Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:20])([C:13]#[C:14][C:15]2OC=[CH:18][CH:19]=2)[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:21])=[CH:4][CH:3]=1.[C:22](=[O:25])([O-])[O-].[Cs+].[Cs+].[I-].[Li+].[H-].[Na+]>>[Cl:21][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:8](=[O:20])[C@H:7]([CH3:6])[O:20][C@:8]([C:13]#[C:14][C:15]3[CH:19]=[CH:18][O:25][CH:22]=3)([C:9]([F:10])([F:11])[F:12])[C:7]=2[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(Cl)cc1C(O)(C#Cc1ccco1)C(F)(F)F
Agent: [Cs+]
Agent: [H-]
Agent: [I-]
Product: C[C@@H]1O[C@](C#Cc2ccoc2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O

Procedure:
The title compound was prepared in a manner similar to the product of Example 11 except that cesium carbonate/lithium iodide rather than sodium hydride was used in the final reaction step: mp 214-215°.
Reaction SMILES: COC1C=C2C(CCC(=O)C2(C)C)=CC=1.Br[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[OH:24].[OH:25][C:26]1[CH:27]=[CH:28][C:29]2[C:41](=[O:42])[C:40]3C4C(=CC(C#N)=CC=4)N[C:32]=3[C:31](C)(C)[C:30]=2[CH:47]=1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]2[C:40]3[C:41](=[O:42])[C:29]4[C:30]([CH2:31][C:32]=3[O:24][C:18]=2[CH:19]=1)=[CH:47][C:26]([OH:25])=[CH:27][CH:28]=4
Reactant: Oc1cc(Cl)ccc1Br
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Product: O=C1c2ccc(O)cc2Cc2oc3cc(Cl)ccc3c21

Procedure:
The compounds described in the following Table 43 were synthesized according to the method shown below. According to the method used for the preparation of Compound Z10, Z11 and Z12, 3-chloro-8-methoxy-6H-benzo[b]naphtho[2,3-d]furan-11-one was prepared from Compound A2 and 2-bromo-5-chlorophenol. Subsequently, demethylation was carried out according to the method that is used for the preparation of Compound A6, and thus 3-chloro-8-hydroxy-6H-benzo[b]naphtho[2,3-d]furan-11-one was obtained. Thereafter, according to Mitsunobu reaction that is used for the preparation of Compound A7-1 or the alkylation method that is used for the preparation of A7-17, a corresponding side chain was introduced and, if necessary, functional group modification such as deprotection, etc. was carried out to prepare the compounds listed below.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]([C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7].[C:18]([C:21]1[C:26]([NH2:27])=[C:25]([CH3:28])[C:24]([O:29][CH3:30])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:18]([C:21]1[C:26]([NH:27][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:6]([CH3:7])[CH3:8])[N:14]=2)=[O:17])=[C:25]([CH3:28])[C:24]([O:29][CH3:30])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: COc1ccc(C(C)=O)c(N)c1C
Reactant: CC(C)c1cccc(C(=O)O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(C)=O)c(NC(=O)c2cccc(C(C)C)n2)c1C
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 125.2 %

Procedure:
POCl3 (0.88 mL, 9.53 mmol) was added at −25° C. drop wise over 5 min under nitrogen, to a stirred solution of 6-isopropylpyridine-2-carboxylic acid (106, 1.43 g, 8.66 mmol) and 6-acetyl-3-metoxy-2-methylaniline (1.55 g, 8.66 mmol) in dry pyridine (70 mL). The resulting solution was stirred at −10° C. for 2.5 h. Then, the reaction mixture was poured on ice, neutralized with aqueous sodium bicarbonate and extracted 3 times with AcOEt. The organic layers were combined, washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography (hexanes/AcOEt, 3:1) to give 3.54 g (72%) of the title compound 107: m/z=327 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([O:7]C(CCCl)=O)=[CH:5][CH:4]=[C:3]([F:13])[CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-]>O>[F:13][C:3]1[CH:2]=[CH:1][C:6]([OH:7])=[C:5]2[C:4]=1[CH2:4][CH2:5][C:6]2=[O:7]
Reactant: O=C(CCCl)Oc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C1CCc2c(F)ccc(O)c21
Temperature: 120 °C

Procedure:
Compound I (219 g) is slowly added to anhydrous AlCl3 (720 g) under nitrogen and kept at room temperature while stirred. Stirring is discontinued when the mixture becomes too viscous. After heating to 120° C. for 1 h, stirring is re-started again and the temperature is further increased to 180° C. (2 hrs). After cooling and addition of excess water, the product is steam-distilled. Extraction with chloroform and evaporation gives 127 g of crude II.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:9]=1[CH3:24])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:13][N:12]1[C:8]([CH2:7][OH:6])=[C:9]([CH3:24])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][CH:15]=2)=[N:11]1
Reactant: Cc1c(-c2ccc(C(F)(F)F)cc2)nn(C)c1C(C)(C)O[SiH2]C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(F)(F)F)cc2)nn(C)c1CO

Procedure:
In analogy to the procedure described for example 2 e], 5-(tert-butyl-dimethyl-silanyloxymethyl)-1,4-dimethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole was treated with tetrabutylammonium fluoride in THF to yield [2,4-dimethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[OH:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:13][CH2:14][CH2:15][CH2:16][O:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([CH2:8][OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1
Reactant: COc1cc(O)c(Cl)cc1CO
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OCCCBr)c(Cl)cc1CO
Temperature: 75 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of 2-chloro-4-(hydroxymethyl)-5-methoxyphenol (intermediate 54; 0.5 g, 2.61 mmol), 1,3-dibromopropane (1.61 ml; 15.71 mmol) and potassium carbonate (737 mg; 5.23 mmol) in 12 ml acetone was heated to 75° C. in a sealed vessel and stirred for 16 hr. The solids were filtered and washed with acetone and the combined filtrates were concentrated to dryness and purified by preparative reversed-phase HPLC (hexane/EtOAc from 0 to 40%), affording the title compound (80%) as a light yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]([NH:11][CH3:12])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH2:42][C:43](OCC)=[O:44])[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[Cl:40])(=[O:32])=[O:31])=[C:25]([F:41])[CH:24]=3)[C:15]=12>>[OH:10][C@@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C@@H:2]([N:11]([CH3:12])[C:43](=[O:44])[CH2:42][N:20]1[C:16]2=[N:17][CH:18]=[N:19][C:14]([NH2:13])=[C:15]2[C:22]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=3[Cl:40])(=[O:32])=[O:31])=[C:25]([F:41])[CH:24]=2)=[N:21]1)[CH3:1]
Reactant: CCOC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Reactant: CN[C@H](C)[C@H](O)c1ccccc1
Product: C[C@@H]([C@@H](O)c1ccccc1)N(C)C(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Yield: 15 %

Procedure:
Using a procedure similar to that above, (+)-ephedrine hydrochloride (0.061 g, 0.302 mmol) and ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.054 g, 0.10 mmol) were combined. Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 11.4-11.9 min) afforded N1-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N1-methyl-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetamide as an off-white solid (0.010 g, 0.015 mmol): RP-HPLC (25 to 100% CH3CN in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt 9.36 min; MS: (M−H)− 656.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].O.[OH-].[Li+].Cl.[Cl-].[Na+]>O1CCCC1.O>[C:9]([O:8][C:6]([NH:5][C@@H:4]([C:3]([OH:18])=[O:2])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
N-tert-Butoxycarbonyl-3-tert-butyl-D-alanine methyl ester (Example 5A, 60 g, 231 mmol) is dissolved in tetrahydrofuran p.a. (463 ml). At RT, a solution of lithium hydroxide monohydrate (19.4 g, 462.7 mmol) in water (463 ml) is slowly added dropwise. When the HPLC chromatogram (Method 2) shows complete conversion (about 20 h), the reaction mixture is cautiously adjusted to pH 3-4 with 1 N aqueous hydrochloric acid with ice cooling. Sodium chloride (150 g) is added to the reaction mixture in order subsequently to extract it with ethyl acetate (2×500 ml). The combined organic phases are dried with a saturated sodium chloride solution and then with sodium sulfate and filtered. The filtrate is concentrated on a rotary evaporator and dried under high vacuum. 55.4 g (98% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]4[C:15](=[O:25])[N:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:18][S:19][CH2:20][CH:13]4[C:12]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[C:9]3[C:10]=2[CH:11]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([N:16]1[C:15](=[O:25])[CH:14]2[CH:13]([C:12]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:9]3[C:10]4[CH:11]=[C:2]([C:35]5[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=5)[C:3]([O:31][CH3:32])=[CH:4][C:5]=4[CH2:6][CH2:7][N:8]32)[CH2:20][S:19][CH2:18][CH2:17]1)([CH3:23])([CH3:22])[CH3:24]
Reactant: COc1cc2c(cc1Br)C1=C(c3cccs3)C3CSCCN(C(C)(C)C)C(=O)C3N1CC2
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(cc1-c1cccnc1)C1=C(c3cccs3)C3CSCCN(C(C)(C)C)C(=O)C3N1CC2

Procedure:
A mixture containing 20 mg of 9j, 6 mg of pyridine-3-boronic acid and 10 mg of K2CO3 and 6 mg of Pd(PPh3)4 in 2 ml of degassed 90% aq. dimethoxyethane was heated under N2 for 16 h. The reaction mixture was cooled and diluted with water. The product was extracted with ethyl acetate. The extract was dried, concentrated and the residue was purified by chromatography over silica gel, using heptane/acetone as eluent. The isolated product was treated with ether/ethyl acetate (9/1 v/v) to give 14 mg of white crystalline 9k; Rf 0.50 (heptane/acetone 1/1);
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-])=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]#[N:14])[CH2:8][CH2:7][CH2:6]2>CO.[Pd]>[CH3:1][O:2][C:3]1[C:4]([NH2:15])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]#[N:14])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1[N+](=O)[O-])CCCC2C#N
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1N)CCCC2C#N
Yield: 98.9 %

Procedure:
A solution of 6-methoxy-5-nitro-l,2,3,4-tetrahydronaphthalene-1-carbonitrile (0.42 g, 1.8 mmol) and catalytic amount of 10% Pd/C in 100 ml of MeOH was stirred under H2 for 12 h at 25° C. The reaction mixture was filtered and concentrated in vacuo to yield the desired product as a colorless oil (0.36 g, >95%). 1H NMR (300 MHz, CDCl3): δ 1.93 (m, 4H), 2.48 (qt, 2H, J=5.7 Hz), 3.79 (s, 3H), 3.99 (t, 1H, J=6.3 Hz), 6.68 (dd, 2H, J=8.0, 8.9 Hz).
Reaction SMILES: [CH2:1](C(CCCCCCCCC)C=O)CCC.[CH2:17]([CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:20]=[O:21])C>>[CH3:17][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:1])[CH:20]=[O:21]
Reactant: CCCCCCCCCCCC(C=O)CC
Reactant: CCCCCCCCCC(C=O)CCCC
Product: CCCCCCCCCCCCC(C)C=O

Procedure:
MS: m/z (%)=168 (9, M+−58), 95 (6), 81 (8), 71 (19), 58 (100), 43 (23).
Reaction SMILES: C([Li])CCC.CCCCCC.C([Mg]Br)CCC.Br[C:19]1[C:20]([CH3:29])=[N:21][C:22]([O:27][CH3:28])=[C:23]([CH2:25][CH3:26])[CH:24]=1.[C:30](=O)([O:33]C)[O:31][CH3:32]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:32][O:31][C:30](=[O:33])[C:19]1[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]([O:27][CH3:28])=[N:21][C:20]=1[CH3:29]
Reactant: COC(=O)OC
Reactant: CCc1cc(Br)c(C)nc1OC
Agent: CCCC[Mg]Br
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cc(C(=O)OC)c(C)nc1OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 122.9 %

Procedure:
An oven dried round-bottom flask is charged with toluene (35 mL) and cooled to −15° C. in a dry ice/acetone bath. A solution of butyl lithium in hexane (1.6M, 11.22 mL, 18.0 mmol) is added in one portion. To this mixture is added a solution of butylmagnesium bromide in tetrahydrofuran (2 M, 4.5 mL, 9.0 mmol) drop-wise over 1.25 hr to give a suspension. The reaction is stirred at −10° C. for 1 hr after which a solution of 3-bromo-5-ethyl-6-methoxy-2-methylpyridine (5 g, 21.7 mmol) in anhydrous toluene (10 mL) is added drop-wise over 1.25 hr. The resulting suspension is stirred at −10° C. for 30 min. The bath is cooled to −30° C. and allowed to warm slowly to 0° C. over 12 hr. The reaction is allowed to stir at −10° C. for 5 hr before diluting with anhydrous tetrahydrofuran (15 mL) to give a cloudy cream solution. This solution is added drop-wise over 1.5 hr to a cold solution of dimethyl carbonate (9.14 mL, 108 mmol) in anhydrous toluene (10 mL) stirring under a nitrogen atmosphere at −20° C. The resulting mixture is allowed to warm slowly to 0° C. After 5.5 hr, the reaction is quenched with saturated aqueous ammonium chloride (20 mL) and then partitioned between water and ethyl acetate. The ethyl acetate layer is washed with a further portion of water, and the combined aqueous washes are extracted with seven portions of ethyl acetate and two portions of dichloromethane. The combined organic extract is dried over magnesium sulfate, filtered and evaporated to give crude 5-ethyl-6-methoxy-2-methyl-nicotinic acid methyl ester (5.58 g) as an orange oil. This material is used without further purification. MS: m/e=210 (M+H); 1H NMR (CDCl3, δ, ppm): 7.94 (1H, s), 4.02 (3H, s), 3.90 (3H, s), 2.77 (3H, s), 2.59 (2H, q), 1.23 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[CH3:17]
Reactant: Cc1ccc([N+](=O)[O-])cc1-c1ccncc1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(N)cc1-c1ccncc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To the mixture containing 3-chloro-4-(2-methyl-5-nitrophenyl)pyridine in acetic acid was added Fe dust (5 eq) and the resulting mixture was stirred at ambient temperature for 6 h. To it was then added saturated sodium carbonate to bring it to neutral pH and extracted with ethyl acetate. The organic layer was washed with brine and dried with sodium sulfate and concentrated and passed through a plug of silica to yield 3-(3-chloro(4-pyridyl))-4-methylphenylamine. MS: MH+=218.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8](N)=[CH:9][C:4]=2[CH2:3][O:2]1.N([O-])=[O:12].[Na+].NC(N)=O>O.OS(O)(=O)=O>[CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:12])=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: Nc1ccc2c(c1)COC2
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc2c(c1)COC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
1,3-Dihydro-2-benzofuran-5-amine (prepared according to U.S. Pat. No. 4,000,286) (2.7 g, 20 mmol) was dissolved in a mixture of water (300 mL) and conc. H2SO4 (21 mL), cooled to 0° C. and NaNO2 (1.43 g, 20.7 mmol) in water (10 mL) was added over 15 min. After stirring at 0° C. for 1 h the mixture was allowed to stir at 10° C. for 30 min and urea was added until a negative test with starch/KI paper was observed. The solution was then poured over 2 min into a mixture of water (180 mL) and conc. H2SO4 (12.6 mL) at 90° C. and stirred at this temperature for 1.5 h. The hot mixture was filtered then allowed to cool to room temperature. The aqueous mixture was extracted with EtOAc (2×100 mL) and the combined organic layers were dried (MgSO4) and evaporated to give the title phenol (974 mg, 36%) as a cream solid; δH (CDCl3, 400 MHz) 5.03 (4H, s), 6.71 (2H, m), 7.08 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>ClCCl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH2:17][Cl:16])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCl)C(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116.3 %

Procedure:
To a solution of 2-amino-5-bromopyridine (100 mg, 0.454 mmol) in dichloromethane (6 ml) were added triethylamine (0.19 ml, 1.364 mmol, 3 equiv.) and 3-chloro-2,2-dimethyl-propionyl chloride (CAS 4300-97-4) (140 mg, 0.909 mmol, 2 equiv.) at 0-5° C. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and the crude product was purified by flash chromatography on silica gel column and eluting with an ethyl acetate:heptane gradient 5:95 to 10:90. The desired N-(5-bromo-pyridin-2-yl)-3-chloro-2,2-dimethyl-propionamide (154 mg, 74% yield) was obtained as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:32][C:21]1=[N:22][C:23]3[CH:24]=[CH:25][C:26]([CH:30]=[O:31])=[CH:27][C:28]=3[CH:29]=[C:20]1[CH2:19]2.Cl.OS(O)(=O)=O.[OH-].[Na+]>CO.O>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:32][C:21]1=[N:22][C:23]3[CH:24]=[CH:25][C:26]([CH:30]=[O:31])=[CH:27][C:28]=3[CH:29]=[C:20]1[CH2:19]2
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc4cc(C=O)ccc4nc3C2)c2cccnc21
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=Cc1ccc2nc3c(cc2c1)C[C@@]1(C3)C(=O)Nc2ncccc21
Reaction time: 3 h

Procedure:
To a solution of (2S)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[cyclopenta[b]quinoline-2,3′-pyrrolo[2,3-b]pyridine]-7-carbaldehyde from Step I (142 mg, 0.320 mmol) in MeOH (17 mL) was introduced gaseous anhydrous hydrogen chloride by bubbling the gas through the solution until the MeOH was saturated and mildly warmed. This saturation with HCl was repeated once again after 3 hours then the sealed reaction was allowed to sit at ambient temperature for 19 hours. The solution was then purged with a stream of nitrogen for 20-30 minutes, before being concentrated in vacuo. MeOH (50 mL) was added, then removed in vacuo, repeating this addition/concentration twice to remove excess HCl. The residue was dissolved in MeOH (17 mL) prior to the addition of concentrated aqueous NH4OH (0.7 mL). After 20 minutes the MeOH was removed in vacuo, fresh MeOH (50 mL) was added then remove in vacuo to produce a residue. This residue was dissolved in water (1.35 mL) plus 4 drops on cone. H2SO4. This aqueous solution was transferred to an Erlenmeyer flask using water (3 mL) and 2 more drops of conc. H2SO4. Slow neutralization with aqueous NaOH (1 M, ˜2.5 mL) provided a solid which was filtered, washed with water, air dried and vacuum dried to give the title compound. MS: m/z=316 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([O:24][CH3:25])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([NH:15][CH:16]2[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH2:17]2)=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])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].O1CCOCC1>[CH3:22][C:19]1([CH3:23])[CH2:20][CH2:21][CH:16]([N:15]2[C:9]3[N:10]=[C:11]([NH2:14])[N:12]=[CH:13][C:8]=3[C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:24][CH3:25])[C:2]2=3)[CH2:17][CH2:18]1
Reactant: COc1nccc(-c2cnc(N)nc2NC2CCC(C)(C)CC2)c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1nccc2c3cnc(N)nc3n(C3CCC(C)(C)CC3)c12
Yield: 133.2 %

Procedure:
To a 30 mL microwave reaction vessel were placed compound 332 (0.55 g, 1.5 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.14 g, 0.15 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.22 g, 0.38 mmol), and sodium tert-butoxide (0.37 g, 3.8 mmol) followed by 1,4-dioxane (15 mL). The vessel was purged with N2 for 5 min, then capped and subjected to microwave condition (3 h at 140° C.). After the volatiles were removed, the crude mixture was taken up in 4% methanol/DCM and subjected to combi-flash column chromatography (1% to 7% methanol in DCM) to give crude compound 333 as an off-white solid (0.65 g). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.01 (1 H, s), 7.92 (1 H, d, J=5.1 Hz), 7.59 (1 H, d, J=4.9 Hz), 6.86 (2 H, br. s.), 4.98-5.14 (1 H, m), 4.06 (3 H, s), 1.53 (4 H, br. s.), 1.31-1.44 (2 H, m), 1.16 (3 H, s), 1.00 (3 H, s). LCMS-ESI (POS), M/Z, M+1: Found 326.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([OH:34])[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([NH:11][C@H:12]([CH:31]([CH3:33])[CH3:32])[C:13]([N:15]1[CH2:20][CH2:19][C@@:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([OH:21])[C:17]([CH3:30])([CH3:29])[CH2:16]1)=[O:14])=[O:10].C(N(CC)CC)C.[C:42](N1C=CN=C1)(N1C=CN=C1)=[O:43].C(O)(C(F)(F)F)=O>C1COCC1.O.CO>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C@@:18]2([OH:21])[CH2:19][CH2:20][N:15]([C:13](=[O:14])[C@H:12]([NH:11][C:9]([CH:5]3[C:4]4([CH2:3][CH2:2][NH:1][C:42](=[O:43])[O:34]4)[CH2:8][CH2:7][CH2:6]3)=[O:10])[CH:31]([CH3:32])[CH3:33])[CH2:16][C:17]2([CH3:29])[CH3:30])=[CH:27][CH:26]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)[C@@H](NC(=O)C1CCCC1(O)CCN)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)[C@@H](NC(=O)C1CCCC12CCNC(=O)O2)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
To a solution of 2-(2-aminoethyl)-N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-2-hydroxycyclopentanecarboxamide (from step G, 30 mg, 0.061 mmol) in THF (0.5 mL) was added triethylamine (0.017 mL, 0.121 mmol) and 1,1′-Carbonyldiimidazole (14.77 mg, 0.091 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was subjected to preparative HPLC (Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA). The fractions corresponding to each individual diasteromer were collected, concentrated and freeze dried to yield (isomer 1: 8 mg, 0.015 mmol, 25% yield; isomer 2: 6 mg, 0.011 mmol, 19% yield).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[N:12]([CH2:20][CH3:21])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CNN>C1COCC1>[CH2:20]([N:12]([C:13]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:19])[NH2:3])[CH3:21]
Reactant: CCN(C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: C1CCOC1
Product: CCN(N)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 74 %

Procedure:
tert-Butyl 1,3-dioxoisoindolin-2-yl(ethyl)-carbamate (790 mg, 2.7 mmol) in THF (16 mL) was cooled to 0° C. and methylhydrazine (250 μL, 4.8 mmol) was added. The reaction mixture was warmed to room temperature and was stirred until all starting material was consumed. The mixture was filtered through a pad of Celite and the solvent was evaporated. The residue was purified by column chromatography (0-10% methanol in dichloromethane) to afford tert-butyl 1-ethylhydrazinecarboxylate (320 mg, 74%). Retention time: 1.13 minutes (3 min run).