Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH:14]([OH:24])[CH:15]([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]2[CH:25]([CH2:26][O:27][CH3:28])[CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].ClCCl>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH:13]([CH:14]([OH:24])[CH:15]([NH:23][C:36](=[O:38])[CH3:37])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]2[CH:25]([CH2:26][O:27][CH3:28])[CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCC1C2CCC1N(C(=O)OC(C)(C)C)C2C(O)C(N)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1C2CCC1N(C(=O)OC(C)(C)C)C2C(O)C(Cc1ccccc1)NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 3-(2-amino-1-hydroxy-3-phenylpropyl)-7-methoxymethyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.243 mg, 0.622 mmol) in tetrahydrofuran (3 mL) and cool the mixture in an ice bath. Add triethylamine (0.091 mL, 0.653 mmol) and acetic anhydride (0.059 mL, 0.622 mmol) in tetrahydrofuran (2 mL). Stir the mixture at room temperature for 1 h. Add dichloromethane (30 mL) and water (10 mL). Separate layers and wash the organic layer with 0.5 N HCl, saturated aqueous sodium bicarbonate, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 3-5% isopropyl alcohol/47-45% dichlomethane in 50% hexanes) to give the title compound Isomer-1 (0.044 g, 16%) and Isomer-2 (0.077 mg, 29%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:51]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:53]=1)[CH2:12][N:13]([CH:48]1[CH2:50][CH2:49]1)[C:14]([C@@H:16]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][C:32]3[C:37]([Cl:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=3[Cl:40])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:17]1)=[O:15])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:48]1([N:13]([CH2:12][C:11]2[CH:51]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:53]=[C:9]([OH:8])[CH:10]=2)[C:14]([C@@H:16]2[C@@H:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][O:31][C:32]4[C:37]([Cl:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=4[Cl:40])=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:17]2)=[O:15])[CH2:50][CH2:49]1
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-{[[3-{[tert-butyl(dimethyl)silyl]oxy}-5-(3-methoxypropyl)benzyl](cyclopropyl)amino]carbonyl}-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in THF (0.1 M) was added a solution of 1 M tetrabutylammonium fluoride in THF (1.3 eq.). The reaction was stirred at it for 1 h and then concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 50% EtOAc in Hex) to afford the title compound as a foam.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:13][CH:12]=[CH:11][CH:10]=3.[H-].[Na+].CCCCCC.Cl[CH2:31][CH2:32][O:33][CH2:34][CH2:35]Cl>CN(C)C=O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:4]=[C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][N:6]2[C:2]=1[N:1]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: ClCCOCCCl
Reactant: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
A solution of 5.5 g of 3-amino-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 3) in 50 ml of dry N,N-dimethylformamide was added dropwise to a solution of 1.8 g of sodium hydride in oil (prewashed with hexane) in 150 ml of dry N,N-dimethylformamide over 30 minutes under dry argon atmosphere at room temperature. After the mixture was stirred for further 1 hour, 3.2 g of bis(2-chloroethyl)ether was added dropwise. The mixture was stirred at room temperature for 2 hours, and then at 60° C. for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 2.0 g of 2-(2-methylphenyl)-3-morpholinoimidazo[2,1-a]isoquinoline (Compound 218) as a yellow oily material. To a solution of 2.0 g of the product in 80 ml of ether was added a saturated solution of hydrogen chloride in ether. Precipitated crystalline was collected by filtration, and washed with ethanol to give 1.1 g of the title compound as a yellowish white powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].N(CCO)CCO>C1COCC1>[Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: O=C(CCCl)c1ccccc1
Solvent: OCCNCCO
Solvent: C1CCOC1
Product: O[C@@H](CCCl)c1ccccc1
Reaction time: 7 h

Procedure:
A solution of 3-chloropropiophenone (8.93 g, 50 mmol in 25 ml THF) was added to (-) diisopinocampheylchloroborane (Ipc2BCl, 18.0 g, 56 mmole, in 25 ml THF at -24° C.). The reaction was complete within 7 hours after which all volatiles were removed under reduced pressure. The residue was dissolved in ether, and diethanolamine (2 equivalents) was added. The resulting suspension was stirred for two hours and filtered. The solid residue was washed with ether and the combined washings and filtrate were concentrated. Distillation furnished [S]-(-)-1-chloro-3-phenyl-3-propanol. Yield: 6.1 g, 72%; mp 56°-57° C.; [α]D23 -25.25, c=7.05, CHCl3 ; 97% ee.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26](C)(C)[O:27][SiH2]C(C)(C)C)[CH:24]=4)[N:19]([CH3:35])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][OH:27])[CH:24]=4)[N:19]([CH3:35])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(C(C)(C)O[SiH2]C(C)(C)C)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
To a solution of 2-[5-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (106 mg, 0.17 mmol) in THF (2 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 1.7 mL, 1.7 mmol). The reaction mixture was stirred at room temperature for 10 min then heated at reflux for 2 h. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc and then with 5% MeOH/CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated. The residue was triturated with EtOAc/MeOH and the solids collected via filtration to afford 30 mg (47%) of 2-(5-hydroxymethyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow solid.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+]>O>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 40 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
6-O-(2-keto-L-gulonoyl)-L-ascorbate substantially free from 2-keto-L-gulonic acid, 1.2 g (3.4 mmol), was dissolved in 50 ml of water, to which a solution of 1.8 g (8.5 mmol) of sodium carbonate in 5 ml of water was added and stirred at 40° C. for about 2 hours. Quantitative analysis of the reaction mixture according to the method described in Reference Example 1 showed that 1.10 g (yield: 91.9%) of L-ascorbic acid was present with 0.05 g of 2-keto-L-gulonic acid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CCCCCCC>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Product: CCOC(=O)C(CCCCCCl)C(C)=O
Temperature: 90 °C
Yield: 113.9 %

Procedure:
A mixture of ethyl acetoacetate [VI-1] (218.6 g), n-heptane (200 g) and 1-bromo-5-chloropentane [V-1] (371.0 g, 2.0 mol) is heated to 90° C. Thereto is added anhydrous potassium carbonate (387 g, 2.8 mol), and the mixture is stirred with heating at 100° C. for 12 hours. The mixture is filtered with suction and the n-heptane layer is collected. The residue is washed with n-heptane (300 g), and the n-heptane layer is combined with the previous n-heptane layer, and concentrated under reduced pressure to give crude ethyl 7-chloro-2-(1-oxoethyl)heptanoate [II-1] (449.2 g), which contains 74.1 % of ethyl 7-chloro-2-(1-oxoethyl)-heptanoate and 22.1 % of 1-bromo-5-chloropentane.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])=[CH:17][C:16]=2[Cl:26])[C:6]=1[CH3:27].[OH-].[Na+]>CO.C1COCC1>[Cl:26][C:16]1[CH:17]=[C:18]([S:21]([CH2:24][CH3:25])(=[O:22])=[O:23])[CH:19]=[CH:20][C:15]=1[CH2:14][N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[C:6]1[CH3:27]
Reactant: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)O)c3cccnc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of [1-(2-chloro-4-ethanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: (3.32 g, 7.89 mmol) in methanol/THF (30 ml of a 1:1 mixture) is added 1M NaOH (15 ml). After stirring at room temperature overnight, the solvent is removed in vacuo and the residue is dissolved in water (20 ml). The solution is acidified to pH1 using 6M HCl and the resulting suspension is filtered and recrystallised from IPA/water to yield the titled product. (MH+ 407)
Reaction SMILES: CO.C[O-].[Na+].C(O)(=O)C.[CH:10]([NH2:12])=[NH:11].S(=O)(=O)(O)O.O.[F:19][CH:20]([CH3:29])[C:21](=O)[CH2:22][C:23](OCC)=[O:24]>CO>[F:19][CH:20]([C:21]1[N:12]=[CH:10][NH:11][C:23](=[O:24])[CH:22]=1)[CH3:29]
Reactant: N=CN
Reactant: CCOC(=O)CC(=O)C(C)F
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(F)c1cc(=O)[nH]cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
To a solution in which 24.3 g of ethyl 4-fluoro-3-oxopentanoate had been dissolved in 330 ml of methanol were added 72.3 g of a 28 % sodium methoxide methanol solution and 15.6 g of formarnidine acetate, and the mixture was stirred at 50° C. for 3 hours. To the mixture was further added 7.81 g of formamidine acetate and after stirring the mixture at 50° C. for 4 hours, the mixture was cooled to 10° C. or lower. After cooling, 18.8 g of conc. sulfuric acid and 13.5 g of water were added to the reaction mixture. After stirring the mixture at 50° C. for 15 minutes, insolubles were removed by filtration and the filtrate was quantitated by the liquid chromatography internal standard method. As a result, 18.0 g of 6-(1-fluoroethyl)-4-pyrimidone was formed (yield: 84.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][N:28]([C:35]([CH:32]4[CH2:34][CH2:33]4)=[O:36])[CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNC2)C[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3CC3)C2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 73, the title [(3S,4R)-4-(4-chloro-phenyl)-1-(1-cyclopropanecarbonyl-pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-1-(pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using cyclopropanecarbonyl chloride instead of propionyl chloride and was obtained as a colorless oil. MS m/e: 514.4 [M]+.
Reaction SMILES: C(OC([N:8]1[CH2:12]C[CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.NCCN1C[CH2:38][O:37][CH2:36][CH2:35]1>>[N:8]1([CH2:9][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:35][CH2:36][O:37][CH2:38][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 4-(2-aminoethyl)morpholine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 372 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (1H, br. s.) 10.03 (1H, s) 8.00 (2H, d, J=5.47 Hz) 7.77 (1H, d, J=5.37 Hz) 7.41 (1H, d, J=5.37 Hz) 7.29 (1H, dd, J=3.42, 2.44 Hz) 6.72 (1H, d, J=5.47 Hz) 6.44 (1H, dd, J=3.47, 1.90 Hz) 3.39-3.46 (4H, m) 3.33-3.39 (2H, m) 2.41 (2H, t, J=6.64 Hz) 2.33 (4H, br. s.)
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14].C(O)(=O)C>C1(C)C=CC=CC=1.C(OC(C)C)(C)C>[CH3:14][C:13]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([CH3:9])=[CH:11][CH:12]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NCc1ccccc1
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1Cc1ccccc1
Yield: 92.3 %

Procedure:
A mixture of benzylamine (10.7 g, 0.10 mol) and 2,5-hexanedione (11.4 g, 0.10 mol) and acetic acid (2.5 mL, 0.04 mol) in 50 mL toluene was heated at reflux under a Dean-Stark trap for 0.75hr. The resulting mixture was concentrated in vacuo to provide a viscous oil. The oil was dissolved in several volumes of isopropyl ether, then the solution was washed with 10% aqueous hydrochloric acid. The ether solution was dried and concentrated in vacuo to provide 2,5-dimethyl-1-benzylpyrrole (17.1 g, 92%) as a thick oil which eventually crystallized. The product was chromatographically homogenous and displayed an NMR spectrum consistent with its assigned structure. ##STR15## Preparation of Ethyl 2,5-Dimethyl-1-benzylindol-3-oyl-acetoacetate (I-3, a representative Friedel-Crafts acylation reaction):
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.Cl.[CH3:17][NH:18][O:19][CH3:20].O>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:7]
Reactant: CNOC
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
Cyclopentane carbonyl chloride (65 g, 0.49 mol) was added dropwise into a mixture of Et3N (180 mL, 1.3 mol) and N,O-dimethyl hydroxylamine hydrochloride (50 g, 0.52 mol) in anhydrous CH2Cl2 at 0° C. After the addition, the reaction mixture was allowed to stir at ambient temperature overnight. To the reaction mixture was added about 100 g of crushed ice followed 100 g of water. The mixture was separated, and the aqueous layer was extracted with CH2Cl2 (100 mL×2). The combined organic layers were washed with 1 N HCl, water, brine and dried over Na2SO4. The solvent was removed under reduced pressure to afford 61 g of desired product as oil in 78.8% of yield.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
t-Butyl piperazine-1-carboxylate (1.52 g, 8.17 mmol, 2.00 equiv), 1-bromo-4-(trifluoromethyl)benzene (1 g, 4.10 mmol, 1.00 equiv), BINAP (124 mg, 0.40 mmol, 0.10 equiv), Pd2(dba)3 (184 mg, 0.20 mmol, 0.05 equiv), NaOt-Bu (1.2 g, 12.50 mmol, 3.00 equiv), and toluene (15 mL) were combined in a 100-mL round-bottom flask, stirred overnight at 100° C. in an oil bath, and concentrated under vacuum. Purification by silica gel column with PE/EA (50:1) yielded 1.06 g (78%) of t-butyl 4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxylate as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:19]([CH2:22][CH2:23][CH2:24][CH3:25])(=[O:21])=[O:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>>[ClH:26].[CH2:22]([S:19]([C:16]1[S:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][CH:17]=1)(=[O:21])=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCS(=O)(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: Cl
Product: CCCCS(=O)(=O)c1cnc(N2CCNCC2)s1
Yield: 92 %

Procedure:
Prepared in analogy to example 4 (d) from 4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester and hydrogen chloride solution. The crude material was purified by recrystallisation from ether to afford the title compound as an off-white crystalline solid (yield 92%). MS (m/e): 290.0 (M+H+, 100%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:37])C(=O)C1.C(OOC(=O)CCCCCCCCCCC)(=O)CCCCCCCCCCC>C(Cl)(Cl)(Cl)Cl>[Br:37][CH:22]1[C:9]2[C:10](=[N:11][C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:21]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: CCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-Butyl 2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 1)(25 g, 64.5 mmol) in carbon tetrachloride (645 ml) at RT under N2 was added NBS (13.78 g, 77 mmol) followed directly by lauroyl peroxide (0.257 g, 0.645 mmol) and the solution was heated at 60° C. for 4 h 15 mins. The mixture was filtered through filter paper and the filtrate was washed with sat. NaHCO3 (300 ml), 2 M Na2SO3 (300 ml) and sat. brine (300 ml). The solution was dried over MgSO4 and filtered, washing MgSO4 bed with DCM (100 ml). The solvent was removed in vacuo. The crude product was dissolved in diethyl ether (300 ml) and was allowed to stand at RT and placed in a fridge overnight. The resulting crystalline solid was isolated by decanting off the mother liquors. The crystals were washed with diethyl ether to afford the title compound. Further product was obtained by chromatography of the mother liquors eluting with iso-hexane/EtOAc to afford the title product;
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH:9][C:10](=[O:12])[CH3:11])[CH3:8].O1CCCC1.CC[Al-]CC.[Na+]>C1(C)C=CC=CC=1>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH:9][CH:10]([OH:12])[CH3:11])[CH3:8]
Reactant: CC(=O)C=C(C)c1ccccc1-c1ccccc1
Agent: CC[Al-]CC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=CC(C)O)c1ccccc1-c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of 1.6 g. 2(p-biphenylyl)-2-penten-4-one in 25 ml. of dry tetrahydrofuran, at 0° C., 10 ml. of a solution of 25% (W/W) of sodium aluminum diethyl dihydride in toluene is dropwise added. After 20 minutes at 0° C., the mixture is poured onto ice and extracted with chloroform. Evaporation of the chloroform gives 2-(p-biphenylyl)-2-penten-4-ol, m.p. 137° - 138° C.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[O:32]=[C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30](=[O:31])[N:22]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccccc2C)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccccc1-c1csc(N2C(=O)c3ccccc3C2=O)c1C(=O)O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-(2-methylphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 10, Part D). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([OH:25])[CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[I-].[Na+].[CH3:30][NH:31][CH3:32]>O1CCCC1>[CH3:30][N:31]([CH3:32])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([OH:25])[CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27]
Reactant: CNC
Reactant: COc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2cc1OCCN(C)C
Temperature: 125 °C

Procedure:
A mixture of 1 g (2.38 mmol) of 7-(2-chloro-ethoxy)-4-(3-hydroxy-4-methyl-phenylamino)-6-methoxy-quinoline-3-carbonitrile and 0.078 g of sodium iodide in 19.5 ml of 2M dimethylamine in tetrahydrofuran was placed in a sealed tube and heated to 125° C. for 14 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate-methanol-triethylamine 70:30:2.5 giving 0.89 g of the title compound as a light yellow solid: mass spectrum (electrospray, m/e) M+H 393.0; (M+2H)+2 196.9.