Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:10]2[C@@:6]([CH3:15])([C@@H:7]([C@H:11]([CH3:14])C=O)[CH2:8][CH2:9]2)[CH2:5][CH2:4][CH2:3]1.O.O.P([O-])(O)(O)=O.[Na+].ClC1C=CC=C([C:31]([O:33]O)=[O:32])C=1>C(Cl)Cl>[CH:31]([O:33][C@H:11]([C@@H:7]1[C@:6]2([CH3:15])[C@H:10]([C@@H:2]([OH:1])[CH2:3][CH2:4][CH2:5]2)[CH2:9][CH2:8]1)[CH3:14])=[O:32]
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H](OC=O)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
Under a nitrogen atmosphere, a solution of (S)-2-{(3R,3aR,7S,7aR)-octahydro-7-hydroxy-3a-methyl-1H-indene-3-yl}propanal (Compound 15: 1.85 g, 8.797 mmol) in methylene chloride (30 ml) was cooled in an ice bath, and sodium dihydrogen phosphate dihydrate (6.86 g, 43.99 mmol) was added thereto. Meta-chloroperbenzoic acid (3.50 g, 13.2 mmol, calculated as 65%) was added thereto over 10 minutes. The reaction solution was stirred in the ice bath for 30 minutes, and at 17° C. to 21° C. for 12.5 hours. The reaction mixture was transferred to a separatory funnel such that insoluble matters were not included therein (the reaction vessel was washed with ethyl acetate), and water (40 ml) and ethyl acetate were added thereto. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium thiosulfate solution (45 ml), saturated aqueous sodium hydrogen carbonate solution (25 ml) and with saturated brine (50 ml), and dried over sodium sulfate, followed by evaporation under reduced pressure. The crude product (2.41 g) was purified by flash column chromatography to obtain (S)-1-{(3S,3aS,7S,7aR)-octahydro-7-hydroxy-3a-methyl-1H-indene-3-yl}ethyl formate (1.80 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([OH:33])=[O:32].C[O-].[Na+:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([O-:33])=[O:32].[Na+:36]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy) chroman-4-carboxylic acid (49.4 mg, 0.0975 mmol), 0.1 molar in tetrahydrofuran, was treated with sodium methanolate (195 μL, 0.0975 mmol) at ambient temperature. After 20 minutes, the solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate and concentrated in vacuo. The solid was taken up in 4:1 dichloromethane-hexanes and concentrated in vacuo and dried under high vacuum to provide sodium 6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylate (51.5 mg, 0.0974 mmol, 99.9% yield) as a solid. MS (apci) m/z=507.6 (M+2H-Na).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH2:12][C:13]([OH:15])=[O:14])(=O)C.[OH-].[NH4+].C(Cl)Cl.CO.CC(O)=O>CO>[F:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[C:6]([CH2:12][C:13]([OH:15])=[O:14])[CH:7]=1
Reactant: CC(=O)Oc1ccc(F)cc1CC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)Cc1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound (7p) (3.5 g, 16.5 mmol) was dissolved in 65 mL of MeOH, and 7 mL of ammonium hydroxide (49.5 mmol) was added. The mixture was stirred at room temperature overnight and then checked by TLC (DCM/MeOH/AcOH (9:1:0.15)), HPLC and MS. No starting material was observed. The material was concentrated to dryness to give the desired product (8p) which was carried onto the next step directly. MS (APCI−) m/z 168.9 (M−H), 338.7 (2M−H) was detected.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34].CN(C=O)C>[Cu](I)I.O>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][CH2:26][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=2[C:13]2[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: Clc1ccccc1CCBr
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2Cl)CCN(C)CC1
Temperature: 90 °C
Reaction time: 12 h
Yield: 14.2 %

Procedure:
The title compound was prepared by following general procedure 4. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1.0 mmol) was taken with copper iodide (19 mg, 0.1 mmol), L-praline (23 mg, 0.2 mmol), potassium phosphate tribasic (426 mg, 2.0 mmol), 1-(2-bromoethyl)-2-chlorobenzene (219 mg, 1.0 mmol) and DMF was added, the reaction was stirred at 90° C. under argon atmosphere for 12 h and monitored by LCMS. After completion of the reaction water was added and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase chromatography to afford 50 mg of the title compound (10.7%).
Reaction SMILES: [CH2:1]([C:3]([C:28]1[CH:33]=[CH:32][C:31]([B:34]2[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]2)=[C:30]([CH3:43])[CH:29]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[C:8]([CH3:27])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[H][H]>CO.[C].[Pd]>[CH2:1]([C:3]([C:28]1[CH:33]=[CH:32][C:31]([B:34]2[O:35][C:36]([CH3:42])([CH3:41])[C:37]([CH3:39])([CH3:40])[O:38]2)=[C:30]([CH3:43])[CH:29]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:23][CH2:24][O:25][CH3:26])([C:15]([F:18])([F:16])[F:17])[C:19]([F:22])([F:20])[F:21])=[C:8]([CH3:27])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Yield: 89 %

Procedure:
Palladium carbon (10%, 53 mg) was added to a solution of 2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 25-(4); 145.0 mg, 0.237 mmol) in methanol (6.5 mL) in a nitrogen atmosphere at room temperature, and the mixture was stirred in a hydrogen atmosphere at room temperature for four hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=30/1) to give the title compound (130 mg, 89%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)[CH:2]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])=[CH:24][CH:23]=1
Reactant: CC1(C)CN(Cc2cccnc2)c2ccc(O)cc21
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)Oc2ccc3c(c2)C(C)(C)CN3Cc2cccnc2)cc1

Procedure:
The title compound was synthesized from 1-(3-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with 4-methoxyphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (4.2 mg, 14%) having the following characteristics.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:19]=[C:18]([N:20]3[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[N:21]3)[CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:36][C:37]([F:50])([F:49])[C:38]1[CH:43]=[CH:42][C:41]([CH:44]=[CH:45]B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:26][C:25]([F:28])([F:27])[C:24]1[N:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6][C:5]3[CH:34]=[CH:35][C:2](/[CH:45]=[CH:44]/[C:41]4[CH:40]=[CH:39][C:38]([C:37]([F:36])([F:49])[F:50])=[CH:43][CH:42]=4)=[CH:3][CH:4]=3)[N:19]=2)[N:21]=[CH:22][C:23]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(Br)cc3)n2)c1C(F)(F)F
Reactant: OB(O)C=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(/C=C/c4ccc(C(F)(F)F)cc4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a vial containing the title compound from Example 2 Step A (50.0 mg, 0.092 mmol) were added 2-(4-trifluoromethylphenyl)vinyl boronic acid (29.6 mg, 0.137 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (6.4 mg, 0.009 mmol). Acetonitrile (0.400 mL) and sodium carbonate (0.229 mL, 1.0 M aqueous, 0.229 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction vial was capped and placed in a pre-heated oil bath (70° C.). After 18 h, the reaction mixture was allowed to cool to ambient temperature and was poured into water. The mixture was extracted with DCM, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 638.4 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=8.0 Hz, 1H), 8.13 (s, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.88 (t, J=7.5 Hz, 1H), 7.61 (br s, 4H), 7.54 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.41-7.39 (m, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.21-7.06 (m, 4H), 5.18 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.Cl>C(O)(=O)C>[O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCOC(=O)CCCCCn1c2ccccc2c(=O)c2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CCCCCn1c2ccccc2c(=O)c2ccccc21
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 49.1 %

Procedure:
To ethyl 6-(9-oxoacridin-10(9H)-yl)hexanoate (0.80 g) was added acetic acid (9 ml) and 2M hydrochloric acid (2.5 ml). The mixture was heated to 100° C. for 18 hours after which time the volatile components were removed on a rotary evaporator. Diethyl ether was added (25 ml) and the mixture stirred for 15 minutes. The resulting material was filtered off and air dried to give 0.36 g final product (Formula XVII). Mass spectrum: 310 (M+H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([O-])(O)=[O:11].[Na+].OOS([O-])=O.[K+]>CO.O>[NH:1]1[C:5]2=[N+:6]([O-:11])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C([O-])O
Reactant: c1cnc2[nH]ccc2c1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 1H-pyrrolo[2,3-b]pyridine (20.0 g) and NaHCO3 (90 g) in 1:1 MeOH/H2O (1000 mL) was added Oxone® (212 g) in portions during a 40 min period. The mixture was stirred at RT for 5 h. The solid was removed by filtration and the filtrate was concentrated to dryness. The solid residue was washed several times with CH2Cl2/MeOH 90/10 (500 mL). The combined organic solutions were concentrated under vacuum. The resulting crystalline solid was dissolved in CH2Cl2 (1 L). The organic solution was dried over MgSO4 and the solvent was removed under vacuum. The crude material was purified on Silica gel using a CH2Cl2/EtOAc gradient (100/0 to 0/100) to afford 1H-pyrrolo[2,3-b]pyridine 7-oxide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[CH2:14][C@@H:13]3[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][C@H:12]23)[CH:18]=1>>[C:2]1([NH:8][C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([CH2:19][CH2:20][N:15]4[CH2:14][C@@H:13]4[CH2:21][NH:22][CH2:23][C@H:12]34)[CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cc(N)cc(c43)[C@H]2C1
Product: c1ccc(Nc2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CC3)cc1

Procedure:
Using bromobenzene and following the procedures described in EXAMPLE 17, Parts B and C, (±)-cis tert-butyl 2-amino-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±)-cis-N-phenyl-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinolin-2-amine, bis-trifluoroacetic acid salt, after HPLC purification (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 116 as the free base. 1H NMR (CDCl3) δ: 7.12 (app t, 2H, J=7.9 Hz), 6.80-6.65 (m, 4H), 6.63 (s, 1H), 5.37 (broad s, 1H), 3.37 (dd, 1H, J=11.1, 7.5 Hz), 3.30-3.10 (m, 5H), 2.95-2.75 (m, 4H), 2.73-2.65 (m, 1H), 2.58 (dd, 1H). LRMS (ES)+: 292.3 (M+H)+.
Reaction SMILES: N(OCCC(C)C)=O.[Cl:9][C:10]1[C:11]([CH3:17])=[C:12]([CH:14]=[CH:15][CH:16]=1)N.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:9][C:10]1[C:11]([CH3:17])=[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: c1ccccc1
Agent: CC(C)CCON=O
Product: Cc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a dry nitrogen atmosphere isoamyl nitrite (37 grams, 0.31 mole) was added to a stirred solution of 3-chloro-2-methylaniline (35 grams, 0.25 mole) in benzene (500 ml). The mixture was heated at reflux for 1.5 hours, then allowed to cool and stirred at 50° for approximately 18 hours. The reaction mixture was cooled to room temperature, then evaporated under reduced pressure to a red residue. The residue was distilled under reduced pressure to give a yellow oil (bp 115°-130°/0.9 mm). The pot residue was washed with chloroform and the distillate dissolved in chloroform. The chloroform fractions were combined, washed with 10% aqueous hydrochloric acid and evaporated to give 3-chloro-2-methyl[1,1'-biphenyl] as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.[Li]CCCC.[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([CH2:27]Br)[CH:21]=1.[NH4+].[Cl-]>C1COCC1.O.CCOC(C)=O>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([F:26])[CH:25]=1)[CH2:27][C@H:7]1[C:6]([O:9][CH3:10])=[N:5][C@H:4]([CH:11]([CH3:13])[CH3:12])[C:3]([O:2][CH3:1])=[N:8]1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: Fc1cc(Br)cc(CBr)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1cc(F)cc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (2 mL, 11.03 mmol) in THF (90 mL) at −78° C. was added n-BuLi (1.6 M in hexanes solution, 7.5 mL, 12 mmol). After stirring for 30 min, 1-bromo-3-(bromomethyl)-5-fluorobenzene (2.68 g, 10 mmol) in THF (10 mL) was added dropwise over 30 min. The temperature was maintained at −78° C. for 30 min then allowed to warm to ambient temperature. After stirring for 16 h, saturated aqueous NH4Cl (30 mL) was added followed by dilution with EtOAc and H2O. The THF was removed in vacuo and the remaining organics were separated and dried over sodium sulfate. After removal of solvent, the crude product was purified by silica gel chromatography to provide (2S,5R)-2-(3-bromo-5-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (3.17 g, 77%). MS (m/z) 371 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:13]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([CH2:11][NH2:10])[CH2:13]2)=[CH:21][CH:22]=1
Reactant: O=C(NCC1CCCN(CCc2ccc(F)cc2)C1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCC1CCCN(CCc2ccc(F)cc2)C1
Reaction time: 17 h

Procedure:
A solution of {1-[2-(4-fluorophenyl)ethyl]-piperidin-3-ylmethyl}carbamic acid benzyl ester (140 mg, 370 μmol) was combined with Pearlman's catalyst (50 mg) and methanol (10 mL) and shaken under an atmosphere of hydrogen (40 psig) for 17 hours. The mixture was filtered, and the filtrate was concentrated to provide a gum (88 mg, quantitative) which was used without further purification. 1H NMR (300 MHz, CD3OD) δ7.21 (m, 2H), 6.99 (t, J=9 Hz, 2H), 3.1-2.9 (m, 2H), 2.80 (m, 2H), 2.60 (m, 2H), 2.1-1.0 (m, 9H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].C(Cl)CCl.C[CH:21]=[CH:22][CH2:23][NH2:24]>CN(C1C=CN=CC=1)C>[CH2:23]([NH:24][C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH:14]=[CH2:15])=[O:12])[CH:22]=[CH2:21]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC=CCN
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: C=CCNC(=O)[C@H](CC=C)NC(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 28.4 %

Procedure:
To a stirred solution of (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentenoic acid (2.82 g, 13 mmol), DMAP (1.9 g, 16 mmol) and EDC (3.1 g, 16 mmol) was added N-methylallylamine (1.38 mL, 14 mmol). The reaction was stirred for 72 hours before being quenched by the addition of 1 M HCl (15 mL). The resulting biphasic mixture was separated and the aqueous phase was extracted once with DCM. The combined organics were dried over sodium sulfate and concentrated to yield 1,1-dimethylethyl {(1S)-1-[(2-propen-1-ylamino)carbonyl]-3-buten-1-yl}carbamate (0.94 g, 28%). LCMS: (M−tBut)+: 238.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][CH2:50][CH2:51][NH2:52])=[CH:45][CH:44]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9](=[O:11])[NH:52][CH2:51][CH2:50][NH:49][C:46]2[CH:47]=[CH:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=2)[NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)NC(C(=O)O)c2ccc(F)cc2)c1
Reactant: COc1ccc(NCCN)cc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(NCCNC(=O)C(NC(=O)c2cccc(C)c2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
4-Fluoro-phenyl glycine 1 (20 mg, 0.12 mmol) was dissolved in H2O (1 mL) containing equimolar amounts of NaOH (5 mg, 0.12 mmol). The solution was cooled to 0° C., then m-toluoyl chloride (16 μL, 0.12 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 12 h. After acidification with 1 M HCl (1 mL), the product was extracted from the reaction mixture with DCM (4 mL). The organic layer was separated and the solvent was removed in vacuo to yield (4-Fluoro-phenyl)-(3-methyl-benzoylamino)-acetic acid 2 (34 mg, 0.12 mmol, quant.) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.67–7.08 (m, 8H), 5.66 (s, 1H), 2.38 (s, 3H). MS calcd. for C16H15FNO3 (M+H+) 288.10. found 288.4. Step B: (4-Fluoro-phenyl)-(3-methyl-benzoylamino)-acetic acid 2 (34 mg, 0.12 mmol) was dissolved in DCM (2 mL), HOBt (20 mg, 0.14 mmol) and DIC (23 μL, 0.14 mmol) were added and the solution was stirred for 10 min at room temperature. N-(4-Methoxyphenyl)-ethane-1,2-diamine (24 mg, 0.14 mmol) was added and the solution was stirred for 3 h at room temperature. The solvent was removed in vacuo, and the remainder was purified by reverse HPLC to afford N-{(4-Fluoro-phenyl)-[2-(4-methoxy-phenylamino)-ethylcarbamoyl]-methyl}-3-methyl-benzamide 3 (19 mg, 0.04 mmol, 36%) as a white solid:
Reaction SMILES: C([N:8]1[C@H:12]([C:13]([S:16]CC2C=CC(OC)=CC=2)([CH3:15])[CH3:14])[CH2:11][C@H:10]([CH2:26][S:27]CC2C=CC(OC)=CC=2)[C:9]1=[O:37])C1C=CC=CC=1.N.[Na].[Cl-].[NH4+]>C1COCC1>[SH:16][C:13]([C@H:12]1[NH:8][C:9](=[O:37])[C@@H:10]([CH2:26][SH:27])[CH2:11]1)([CH3:15])[CH3:14]
Reactant: COc1ccc(CSC[C@H]2C[C@@H](C(C)(C)SCc3ccc(OC)cc3)N(Cc3ccccc3)C2=O)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(S)[C@@H]1C[C@H](CS)C(=O)N1
Yield: 45.7 %

Procedure:
A solution of cis-N-benzyl-4-[1-(4-methoxybenzylthio)-1-methylethyl]-2-(4-methoxybenzylthiomethyl)-4-butanelactam (compound No.14-1, 0.40 g) in THF (8 ml) was added in liquid ammonia (60 ml). To the solution sodium metal (0.12 g) was added in a small portion under nitrogen atmosphere. After an addition of ammonium chloride, ammonia was evaporated and a product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The separated crystals were filtered to give 70 mg (46%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2Br)[C:35]([F:38])([F:37])[F:36])[N:3]=1.O1CCOCC1.CC1(C)C(C)(C)OB([C:61]2[CH:62]=[C:63]([S:67]([NH2:70])(=[O:69])=[O:68])[CH:64]=[CH:65][CH:66]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([S:67](=[O:69])(=[O:68])[NH2:70])[CH:62]=2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4cccc(S(N)(=O)=O)c4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 0.688 mmol) in 10:1 dioxane:water (11 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (195 mg, 0.7 mmol), KHCO3 (207 mg, 2.06 mmol), and PdCl2(dppf)-CH2Cl2 (56 mg, 0.069 mmol). The reaction was heated to 100° C. for 15 h, cooled to RT, and concentrated in vacuo. The residue was diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.