]([CH3:11])=[CH:8][CH:7]=2)[N:1]=1
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Reactant: Cc1ccc(C(N)=O)c(N)c1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a mixture of 2-amino-4-methylbenzamide (804 mg, 5.36 mmol) and sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (1.25 g, 5.89 mmol) was added trimethylsilyl polyphosphate (ca. 10 mL) and the mixture was heated at 130° C. in a sand bath overnight. The mixture was allowed to cool to rt, and then water (75 mL) and EtOAc (75 mL) were added and the mixture was stirred at rt for 1 h. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-60% EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methylquinazolin-4-ol (1.09 g, 66%). LCMS (ESI) m/z 306 (M+H)+.