Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:13][C:14]1[CH:23]=[C:22]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34](Cl)=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)[C:21]2[CH2:20][CH:19]=[CH:18][CH2:17][C:16]=2[N:15]=1>C(Cl)Cl.O>[CH3:13][C:14]1[CH:23]=[C:22]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([NH:1][C:2]4([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)[C:21]2[CH2:20][CH:19]=[CH:18][CH2:17][C:16]=2[N:15]=1
Reactant: COC(=O)CC1(N)CCOCC1
Reactant: Cc1cc(Cn2ccc3cc(C(=O)Cl)ccc32)c2c(n1)CC=CC2
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC1(NC(=O)c2ccc3c(ccn3Cc3cc(C)nc4c3CC=CC4)c2)CCOCC1
Yield: 17.2 %

Procedure:
The methyl (4-aminotetrahydro-2H-pyran-4-yl)acetate (0.13 g, 0.75 mmol) from example (355) was combined with the acid chloride (0.20 g, 0.49 mmol) from step (402b) in methylene chloride (15 ml) and water saturated sodium bicarbonate (15 ml). The reaction was stirred for 3.5 hs, partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a solid. This was purified by flash chromatography on silica gel eluting hexane: ethyl acetate (25:75, v:v) to give the methyl {4-[({1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indol-5-yl}carbonyl)amino]tetrahydro-2H-pyran-4-yl}acetate (0.04 g, 17%) as a solid, MS (M+H)+=472.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].[CH3:11][O:12][C:13](=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][C:15]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Br-]>CN(C=O)C>[CH3:11][O:12][C:13](=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:16][C:15]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCc1cccnc1
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COCc2cccnc2)cc1-c1ccccc1

Procedure:
To a solution in DMF of 3-pyridinemethanol (0.59 mL) was added sodium hydride (60% in mineral oil, 0.19 g), and the mixture was stirred until gas evolution ceased. A solution of 2-phenyl-4-bromomethylbenzoic acid methyl ester (0.98 g) in DMF was then added and the reaction mixture was stirred until the bromide was consumed. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried, and concentrated. The residue was purified by chromatography on silica gel (1:1 ethyl acetate-hexanes) to give [4-(3-pyridylmethyloxymethyl)-2-phenylbenzoic acid methyl ester (0.58 g).
Reaction SMILES: [CH3:1]N(C)C1C=C(C=CC=1)CC1C(=O)N(C2N=CC(S(N(CC)C3C=CC=CC=3)(=O)=O)=CC=2)NC=1C.[CH2:36]([O:43][CH2:44][C@H:45]1[CH2:49][CH2:48][C@@H:47]([NH:50][S:51]([C:54]2[CH:55]=[N:56][C:57]([Cl:60])=[CH:58][CH:59]=2)(=[O:53])=[O:52])[CH2:46]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CI>>[CH2:36]([O:43][CH2:44][C@H:45]1[CH2:49][CH2:48][C@@H:47]([N:50]([CH3:1])[S:51]([C:54]2[CH:55]=[N:56][C:57]([Cl:60])=[CH:58][CH:59]=2)(=[O:53])=[O:52])[CH2:46]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=S(=O)(N[C@@H]1CC[C@H](COCc2ccccc2)C1)c1ccc(Cl)nc1
Reactant: CCN(c1ccccc1)S(=O)(=O)c1ccc(-n2[nH]c(C)c(Cc3cccc(N(C)C)c3)c2=O)nc1
Solvent: CI
Product: CN([C@@H]1CC[C@H](COCc2ccccc2)C1)S(=O)(=O)c1ccc(Cl)nc1
Yield: 86 %

Procedure:
According to process 23.2, starting with 0.66 g of 4 N-{(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}-6-chloropyridine-3-sulfonamide and 0.22 mL of methyl iodide, 0.58 g of N-{(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}-6-chloro-N-methylpyridine-3-sulfonamide is obtained in the form of an oil.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.CN(C=O)C.CS(O[CH2:23][C:24]1([CH3:35])[O:28][C:27]2=[N:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][N:26]2[CH2:25]1)(=O)=O>O>[CH3:23][C:24]1([CH2:35][S:3][C:4]2[O:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[O:28][C:27]2=[N:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][N:26]2[CH2:25]1
Reactant: CC1(COS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Reactant: Sc1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(CSc2nc3ccccc3o2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
Sodium hydride (50 mg, 1.25 mmol) was added to a mixture of 2-mercaptobenzoxazole (200 mg, 1.3 mmol) and DMF (3 ml) followed by stirring at room temperature for 1 hour. To the reaction mixture, 2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl methanesulfonate prepared in Example 41 (330 mg, 1.2 mmol) was added, and the resulting mixture was stirred at 60-70° C. for 5 hours. The reaction mixture was allowed to return to room temperature. Water was added to the solution, and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with 5% sodium hydroxyde solution and water three times, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography(n-hexane/ethyl acetate=1/1) to afford 2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethylthio)benzoxazole (37 mg, yield 9%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:27].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3[OH:27])=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1C(Cl)=C(C2CCC(c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1C(O)=C(C2CCC(c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21

Procedure:
The product of stage (b) was suspended in 10 ml of boiling methanol and 0.55 g of potassium hydroxide in 5.5 ml of water was added dropwise over 15 mins. The mixture was refluxed until a dark red solution formed, (after ca. 6 hrs) when 2 ml of concentrated hydrochloric acid was cautiously added dropwise. The mixture was cooled and filtered, and the solid residue washed thoroughly with water. The water washings were re-acidified and filtered. The combined solid residues (500 mg) mp 200°-209°, were recrystallised from acetonitrile to give the title product as the trans-isomer (300 mg) m.p. 216°-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.[Br:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:29][CH2:28][CH2:27][Br:26])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1
Reactant: BrCCCBr
Reactant: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(OCCCBr)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12

Procedure:
A mixture of 3.2 g. (9.2 mmol.) of 5-chloro-3-(4-hydroxybenzoyl)-2-phenylbenzofuran, 3.5 ml. (0.035 mol.) of 1,3-dibromopropane and 4.0 g. (0.029 mol.) of potassium carbonate in 100 ml. of acetone is refluxed for three hours. After cooling, the reaction mixture is filtered and the filtrate is concentrated to give 5-chloro-3-[4-(3-bromopropoxy)benzoyl]-2-phenylbenzofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:8]([CH2:18][OH:19])=[CH:7]2>ClC1C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:8]([CH:18]=[O:19])=[CH:7]2
Reactant: OCc1cc2cccc(Cl)c2nc1-c1cccnc1
Agent: O=[Mn]=O
Solvent: Clc1ccccc1
Product: O=Cc1cc2cccc(Cl)c2nc1-c1cccnc1
Temperature: 70 °C
Yield: 86.3 %

Procedure:
A mixture of [8-chloro-2-(pyridin-3-yl)quinolin-3-yl]methanol (0.6 g, 2.2 mmol) and MnO2 (1.0 g) in chlorobenzene (30 mL) was heated at 70° C. overnight, filtered through a celite plug, concentrated in vacuo and washed with DCM to give the title compound (510 mg, 86%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([OH:18])=O)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:48][C:47]=1[CH3:58].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:16](=[O:18])[CH2:15][N:8]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:14]4[C:6]([C:2]4[NH:1][CH:5]=[CH:4][N:3]=4)=[N:7]3)[CH2:54][CH2:53]2)=[CH:48][C:47]=1[CH3:58]
Reactant: Cc1cc(N2CCNCC2)ccc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)ccc1Cl
Temperature: 45 °C
Reaction time: 8 h

Procedure:
This compound was prepared by Protocol A. A vial was charged with 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (55 Mg, 0.226 Mmol), HBTU (125 mg, 0.33 Mmol), 1-(4-Chloro-3-methyl-phenyl)-piperazine dihydrochloride (142 Mg, 0.50 mmol), anhydrous DMF (2.0 mL), and DIPEA (0.5 mL). The vial was capped, heated to 45° C., and stirred overnight. The following day, the volatiles were removed in vacuo and separation by preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-methyl-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone: MS (ES) [M+H]+ found: 436.4
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([C:23]([O:25]C)=[O:24])[CH2:10][C:9]2([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([C:23]([OH:25])=[O:24])[CH2:10][C:9]2([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@]1(c2ccc(Br)cc2)CC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)[C@@]1(c2ccc(Br)cc2)CC1(c1ccccc1)c1ccccc1
Yield: 69.6 %

Procedure:
To a round-bottom flask at room temperature was added (R)-methyl 1-(4-bromophenyl)-2,2-diphenylcyclopropanecarboxylate (17.9 mmol, 7.3 g, 1.0 equiv) in dry DMSO (35 mL). t-BuOK (39.6 mmol, 4.4 g, 2.2 equiv) was added in several portions over 30 minutes under argon. The reaction was monitored by TLC technique until the starting material was consumed completely. The reaction mixture was cooled with ice bath and acidified by saturated ammonium chloride aqueous (15 mL), followed by a slow addition of 1 N HCl (50 mL) with vigorous stirring until the pH value reached 3-4. Sticky solid precipitate was collected by filtration, washed with water (3×5 mL), dissolved in ethyl acetate (150 mL), washed with brine (3×10 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The crude material was purified using flash column chromatography eluting with a 4:1 mixture of hexanes/ethyl acetate to provide the desired product as a white solid (4.9 g, 69% yield). Recrystallization in pentane/ethyl acetate (50/1) provided the enantioenriched product as a white solid (4.46 g, 64% yield, 99% ee). (S)-1-(4-bromophenyl)-2,2-diphenylcyclopropanecarboxylic acid was prepared by the same procedure,
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9]([N:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1)([CH3:12])([CH3:11])[CH3:10].[OH-].[K+]>Cl>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:8][CH2:16][CH:15]([OH:17])[CH2:14][NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:2][CH:1]=1
Reactant: CC(C)(C)N1CC(O)C1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)NCC(O)COc1ccc(N)cc1
Temperature: 140 °C
Yield: 19.7 %

Procedure:
A mixture of 21.8 g of p-aminophenol, 22 g of 1-(tert.-butyl)-3-azetidinol and 0.73 g of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction mixture was cooled and dissolved in concentrated hydrochloric acid and the solution was extracted with ether. The hydrochloric acid aqueous solution was made alkaline with 10% -NaOH aqueous solution and then extracted with ether. The ether solution was washed with water and dried over anhydrous sodium sulfate. Then ether was distilled off and the residue was recrystallized from benzene. as a result, 8 g of 1-(p-aminophenoxy)-3-(tert.-butylamino)-2-propanol melting at 125°-127° C. were obtained. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis are as follows:
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8](O)(=O)[CH2:9][CH2:10][CH3:11]>>[CH2:9]([C:8]1[O:4][CH2:3][C:2]([CH3:7])([CH2:5][OH:6])[N:1]=1)[CH2:10][CH3:11]
Reactant: CCCC(=O)O
Reactant: CC(N)(CO)CO
Product: CCCC1=NC(C)(CO)CO1

Procedure:
The procedure described in Example 1 is repeated in all essential details with the exception that 2-amino-2-methyl-1,3-propanediol is reacted with butyric acid in a 1:1 molar ratio according to the method of Purcell to produce 2-propyl-4-methyl-4-hydroxymethyl-2-oxazoline.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:39]([CH:40]=O)=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:40][C:39]3[C:30]([Cl:29])=[N:31][C:32]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc2ccccc2nc1Cl
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cc5ccccc5nc4Cl)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-chloroquinoline-3-carboxaldehyde to the procedure of step 1, Example 66. MS (ESI) m/z 554.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[C:17]([CH3:28])[C:16]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]O)[CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:28][C:17]1[CH:18]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:20]=[C:15]([CH3:14])[C:16]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:30]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1cc(OC2CCCCO2)cc(C)c1-c1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OC4CCCCO4)cc3C)c2)cc1
Yield: 37.3 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (3.28 g, 18.2 mmol), [2′,6′-dimethyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methanol (5.15 g, 16.5 mmol) and triphenylphosphine (5.63 g, 21.5 mmol) in tetrahydrofuran (100 mL) was added dropwise diethyl azodicarboxylate (40% toluene solution, 9.7 mL) at 0° C. with stirring, and the mixture was stirred at room temperature for 48 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) to give the title compound (2.92 g, yield 37%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[O:23]1[CH2:28][CH2:27][O:26][C:25]2[CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=[CH:32][C:24]1=2>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:33]([C:30]2[CH:31]=[CH:32][C:24]3[O:23][CH2:28][CH2:27][O:26][C:25]=3[CH:29]=2)=[O:34])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc4c(c3)OCCO4)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 26b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as brown solid. MS 466 (MH+).
Reaction SMILES: C[C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].CI.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:3]1[CH:2]=[C:10]([CH3:11])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1c(C(=O)O)ccc(C)c1C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl 2-methoxy-4-methylbenzoic acid (1.5 g, 9.0 mmol, 1 eq) was dissolved in DMF, methyl iodide (0.86 ml, 13.5 mmol, 1.5 eq) was added to it followed by the addition of potassium carbonate (3.11 g, 22.5 mmol, 2.5 eq). The above mixture was stirred at room temperature for 12 h. Finally, the reaction mixture was passed through celite. The filtrate was evaporated and water was added and the product was extracted with ethyl acetate. The organic layer was washed with water and concentrated. Yield: 1.6 g (98%). 1HNMR (400 MHz, CDCl3): δ 2.31 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 6.77 (s, 1H), 6.79 (d, 1H), 7.14 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C=C[C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.ClC1[S:20]C(CCl)=CC=1>>[Cl:17][C:16]1[S:20][C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]2)=[CH:3][CH:2]=1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: ClCc1ccc(Cl)s1
Product: NCC1CN(Cc2ccc(Cl)s2)CCO1

Procedure:
Intermediate 13 was prepared in an analogous manner to Intermediate 1 (Alternative procedure) from Intermediate 19 and 2-chloro-5-(chloromethyl)thiophene, followed by a deprotection reaction yielding the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:41][N:42]([CH2:44][C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1)[CH3:43]>ClCCl>[CH3:43][N:42]([CH2:44][C:45]1[CH:46]=[CH:47][C:48]([NH:49][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:30])=[CH:50][CH:51]=1)[CH3:41]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a stirred solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (60 mg, 0.128 mmol) in dichloromethane (5.00 ml) were added N,N-DIISOPROPYLETHYLAMINE (100 mg) and 4-((dimethylamino)methyl)aniline (29.8 mg, 0.198 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (90.3 mg, 0.237 mmol, Chem-Impex) and the reaction mixture was stirred for 1 hr. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 4% to 50% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)-amide as white solid (54.1 mg, 70%). MS (ES+) m/z Calcd: [(M+H)+]: 599. found: 599.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:13][C:14](N)=[O:15]>>[Cl:12][C:9]1[C:10]([Cl:11])=[C:2]2[C:3]([C:4](=[O:5])[NH:13][C:14](=[O:15])[NH:1]2)=[CH:7][CH:8]=1
Reactant: Nc1c(C(=O)O)ccc(Cl)c1Cl
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)c2ccc(Cl)c(Cl)c2[nH]1

Procedure:
Prepared according to general method C from 2-amino-3,4-dichlorobenzoic acid (2.23 g) and urea (6.49 g). Yield 2.18 g (87%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 11.64 (br s, 1H), 10.87 (br s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:22](OC(C)(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>CN(C=O)C>[CH3:22][N:23]([CH:25]=[C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13][C:12]1=[O:16])[CH3:24]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)Nc2cc(-c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
6-Phenyloxindole (0.053 mg, 0.25 mmol) and dimethylformamide di-t-butylacetal (0.08 mL, 0.32 mmol) were combined and dissolved in DMF. The reaction mixture was stirred at room temperature for 4 hours. The volatiles were removed in vacuo and the resulting residue was triturated with diethyl ether. The solids were collected by filtration (50 mg, 75% yield). ). 1H NMR 400 MHz (DMSO-d6) mixture of E and Z isomers: δ 10.09 (s, 1H); 10.02 (s, 1H); 7.59–7.51 (m, 4H); 7.45–7.22 (m, 1OH); 7.10–7.05 (m, 2H); 6.98 (s, 1H); 6.91 (s, 1H); 3.29 (s, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12]C)[CH:3]=1.Br.N>O>[OH:12][C:4]1[CH:3]=[C:2]([Br:1])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: COc1cc(Br)cc2ncccc12
Agent: Br
Agent: N
Solvent: O
Product: Oc1cc(Br)cc2ncccc12
Temperature: 25 °C

Procedure:
1.5 g (0.0064 mol) of 7-bromo-5-methoxy-quinoline were refluxed with 48% HBr (30 ml) for 20h. After cooling to room temperature reaction mixture was poured into 100 ml of water and basified with saturated ammonia solution. Product was filtered off, washed with water and dried at 50° C. in vacuo. Yield of 7-bromo-5-hydroxy-quinoline was 600 mg (41%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]=[C:15]1[C:20]2([CH2:22][CH2:21]2)[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][CH2:16]1>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[C:20]3([CH2:22][CH2:21]3)[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:17][CH2:16]2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C2(CC2)C1
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C2(CC2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
In a flame-dried 100 mL three necked flask, a solution of 1-bromo-4-chlorobenzene (3.51 g, 18.36 mmol) in THF (20 mL) was cooled to −78° C. and treated with the dropwise addition of 1.6 M BuLi in hexanes (12.00 mL, 19.19 mmol) at a rate which did not allow the temperature to exceed −60° C. The mixture was stirred at −78° C. for 1 h, during which time a white precipitate was observed. The mixture was treated with the dropwise addition of a solution of tert-butyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylate (1.88 g, 8.35 mmol) in THF (5 mL), at a rate which did not allow the temperature to exceed −60° C. The mixture was stirred for 3 h, then allowed to warm to −20° C. and quenched with saturated ammonium chloride solution. The mixture was extracted 3× with ethyl acetate, the combined organic phases were washed with water followed by brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was purified over a 5×15 cm silica gel column, eluting with ethyl acetate/hexanes (5%-10%-15%-20% ethyl acetate, to yield the title compound (1.81 g, 5.36 mmol, 64.2% yield) as a colorless powder. MS (ESI+)=264.27, (M-tBuO)+, 220 (M−H2O-Boc)+.