Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26](I)=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].CN[C@@H]1CCCC[C@H]1NC>CS(C)=O.O.[Cu]I>[N:35]([C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:18]([C:15]3[C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[C@@H:8]4[C@H:13]([C:14]=3[OH:31])[C@@H:12]3[CH2:32][C@H:9]4[CH2:10][CH2:11]3)=[N:19][S:20](=[O:30])(=[O:29])[C:21]=2[CH:27]=1)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.2 %

Procedure:
(1R,2S,7R,8S)-3-(4-Fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 1a, 0.513 g, 0.864 mmol), sodium azide (1.12 g, 17.2 mmol), sodium ascorbate (0.086 g, 0.43 mmol), copper (I) iodide (0.16 g, 0.84 mmol), and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.20 mL, 1.27 mmol) were dissolved in a 5:1 mixture of dimethyl sulfoxide and water (10 mL) at 25° C. The reaction flask was degassed and backfilled with nitrogen (5×). After stirring at 25° C. for 14 h, the reaction mixture was partitioned between water (150 mL) and ethyl acetate (2×150 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 60% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-5-(7-azido-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.348 g, 0.684 mmol, 79%), as a dark brown foam, which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]=C)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9].N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:31].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:31])[C:14]=2[CH:13]=[CH:12]1)(=[O:10])=[O:9]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1C
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: Cc1ccccc1S(=O)(=O)n1ccc2c(C=O)cccc21
Reaction time: 0.05 h

Procedure:
OsO4 (15 mg, 0.06 mmol) was added to a stirred mixture of 1-[(2-methylphenyl)sulfonyl]-4-vinyl-1H-indole (300 mg, 1.01 mmol; Intermediate 15) and 2,6-lutidine (235 μl, 2.02 mmol) in dioxane (24 mL). The mixture turned from colorless to black in 3 minutes. Sodium periodate (0.865 g, 4.04 mmol) in water (8 mL, warmed to dissolve) was added. A grey precipitation was immediately formed. The mixture was stirred for 1.40 h and extracted with 2M aqueous HCl (25 mL) and DCM (2×25 mL). The organic layers were combined, dried, filtered and concentrated to give the title compound (358 mg, 118%, still some dioxane according to HNMR) as a black gum. MS (ESI+) for C16H13NO3S m/z 300 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[O:29][N:28]=1)([CH3:26])[CH3:25].C(C1C=C(NC(=O)N)ON=1)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:33]([NH:32][C:30]2[O:29][N:28]=[C:27]([C:24]([F:23])([CH3:25])[CH3:26])[CH:31]=2)=[O:34])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Agent: CC(C)c1cc(NC(N)=O)on1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)c2cc1OC
Yield: 44.9 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) and phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (95 mg, 0.36 mmol) were reacted according to the method described for 143-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea as a colorless solid (63 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ 10.50 (brs, 1H), 9.15 (s, 1H), 8.56 (s, 1H), 7.57-7.58 (m, 2H), 7.40-7.45 (m, 2H), 7.32 (m, 1H), 7.00 (m, 1H), 6.14 (s, 1H), 3.99-4.00 (2×s, 6H), 1.67 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 468 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]1=[O:1])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: Cc1cccnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cccc(C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-hydroxy-3-methyl-pyridine (4.1 g, 37 mmol), ethyl bromoacetate (5.9 g, 35 mmol) and potassium carbonate (4.9 g, 35 mmol) in DMF (60 ml) was stirred at rt for 16 h. After evaporation of the solvent and extractive workup (ethyl acetate/water) the organic phase was concentrated and chromatographed (SiO2, heptane:ethyl acetate=100:0 to 40:60). The title compound elutes as the second product and was isolated as a colorless liquid (6.1g, 84%). MS: m/e=196.0[M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[NH:10][N:9]=[CH:8][NH:7]1)=[O:5])[CH3:2].C(OC1C(OC(=O)C)=C(I=O)C=CC=1)(=O)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][N:9]=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1NC=NNC1=O
Agent: CC(=O)Oc1cccc(I=O)c1OC(C)=O
Solvent: CCO
Product: CCOC(=O)c1ncn[nH]c1=O
Yield: 64.6 %

Procedure:
6-Oxo-1,4,5,6-tetrahydro-[1,2,4]triazine-5-carboxylic acid ethyl ester (329 mg, 1.92 mmol) was dissolved in ethanol (9 ml) and diacetoxyiodosobenzene (644 mg, 1.99 mmol) was added in one portion. After 2 h at ambient temperature all volatiles were removed and the remaining residue was purified by column chromatography (silica gel, heptane/ethyl acetate 70:30 to 50:50) to give the title compound (209 mg, 1.24 mmol; 64%) as yellow solid. MS: m/e=170.1 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH2:18][CH2:17][CH2:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.CN1CCOCC1.Cl.[CH3:33][NH:34][O:35][CH3:36]>C(Cl)Cl.C1COCC1.C(Cl)Cl>[C:14]1([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:34]([O:35][CH3:36])[CH3:33])=[O:12])[CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1=CCCC1)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@H](CC1=CCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a flask charged with (S)-2-(tert-Butoxycarbonylamino)-3-cyclopentenylpropanoic acid (55.0 g, 214 mmol) was added THF/DCM (800 mL, 1:1). The solution was cooled to 0° C. and ethyl chloroformate (24.5 mL, 257 mmol) and NMM (28.4 mL, 257 mmol) were added dropwise sequentially. After addition, the mixture was stirred at 0° C. under nitrogen for 1 h. To the other flask charged with N,O-dimethylhydroxylamine HCl (25 g, 257 mmol) was added DCM (400 mL). The mixture was cooled to 0° C. and TEA (38.7 mL, 278 mmol) was added. The resulting mixture was transferred into the former reaction flask. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was quenched with water (500 mL) and the organic phase was washed with water (500 mL), dried over anhydrous sodium sulfate, and concentrated to afford (S)-tert-butyl (3-(cyclopent-1-en-1-yl)-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate as colorless oil (60 g, 93% yield), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]#[N:13])=[CH:10][C:4]=2[O:3]1.[OH-].[K+].[CH3:17][C:18](OC)(C)C>O>[F:14][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:12]#[N:13])[CH2:18][CH2:17]3)=[CH:10][C:4]=2[O:3]1
Reactant: COC(C)(C)C
Reactant: N#CCc1ccc2c(c1)OC(F)(F)O2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CC1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 70 °C

Procedure:
A mixture of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (1.0 eq), 50 wt % aqueous KOH (5.0 eq) 1-bromo-2-chloroethane (1.5 eq), and Oct4NBr (0.02 eq) is heated at 70° C. for 1 h. The reaction mixture is cooled then worked up with MTBE and water. The organic phase is washed with water and brine then the solvent is removed to afford (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]3[CH:35]=[CH:34][CH:33]=[CH:32]3)[CH2:20][CH:19]2[OH:36])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]3[CH:32]=[CH:33][CH:34]=[CH:35]3)[CH2:20][C:19]2=[O:36])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:7]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3-n3cccc3)CC2O)CCCCC1)c1ccco1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3-n3cccc3)CC2=O)CCCCC1)c1ccco1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To the solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexane carbonyl]amino]-1-[4-fluoro-2-(pyrrol-1-yl)phenyl]piperidin-3-ol (1.8 g) obtained in Step 1 in 10 ml of dimethylsulfoxide, was added 2 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (1.8 g) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 1.5 g of the titled compound as white color.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[C:23]([O-:26])(O)=[O:24].[Na+].[OH-].[Na+].O>CC1OCCC1>[CH2:16]([O:26][C:23]([CH2:6][NH:1][CH2:2][CH2:3][N:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:6]1)=[O:24])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:10]=1
Reactant: O=C([O-])O
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC1CCCO1
Product: O=C(CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)OCc1ccccc1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
The product from the previous step (in MeTHF) and biphenyl-2-yl-carbamic acid piperidin-4-yl ester (10.0 kg, 32.6 mol, 1.0 eq.) in MeTHF (28.5 kg) were placed in the reaction vessel and heated to 30° C. for one hour. The mixture was then cooled to 5° C. NaHB(OAc)3 (10.0 kg, 45.8 mol, 1.4 eq.) was added portion wise over a period of 40 minutes while maintaining the temperature below 20° C. The mixture was then stirred for 30 minutes. Additional NaHB(OAc)3 (0.5 kg) was added the reaction allowed to progress to completion. A saturated solution of NaHCO3 (14.3 kg, 15.3 mol, 1.1 volumes) was added and stirred for 10 minutes. The aqueous phase was separated and discarded. A 33% NaOH solution (15.8 kg, 129.9 mol, 4.0 eq.) was added to the reaction mixture to adjust the pH to be in the range of 8-12. Water (40 kg) was added in two portions, after which phase separation occurred. A saturated NaHCO3 (7.1 kg, 7.6 mol, 0.7 volumes) was added to the reaction mixture and stirred for 10 minutes. The aqueous phase was separated and discarded. Additional water (4.9 kg) was added to dissolve any remaining salts and a vacuum distillation was conducted at a maximum temperature of 45° C. to remove part of the solvent (7.2 volumes). MeOH (56.1 kg, 7.2 volumes) was added to the reaction mixture before continuing with the next step.
Reaction SMILES: [C:1]([C:3]1[C:20]([C:21]#[N:22])=[CH:19][C:6]2[N:7](CCC)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1)#[N:2].[CH2:23]([C:26](C1C=CC(C=O)=CC=1)([CH2:30][CH:31]=[CH2:32])[CH2:27][CH:28]=[CH2:29])[CH:24]=[CH2:25]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH2:23]([C:26]([C:13]1[CH:14]=[CH:15][C:10]([C:8]2[NH:7][C:6]3[CH:19]=[C:20]([C:21]#[N:22])[C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)=[CH:11][CH:12]=1)([CH2:30][CH:31]=[CH2:32])[CH2:27][CH:28]=[CH2:29])[CH:24]=[CH2:25]
Reactant: CCCn1c(-c2ccccc2)nc2cc(C#N)c(C#N)cc21
Reactant: C=CCC(CC=C)(CC=C)c1ccc(C=O)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C=CCC(CC=C)(CC=C)c1ccc(-c2nc3cc(C#N)c(C#N)cc3[nH]2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
A solution of 1 (198 mg, 1.25 mmol) in NMP (2.5 mL) and a solution of 2 (300 mg, 1.25 mmol) in NMP (3.5 mL) were combined in a flask fitted with a Hickman still. The mixture was heated at 120° C. and stirred for 2 h. Then FeCl3.6H2O (17 mg, 63 μmol) was added and oxygen was bubbled through the mixture with continued heating and stirring for 20 h. The cooled reaction mixture was diluted with ethyl acetate. The organic solution was washed with water and brine. The organic layer was dried (Na2SO4), filtered, concentrated, and chromatographed (silica, CH2Cl2 w/ethyl acetate gradient of 0-5%). Fractions containing the desired compound were concentrated to give a reddish solid, which was chromatographed over a short plug of alumina (CH2Cl2 w/ethyl acetate gradient of 10-100%) yielding a colorless solid (268 mg, 57%): mp 264-266° C.; 1H NMR (d6-acetone) δ 2.57 (d, J=7.2 Hz, 6H), 4.88-5.11 (m, 6H), 5.56-5.69 (m, 3H), 7.65 (d, J=8.8 Hz, 2H), 8.26 (d, J=8.8 Hz, 2H), 12.89 (brs, 1H); 13C NMR (d6-acetone) δ 41.6, 44.0, 108.2, 116.9, 117.7, 126.4, 127.3, 128.0, 134.4, 150.2; FABMS obsd 379.1909, calcd 379.1923 (C25H22N4).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].[Cl-].[NH4+]>ClCCl>[CH3:12][C:9]1[C:8]2[C:7](=[O:13])[CH2:6][CH2:5][CH2:4][C:3]=2[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(N)c2c1C(=O)CCC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NS(C)(=O)=O)c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-amino-8-methyltetralone (De, B. Synth. Commun. (1988), 18, 481-486) (0.25 g, 1.4 mmol) in dichloromethane (7 mL) was treated with pyridine (0.35 mL, 4.3 mmol), treated with methanesulfonyl chloride (0.12 mL, 1.5 mmol), stirred at ambient temperature for 1.5 hours, treated with aqueous ammonium chloride solution (20 mL) and extracted with dichloromethane (4×25 mL). The combined dichloromethane extracts were washed with brine, dried (Na2SO4) and concentrated. Purification of the residue on silica gel with ethyl acetate:hexanes 1:1 provided the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([C:7]1[N:11]2[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[C:10]2=[CH:9][CH:8]=1)=[O:6].BrC1C=CC([C:28](C2N3CCCC(C(OC)=O)C3=CC=2)=[O:29])=CC=1>>[CH3:28][O:29][C:22]1[CH:21]=[CH:20][C:4]([C:5]([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[C:10]3=[CH:9][CH:8]=2)=[O:6])=[CH:3][CH:2]=1
Reactant: COC(=O)C1CCCn2c(C(=O)c3ccc(Br)cc3)ccc21
Reactant: COC(=O)C1CCCn2c(C(=O)c3cccc(Br)c3)ccc21
Product: COC(=O)C1CCCn2c(C(=O)c3ccc(OC)cc3)ccc21

Procedure:
methyl 3-m-bromobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate, and p0 methyl 3-p-bromobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate; and
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.[CH2:73]([OH:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1.[H-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:80][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccccc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(OCc4ccccc4)nc3N21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g (8.15 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) in 30 ml toluene was added 0.20 g (0.29 mmol) (S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl and 0.12 g (0.12 mmol) di-palladium-tris(dibenzylideneacetone)chloroform complex. After 30 min, 1.0 ml (1.06 g, 9.80 mmol) benzylalcohol and 0.70 g (16.0 mmol) sodium hydride (55–65% dispersion in oil) were added and the reaction mixture was stirred for 3.5 h at 70 deg C. After cooling to room temperature, the reaction mixture was poured onto 10% aqueous sodium carbonate solution and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and filtered. After evaporation of the volatile components, the residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:4) as eluant.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13](=[O:27])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[NH:17][C:16]=2[CH3:26])[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:50]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])(=[O:53])[CH:51]=[CH2:52].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:55]([O:54][C:50](=[O:53])/[CH:51]=[CH:52]/[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13](=[O:27])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[NH:17][C:16]=2[CH3:26])[CH:3]=1)([CH3:58])([CH3:57])[CH3:56]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(C)c(CC(=O)Nc3cc(/C=C/C(=O)OC(C)(C)C)ccc3C(=O)O)c2c1
Temperature: 110 °C

Procedure:
To methyl 4-bromo-2-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}benzoate (20 mg) was added palladium acetate (2 mg), tri-o-tolylphosphine (3 mg), t-butyl acrylate (33 μl), triethylamine (32 μl) and dimethylformamide (1 ml). After heating at 110° C. for 18 h, the solvent was removed in vacuo and the residue diluted with dichloromethane (10 ml) and washed with 5% citric acid (5 ml). Purification by SPE eluting with dichloromethane, chloroform, and chloroform: ether mixtures afforded the title compound (5 mg), MH+ 465; MH− 463; TR 4.47 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.[F-].[Cs+]>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:14][C:6]1[CH:5]=[C:4]([CH:15]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C)cc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-methyl phenylboronic acid (0.237 g, 1.74 mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (375 mg), as a thick oil.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][N:8](CC2C=CC=CC=2)[C@@H:7]([CH3:17])[CH2:6]1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([NH:4][C@@H:5]1[CH2:9][NH:8][C@@H:7]([CH3:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1C[C@H](C)N(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H]1CN[C@@H](C)C1
Yield: 94.1 %

Procedure:
A 2.93 g (12.61 mmol) sample of (2S,4S)-4-acetylamino-2-methyl-1-N-benzylpyrrolidine, from Example 1, step g above, was dissolved in 50 mL of methanol, 0.60 g of 10% Pd/C was added and the mixture shaken under 4 atm of hydrogen at room temperature for 13 hours. The mixture was concentrated, the catalyst was removed by filtration, and the solvent removed to afford 1.688 g (94.1% yield) of the title compound as a white solid. MS M/Z: 143 (M+H). NMR (CDCl3) δ: 1.16 (d, 3H, J=6 Hz), 1.63 (m, 1H), 1.79 (m, 1H), 1.95 (s, 3H), 2.65 (m, 1H), 3.28 (m, 1H), 3.41 (m, 1H), 4.40 (m, 1H), 5.81 (br, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.Cl[C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:10]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Temperature: 90 °C
Yield: 75.1 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (378 mg, 1.272 mmol), (chloromethanetriyl)tribenzene (426 mg, 1.53 mmol) and triethylamine (193 mg, 1.91 mmol) in dry DMF (20 mL) was heated to 90° C. for 16 hours. Reaction mixture was extracted with ethyl acetate (100 mL), organic phase washed with water (3×10 mL) and brine (2×10 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with EtOAc: petroleum ether=1:15) to afford 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (515 mg, 75%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 8.29 (s, 1H), 8.01 (s, 1H), 7.29-7.26 (m, 10H), 7.13-7.11 (m, 5H), 1.51 (s, 9H). LCMS: (M+H)+=539.