Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([O:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)=[CH:7]2.[Cl:30]C1C(O)=CC=C2C=1C=CC([C@]1(C)COC(=O)N1)=C2>>[C:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([O:12][C:11]2[C:2]([Cl:30])=[C:3]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([C@:23]2([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]2)[CH:5]=[CH:4]3)[CH2:14][CH2:15]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@@]1(c2ccc3c(Cl)c(O)ccc3c2)COC(=O)N1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Br)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Cl)CC1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(5-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 213) in 57% yield using (R)-4-(5-chloro-6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one as the to starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=O)[CH2:7][CH2:6]2.Cl.[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.O>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8]1[NH:22][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:7]=1[CH2:6]2
Reactant: NNc1ccccc1
Reactant: COc1c(C)cc2c(c1C)CCC2=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1c(C)cc2c(c1C)Cc1c-2[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 5-methoxy-4,6-dimethyl-1-indanone (3.0 g, 16 mmol) and phenylhydrazine hydrochloride (2.3 g, 16 mmol) was heated to reflux in ethanol (20 cm3) containing concentrated hydrochloric acid (2 cm3). The reaction mixture was heated at reflux for 6 hours, and cooled to room temperature. Water was added, and the resulting precipitate filtered off. This product was dried in a vacuum oven, and purified by column chromatography to yield the title compound as a colourless solid. Yield: 2.8 g, (67%). M.p. 177° C. from ethyl acetate petrol (60°-80° C.). 1H NMR (CDCl3)δ: 2.36 (6H, s,), 3.56 (2H, s,), 3.76 (3H, s,), 7.1-7.6 (5H, m,), 8.2 (1H,br,).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[NH2:14][C:15]1[C:20]([CH2:21]O)=[CH:19][CH:18]=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]([CH2:21][O:10][C:9]2[C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[Br:1])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Nc1ncccc1CO
Reactant: CCOc1cc(C=O)cc(Br)c1O
Product: CCOc1cc(C=O)cc(Br)c1OCc1cccnc1N

Procedure:
Mitsunobu reaction of 3-bromo-5-ethoxy-4-hydroxy benzaldehyde (490 mg) with (2-amino-pyridin-3-yl)-methanol (250 mg) was preformed according to the method described for example 21d. The residue was chromatographed on silica gel in dichloromethane/methanol=99/1 (v/v) as eluent. Yield: 500 mg. MS-ESI: [M+H]+=351/353.
Reaction SMILES: C(O)(=O)C.N[C@@](C)([C@H](O)C)CO.[C:13]([O:16][CH2:17][C:18]([CH:24]([CH3:26])[CH3:25])([N+:21]([O-])=O)[CH2:19][OH:20])(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:17][C:18]([NH2:21])([CH:24]([CH3:25])[CH3:26])[CH2:19][OH:20])(=[O:15])[CH3:14]
Reactant: CC(=O)OCC(CO)(C(C)C)[N+](=O)[O-]
Agent: C[C@@H](O)[C@](C)(N)CO
Solvent: CC(=O)O
Product: CC(=O)OCC(N)(CO)C(C)C

Procedure:
Using the procedure in 5E, 2-isopropyl-2-nitro-1,3-propanediol acetate mp 155°-155.5°. H. S. Broadbent et al., J. Heterocyclic Chem., 13, 337 (1975) report the synthesis of this compound as the free base (mp 70°-72°)).
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH:25]=[C:26](Br)[Br:27])[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1.C(OP([O-])OCC)C.C(N(CC)CC)C>C(O)C.ClCCl>[O:31]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23](/[CH:25]=[CH:26]/[Br:27])[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:6][CH2:7]1
Reactant: O=C1O[C@@H](Cn2cc(C=C(Br)Br)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Agent: CCOP([O-])OCC
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1O[C@@H](Cn2cc(/C=C/Br)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (0.4 g, 0.69 mmol) was dissolved/supended in ethanol (2 ml) and diethylphosphite (0.36 ml, 2.79 mmol). Triethylamine (0.195 ml, 1.39 mmol) was added and the reaction mixture heated under vigorous stirring at 90° C. for 5 hours. It was cooled to room temperature, diluted with dichloromethane, washed with phosphate buffer (pH 7) and dried over sodium sulfate. Chromatography on silica gel with dichloromethane/DMF (50:1 to 40:1) gave 151 mg (44%) of the title compound as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[NH2:9].C(=O)([O-])[O-].[Na+].[Na+].[C:16](Cl)(Cl)=[S:17]>C(Cl)Cl>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:9]=[C:16]=[S:17])=[CH:4][N:5]=1
Reactant: Nc1cnc(Cl)cc1Cl
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: S=C=Nc1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring slurry of 4,6-dichloropyridin-3-amine (2.00 g, 12 mmol) and sodium carbonate (3.4 g, 32 mmol) in 10 mL DCM was added thiophosgene (1.2 mL, 16 mmol). The orange mixture was sealed and allowed to stir at ambient temperature overnight. The reaction mixture was filtered, rinsing with DCM, and the filtrate concentrated in vacuo to give 2,4-dichloro-5-isothiocyanatopyridine as an orange solid. MS (ESD m/z: calculated: 203.9; Observed: 204.9 (M++1).
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.C(NCCNCC1C=CC=CC=1)C1C=CC=CC=1.[N+:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]CCCCCCCCCC)([O-:29])=[O:28].C=O>C1(C)C=CC=CC=1.CO>[N+:27]([CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([O-:29])=[O:28]
Reactant: CCCCCCCCCCCCCCCCCC[N+](=O)[O-]
Agent: C=O
Agent: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=[N+]([O-])CCc1ccccc1
Yield: 222.9 %

Procedure:
In a 500 mL round-bottom flask N,N′-dibenzylethylenediamine diacetate (4.78 g, 13 mmol) and 1-nitrooctadecane (3, 3.97 g, 13 mmol) are dissolved in 1:1 toluene/methanol (100 mL). Paraformaldehyde (1.39 g, 46.5 mmol) is added portion wise to the solution and the resulting suspension is refluxed. The mixture becomes homogeneous (dissolution of paraformaldehyde) and after 3 h at reflux, the mixture is cooled and evaporated in vacuo. The residue is recrystallized from ethanol, obtaining pure 4 (4.38 g, 61%) as colorless solid. M.p. 70-72° C. (EtOH), ESI-MS: 586 (MNa+), 564 (MH+); (Calc. for C36H57N3O2: 563 u.m.a.).
Reaction SMILES: [NH2:1][CH:2]([P:4]([CH2:7][CH:8]([C:10]([OH:12])=[O:11])[CH3:9])(=[O:6])[OH:5])[CH3:3].Cl.[CH3:14]O>>[NH2:1][CH:2]([P:4]([CH2:7][CH:8]([C:10]([O:12][CH3:14])=[O:11])[CH3:9])(=[O:5])[OH:6])[CH3:3]
Reactant: CO
Reactant: CC(CP(=O)(O)C(C)N)C(=O)O
Agent: Cl
Product: COC(=O)C(C)CP(=O)(O)C(C)N

Procedure:
A solution of 100 mg of 1-aminoethyl-(2-carboxy-1-propyl)phosphinic acid in methanol (5 ml) was cooled to 0° C. and saturated with HCl gas. The sealed reaction mixture was then stirred 12 hours at room temperature whereupon the methanol was removed in vacuo to provide the title compound as a hydrochloride salt which was desalted via the procedure, in Example 2 using propylene oxide to provide the title compound. (80 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13][NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C=O.[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]3[CH2:22][N:14]([C:15]([O:16][CH2:17][CH3:18])=[O:19])[CH2:13][CH2:12][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)NCCc1coc2c(OC)cccc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: O
Product: CCOC(=O)N1CCc2c(oc3c(OC)cccc23)C1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of ethyl 2-(7-methoxy-1-benzofuran-3-yl)ethylcarbamate (from step 4) (0.649 g, 2.5 mmol), paraformaldehyde (0.150 g, 5.0 mmol) and 4-toluene sulphonic acid (0.0475 g, 0.125 mmol) was subjected to Dean-Stark for 2-3 hrs. After cooling to RT, water was added and organic layer was separated dried over anhy. sodium sulphate and concentrated. On purification on silica gel, it yielded ethyl 8-methoxy-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (96%).
Reaction SMILES: [OH:1][CH:2]([CH2:12]Cl)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10].[OH-].[Na+]>C(OCC)(=O)C>[O:1]1[CH2:12][CH:2]1[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1nccn1CC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1nccn1CC1CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Nitroimidazole (1 molar equivalent) in acetone was mixed with epichlorohydrin (1.1 molar equivalent) and potassium carbonate (0.001 molar equivalent). The mixture was refluxed overnight and taken to dryness in vacuo to give 1-(2-hydroxy-3-chloropropyl)-2-nitroimidazole. 1-(2-Hydroxy-3-chloropropyl)-2-nitroimidazole is taken up in ethyl acetate and mixed with an equal volume of 10% aqueous sodium hydroxide with vigorous stirring for 1 hour at room temperature. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and taken to dryness to give 1-(2,3-epoxypropyl)-2-nitroimidazole. 1-(2,3-epoxypropyl)-2-nitroimidazole (1 molar equivalent) dissolved in acetone was mixed with N′-1,1,1,3,3,3-hexafluoroisopropylpiperazine (1.1 molar equivalent) and the solution refluxed overnight. The reaction solution was taken to dryness in vacuo to give 1-(2-hydroxy-3-(N′-1,1,1,3,3,3-hexafluoroisopropylpiperazino)-2-nitroimidazole (XVI) that was recrystallized from ethanol. The chemical intermediate, N′-1,1,1,3,3,3-hexafluoroisopropylpiperazine, was prepared by heating 1,1,1,3,3,3-hexafluoroisopropyl bromide (1.0 molar equivalent) and piperazine (1.1 molar equivalent) at reflux in ethanol overnight. The chemical intermediate 1,1,1,3,3,3-hexafluoroisopropyl bromide was prepared by reacting commercially available 1,1,1,3,3,3-hexafluoroisopropyl alcohol (1 molar equivalent) with phosphorus tribromide (0.33 molar equivalent) in ethyl ether overnight at room temperature.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(-c3cccs3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(-c4cccs4)cc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester (1.3 g, 2.61 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction rnlxture was worked up as outlined in example 83. Yield 950 mg (77%); brown solid; mp 235° C.; MS: 471.8 (M+H)+
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:25][CH:26]1[CH:31]2[CH:27]1[CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30]2.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:25][CH:26]3[CH:31]4[CH:27]3[CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30]4)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC2C(N)C2C1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2NC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.250 g, 1.0 eq.) was dissolved in DCM (12 mL). tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.17 g, 1.2 eq.) was added and the reaction mixture was cooled to −60° C. T3P (0.51 mL, 1.2 eq.), followed by DIPEA (0.24 mL, 2.0 eq.) was then added at the same temperature. The reaction mixture was stirred for 30 min. and transferred into water (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford crude product, which was purified by chromatography (0-5% MeOH in DCM) to give (Z)-tert-butyl 6-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.28 g; 66.1% yield).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([O:28]S(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:36][C:37]([F:42])([F:41])[CH:38](O)[CH3:39]>>[C:1]([O:5][C:6]([C:8]1[C:9]([O:28][CH:38]([CH3:39])[C:37]([F:42])([F:41])[F:36])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:25])[CH3:26])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(O)C(F)(F)F
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)nc3ccc(Cl)cc23)c1
Product: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(OC(C)C(F)(F)F)nc3ccc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 79 step A from 6-chloro-4-(3-isopropyl-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 78 step C, 250 mg, 0.47 mmol) and 1,1,1-trifluoro-propan-2-ol (64.57 mg, 0.57 mmol). Off white solid (100 mg, 43%). LC-MS (ESI): 494 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[C:9]([CH:14]3[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]C)=[O:27])[CH:20]=4)[NH:15]3)[CH:10]=[CH:11][C:12]=2[F:13])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[C:9]([CH:14]3[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=4)[NH:15]3)[CH:10]=[CH:11][C:12]=2[F:13])=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C3CC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(NC(=O)C2CC2)c1
Yield: 71.4 %

Procedure:
A mixture of methyl 2-(3-(cyclopropanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (0.26 mmol, 1.0 eq) and 4.5 mL sodium hydroxide (1 mol/L) in 3 mL methanol was stirred at reflux for 1-2 h. LC-MS indicated that the starting material was consumed completely. The methanol was removed by reduced pressure. The residue was acidified pH to 5-6 with 1 M hydrochloric acid. A lot of precipitates were formed and collected by filtration to afford 71 mg of 2-(3-(cyclopropanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid; yield: 72%. MS (ESI+APCI) M+1=383.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.O>[N:11]([CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1)=[N+:12]=[N-:13]
Reactant: O=c1cc(CCl)occ1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cc(=O)c(O)co1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
To a stirred solution of 2-chloromethyl-5-hydroxy-pyran-4-one (2) (105.0 g, 656.2 mmol) in DMF (600 mL) was added NaN3 (55.45 g, 853.12 mmol) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. Then, the combined organic layer was washed with water and brine, and dried over Na2SO4 and concentrated under reduced pressure to get 2-azidomethyl-5-hydroxy-pyran-4-one (3) (70.0 g, 63.83%) as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:19](B1OC(C)(C)C(C)(C)O1)([CH3:21])=[CH2:20].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(NC(C)C)(C)C>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:21])=[CH2:20]
Reactant: COC(=O)c1cc(Br)cc(-c2ccc(C)cn2)c1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: C=C(C)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Temperature: 80 °C
Reaction time: 0.83 h
Yield: 98.8 %

Procedure:
To a solution of methyl 3-bromo-5-(5-methylpyridin-2-yl)benzoate (1.00 g, 3.27 mmol) in N,N-dimethylformamide (9.80 mL) and water (3.27 mL) was 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.921 mL, 4.90 mmol), palladium(II) acetate (37.0 mg, 0.163 mmol), 3,3′3″-phosphinidynetris(benzenesulfonic acid)trisodium salt (278 mg, 0.490 mmol) and diisopropylamine (1.16 mL, 8.17 mmol) and the mixture was heated to 80° C. After 50 min, the reaction was allowed to cool to ambient temperature and filtered. Purification by reverse phase chromatography (C-18, 90% water/acetonitrile→40% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (864 mg). MS 268.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([C@@H:7]([C:9]1[O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[CH3:14])[CH3:8])[C:3](=[O:6])[CH:4]=[CH2:5].Br[C:20]1[CH:33]=[N:32][C:23]2[NH:24][C:25](=[O:31])[C:26]([CH3:30])([CH3:29])[CH2:27][O:28][C:22]=2[CH:21]=1.CCN(C(C)C)C(C)C>C(C#N)C.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:29][C:26]1([CH3:30])[C:25](=[O:31])[NH:24][C:23]2[N:32]=[CH:33][C:20]([CH:5]=[CH:4][C:3]([N:2]([CH3:1])[C@@H:7]([C:9]3[O:10][C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[C:13]=3[CH3:14])[CH3:8])=[O:6])=[CH:21][C:22]=2[O:28][CH2:27]1
Reactant: C=CC(=O)N(C)[C@H](C)c1oc2ccccc2c1C
Reactant: CC1(C)COc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c([C@@H](C)N(C)C(=O)C=Cc2cnc3c(c2)OCC(C)(C)C(=O)N3)oc2ccccc12
Temperature: 25 °C
Yield: 25.6 %

Procedure:
A suspension of (R)—N-methyl-N-[1-(3-methyl-benzofuran-2-yl)-ethyl]acrylamide (328 mg, 1.35 mmol), 3-bromo-7,7-dimethyl-6,7-dihydro-9H-5-oxa-1,9-diaza-benzocyclohepten-8-one (400 mg, 1.48 mmol), (o-tol)3P (1.32 mg, 0.43 mmol) and DIEA (0.3 mL, 1.6 mmol) in EtCN (10 mL) and DMF (5 mL) was deoxygenated with argon for 30 min. Pd(OAc)2 (50 mg, 0.22 mmol) was added, the mixture was deoxygenated again with argon for 20 min and the mixture was heated to reflux overnight. The mixture was cooled to room temperature and partitinned between EtOAc and water. The residue was suspended in Et2O and then sonicated to give a solid. The solid was collected by filtration. Purification by column chromatography (silica gel, 1:1 hexanes/EtOAc) and sonication in Et2O gave the title compound (150 mg, 26%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ10.13 (s, 1H), 8.27 (s, 1H), 8.0.1-7.89 (m, 1H), 7.58-7.50 (m, 3H), 7.32-7.18 (m, 3H), 6.19-5.99 (m, 1H), 4.07 (s, 2H), 3.04-2.79 (m, 3H), 248 (s, 3H), 1.64-1.54 (m, 3H), 1.19 (s, 6H); MS (ESI) m/e 434 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH2:19][CH2:20][CH2:21][C:22]([O-:24])=O)[CH2:5][N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Li+].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:24]=[C:22]1[NH:1][C:2]2[C:3]3[CH:4]([CH2:5][N:6]([CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)CN1CC(CCCC(=O)[O-])c2c(N)cccc21
Agent: On1nnc2cccnc21
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN1CC2CCCC(=O)Nc3cccc1c32

Procedure:
A mixture of lithium 4-[4-amino-1-(2-tert-butoxy-2-oxoethyl)-2,3-dihydro-1H-indol-3-yl]butanoate from Step E (900 mg, 2.69 mmol), EDC (1.29 g, 6.73 mmol), HOAT (916 mg, 6.73 mmol), and N,N-diisopropylethylamine (0.94 mL, 5.38 mmol) was stirred in DMF (10 mL) at ambient temperature for 4 h, then concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (5 mL) and EtOAc (50 mL). The organic layer was washed with H2O (5 mL), then 10% aqueous citric acid (5 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—80:20 to 0:100, to give the racemic product. The enantiomers were resolved by HPLC, utilizing a Chiralpak AS column and eluting with CH3CN:MeOH—25:75. The first major peak to elute was tert-butyl (6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1 (2H)-yl)acetate, enantiomer A, the title compound, and the second major peak to elute was tert-butyl (6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)acetate, enantiomer B. MS: m/z=317 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH:15]=[C:14]2[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33].CN1CCOCC1.Cl>ClCCl>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[CH:15]=[C:14]3[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Cyclopentyl chloroformate (0.11 g.) was added to a stirred solution of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.25 g.) and N-methylmorpholine (0.23 g.) in dichloromethane (3 ml.), under an atmosphere of nitrogen. The mixture was stirred for 2 hours and then poured into 1M hydrochloric acid (20 ml.). This acid mixture was extracted with ethyl acetate (2×30 ml.). The combined extracts were washed with saturated brine (20 ml.), dried (MgSO4), and evaporated to give a viscous oil. This was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane, to give the title compound as a foam (0.25 g., 74%); NMR: 1.62[m,8H, (CH2)4 ], 3.68(s,3H, NCH3), 3.83(s,3H, CO.OCH3), 3.91(s,3H, OCH3), 3.95(s, 2H, CH2.Ar), 5.05(m,1H, --CHO--), 7.11(m,2 H), 7.26(d, 1H), 7.43(m,2H), 7.59(br,1H), 9.18 (br,1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:25])[CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(C=Cc1ccccc1)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylprop-2-enamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and cinnamoyl chloride in a similar manner as described above to give an off-white solid (35% yield).