Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]([CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:14](=[O:23])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:35](I)[CH:36]=[CH2:37].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]([CH2:24][CH2:25][CH2:26][N:27]([CH2:37][CH:36]=[CH2:35])[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:14](=[O:23])/[CH:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(N(CCCNCc3ccccc3)C(=O)/C=C/c3ccccc3)cc21
Reactant: C=CCI
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN(CCCN(C(=O)/C=C/c1ccccc1)c1ccc2c(c1)N(C(C)=O)CC2)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of trans-N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-N-(3-benzylamino-propyl)-3-phenyl-acrylamide (Example 47, 39 mg, 0.090 mmol), allyl iodide (0.01 mL, 0.1 mmol), and diisopropylethylamine (0.03 mL, 0.2 mmol) in CH2Cl2 (3.0 mL) was stirred at rt for 20 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified on silica gel (60% EtOAc/hexanes) to provide the title compound (37 mg, 87%). 1H NMR (500 MHz, CDCl3): 8.13 (s, 1H), 7.65 (d, J=15.5 Hz, 1H), 7.31-7.24 (m, 10H), 7.15 (d, J=7.6 Hz, 1H), 6.71 (d, J=7.3 Hz, 1H), 6.30 (d, J=16.5 Hz, 1H), 5.84-5.80 (m, 1H), 5.10 (dd, J=17.0, 10.1 Hz, 2H), 4.11 (t, J=7.3 Hz, 2H), 3.84 (br s, 2H), 3.50 (s, 2H), 3.24 (t, J=8.5 Hz, 2H), 3.02 (d, J=6.3 Hz, 2H), 2.46 (t, J=7.1 Hz, 2H), 2.23 (s, 3H), 1.81-1.75 (m, 2H). MS: exact mass calculated for C32H35N3O2, 493.64; m/z found, 494.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:14]([CH3:13])[C@H:15]2[CH2:34][N:19]3[C:20]4[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:11])=[CH:5][CH:4]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(CC(=O)N(C)[C@@H]2CCc3c(CC(=O)O)c4ccccc4n3C2)cc1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from (4-methoxyphenyl)acetyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 407.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[CH:20]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][Si](C)(C)C)[CH3:2].C(OCC)(=O)C.O>CO.O1CCCC1.[F-].[K+]>[CH2:1]([N:3]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[CH:20]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[CH:8])[CH3:2]
Reactant: CCN(C/C=C/C#C[Si](C)(C)C)CCOCCOc1cccc(-c2ccsc2)c1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: C#C/C=C/CN(CC)CCOCCOc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
2.0 g of the resulting allylamine compound was dissolved in a mixture of methanol (5 ml) and tetrahydrofuran (5 ml), and 10 ml of a saturated aqueous solution of potassium fluoride was added. The mixture was stirred overnight at room temperature, and then ethyl acetate and water were added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [methylene chloride/methanol=100/1] to give 1.3 g of (E)-N-ethyl-N-(2-penten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH:5]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH:18](O)[CH2:17][CH2:16]2)[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:3])[CH3:2].CS(Cl)(=O)=O.C(OCC)C.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[C:1]([O:4][CH:5]([C:13]1[CH:14]=[C:15]2[C:19]([CH:18]=[CH:17][CH2:16]2)=[CH:20][CH:21]=1)[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CCC2O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CC=C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
In 5 ml of pyridine was dissolved 1.0 g of 1-acetoxy-1-[(1-hydroxy)indan-5-yl]-2-[2-(N,N-dimethylamino)ethoxy]ethane. To the solution was added 0.3 ml of methanesulfonyl chloride at room temperature. The resulting mixture was stirred at the same temperature overnight. The reaction mixture was added to a mixture of 50 ml of ice water and 50 ml of diethyl ether. The resulting mixture was adjusted to pH 8.5 with potassium carbonate. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/methanol=10/1) to obtain 80 mg of oily 1-acetoxy-1-(1H-inden-6-yl)-2-[2-(N,N-dimethylamino)ethoxy]ethane (compound No. 297).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15](O)=[O:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:54])[CH3:53]>ClCCl>[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][N:62]([C:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[C:4]([C:18]4[NH:22][C:21]5[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=5[N:19]=4)[CH:5]=3)[CH2:10][CH2:11]2)=[O:16])[CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:53])[CH3:54]
Reactant: Cc1ccc2[nH]c(-c3cc(N4CCC(C(=O)O)CC4)ccc3F)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2[nH]c(-c3cc(N4CCC(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)CC4)ccc3F)nc2c1
Temperature: 35 °C
Yield: 14.7 %

Procedure:
Method I—Step a To a vial with [1-[4-Fluoro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-4-carboxylic acid hydrochloride (obtained as described in general method 8, step b) (0.10 g, 0.26 mmol) and HATU (0.10 g, 0.27 mmol) in dichloromethane (2 mL), TEA (0.08 mL, 0.56 mmol) and tert-butyl-1-piperazinecarboxylate (0.32 mmol, 0.06 g) were added. The reaction mixture was heated at 35° C. overnight, washed with water (3×2 mL) and saturated Na2CO3 solution (3×2 mL). The crude was then purified by flash chromatography (eluent: EtOAc), and then a filtration on an NH2 cartridge was run (eluent EtOAc), to obtain 0.02 g of the title compound (15%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH3:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[NH:30][C:31]3[CH:32]=[C:33]([NH3+:43])[CH:34]=[C:35]4[C:41](=[O:42])[NH:40][N:39]=[CH:38][C:37]=2[C:36]=34)=[CH:25][CH:24]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[NH:30][C:31]3[CH:32]=[C:33]([NH:43][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:12])[CH:34]=[C:35]4[C:41](=[O:42])[NH:40][N:39]=[CH:38][C:37]=2[C:36]=34)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Reactant: Cc1ccc(-c2[nH]c3cc([NH3+])cc4c3c2C=NNC4=O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2[nH]c3cc(NC(=O)[C@@H](CCc4ccccc4)NC(=O)OC(C)(C)C)cc4c3c2C=NNC4=O)cn1

Procedure:
To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-4-phenylbutanoic acid and 2-(6-methylpyridin-3-yl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-aminium chloride 267(b) in 8 mL of anhydrous dimethylformamide containing triethylamine (0.3 mL, 2.3 mmol) stirred in an ice/water bath was added HATU (244 mg, 0.64 mmol), portion-wise. The mixture was then stirred overnight at room temperature.
Reaction SMILES: [C:1]1([C:10]([O:12]CC)=[O:11])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[C:1]1([C:10]([OH:12])=[O:11])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C1(C(=O)O)CCC1
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 100 ml of diethyl cyclobutane-1,1-dicarboxylate in 110 ml of methanol was added 290 ml of a 10% (w/w) sodium hydroxide aqueous solution over a period of 60 minutes while stirring. The solution was then stirred at room temperature for 18 hrs. The organic solvent methanol was then removed under reduced pressure. The aqueous layer was washed with chloroform and the aqueous layer was then acidified with conc. hydrochloric acid to a pH of 2.5. The aqueous layer was extracted with ethyl acetate, and the extract was washed with a sat. sodium chloride aqueous solution. The extract was dried and the solvent ethyl acetate was removed under reduced pressure. The residue was purified by vacuum distillation to yield 85 g of the titled compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:21](OC)(OC)(OC)[O:22][CH3:23].C(O)(=O)CC>O>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[N:19]=[C:21]2[O:22][CH3:23])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)(OC)OC
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2ncccc2N)C1
Solvent: CCC(=O)O
Solvent: O
Product: COc1nc2cccnc2n1[C@H]1C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
To a glass microwave vial was added tert-butyl(trans-3-((3-aminopyridin-2-yl)amino)cyclobutyl)carbamate (intermediate 12, step 2, 1.7367 g, 6.24 mmol), tetramethyl orthocarbonate (16.66 ml, 125 mmol), and propionic acid (0.233 ml, 3.12 mmol). The reaction mixture was heated at 100° C. for 5 hours then was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, brine, and dried over magnesium sulfate before evaporating to dryness under reduced pressure. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% ethyl acetate in hexane, to provide tert-butyl(trans-3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)carbamate (0.968 g, 3.04 mmol, 48.7% yield).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([CH2:9]O)=[CH:7][N:6]=[CH:5]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[N:23]=[C:22]([SH:24])[N:21]=[C:20]([OH:25])[CH:19]=1.CC(C)=O>O=S(Cl)Cl.C(OCC)C>[CH3:17][C:18]1[N:23]=[C:22]([S:24][CH2:9][C:8]2[N:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=[N:6][CH:7]=2)[N:21]=[C:20]([OH:25])[CH:19]=1
Reactant: CC(C)n1cncc1CO
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: Cc1cc(O)nc(SCc2cncn2C(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
[1-(propan-2-yl)-1H-imidazol-5-yl]methanol (255 mg, 1.8 mmol) was dissolved in SOCl2 (2 mL) and diethyl ether (10 mL). After 3 hours, the solvents were evaporated. To the solid was added potassium carbonate (414 mg, 3 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (200 mg, 1.4 mmol), and acetone (20 mL). The resulting mixture was stirred at room temperature overnight. Acetone was evaporated, and the crude solid was purified by column chromatography to provide the title compound as a white solid (150 mg, 32% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.51 (m, 6H), 2.27 (s, 3H), 4.53 (m, 1H), 4.92 (s, 2H), 6.01 (br, 1H), 6.99 (s, 1H), 7.83 (s, 1H); M+265.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>O1CCCC1.CO>[CH:12](=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCCc2ccccc21
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C(=Cc2ccccc2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 250 mL flask was charged with tetralone (4 g, 27.4 mmol) and benzaldehyde (3.88 g, 36.6 mmol). This was dissolved in warm tetrahydrofuran (15 mL), and to this yellow solution was slowly added a 4 wt % solution of KOH in methanol (125 mL). The reaction was stirred for 4 days at room temperature. The solvent was then removed under reduced pressure, and it was poured into 150 mL of water and extracted with methylene chloride. The organic extract was dried over magnesium sulfate and filtered, and the solvent was removed at reduced pressure to afford 4.1 g (64%) as white powder.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([B:23]2[O:27]C(C)(C)C(C)(C)[O:24]2)[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]([O:56]C(C)(C)C)(=[O:55])[C@@H:52]([CH3:54])O>C1COCC1>[B:23]([C:18]1[CH:17]=[C:16]([Cl:15])[CH:21]=[CH:20][C:19]=1[O:22][C@@H:52]([CH3:54])[C:51]([OH:56])=[O:55])([OH:24])[OH:27]
Reactant: CC1(C)OB(c2cc(Cl)ccc2O)OC1(C)C
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O

Procedure:
DIAD (3 ml) was added to a mixture of the product from step b) (3.51 g), triphenyl phosphine (3.98 g), tert-butyl (R)-(+) lactate (2.02 g) and THF (80 ml) at 0° C. overnight. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography eluting with isohexane:ethyl acetate (7:3) to give the sub-title compound (4 g). The intermediate obtained was dissolved in acetone and 1M HCl (15 ml) was added, stirred for 20 min, then concentrated in vacuo. Redissolved in dichloromethane (10 ml) and added TFA (5 ml). Stirred for 2 h, then added water (1 ml), stirred for 1 h. The reaction mixture was then diluted (water) and made alkaline by adding dilute NaOH. The organic layer was separated and discarded. The aqueous phase was acidified with concentrated HCl to pH1, then washed with dichloromethane (×2). These organic extracts were dried (MgSO4) then concentrated in vacuo to give the sub-title compound. Yield 1.4 g
Reaction SMILES: C(=O)C1C=CC=CC=1.C(NCCN1C(=O)CSC1=O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.[NH2:44][CH2:45][CH2:46][N:47]1[C:51](=[O:52])[CH:50]([CH2:53][C:54]2[CH:59]=[CH:58][C:57](OCC)=[CH:56][CH:55]=2)[S:49][C:48]1=[O:63]>C(O)C>[NH2:44][CH2:45][CH2:46][N:47]1[C:51](=[O:52])/[C:50](=[CH:53]/[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)/[S:49][C:48]1=[O:63]
Reactant: CCOc1ccc(CC2SC(=O)N(CCN)C2=O)cc1
Agent: O=C1CSC(=O)N1CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O=Cc1ccccc1
Product: NCCN1C(=O)S/C(=C\c2ccccc2)C1=O
Temperature: 75 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
Benzaldehyde (63 μL, 0.62 mmol) and compound 29 (250 mg, 0.62 mmol) were dissolved in 10 mL of anhydrous ethanol at room temperature, and piperidine (7 μL, 0.062 mmol) was added to the reaction solution. The reaction mixture was stirred at 75° C. for 1 day and then allowed to cool down to room temperature until a yellow crystalline precipitate formed, and the solid was collected by filtration, washed with water and ethyl acetate, and dried to afford a white solid. Deprotection following the procedure of compound 6 gave the title compound 30a as a white solid (48.1%, 74 mg).
Reaction SMILES: [Br-].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13].[Li]CCCC.[CH3:38][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:40]=O>>[CH3:40][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:38]=[C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=1)[CH3:13]
Reactant: CC(c1ccc2ccccc2c1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCC(C)C=O
Agent: [Br-]
Agent: [Li]CCCC
Product: CCCCCCCCCC(C)C=C(C)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.6 %

Procedure:
Starting from (1-(2-naphthyl)ethyltriphenylphosphonium bromide (6.40 g, 12.9 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 8.0 mL, 12.9 mmol, 1.0 equiv.) and 2-methylundecanal (3.56 g, 19.3 mmol, 1.5 equiv.), and after stirring the mixture at 25° C. for 3 h, 0.94 g (23%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22](Br)[S:21]2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:35]([NH:42][C:43]1[CH:48]=[CH:47][C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][CH:44]=1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[C:38]([O:37][C:35](=[O:36])[NH:42][C:43]1[CH:44]=[CH:45][C:46]([C:22]2[S:21][C:20]3=[N:19][C:18]([NH:17][C:16]([C@@H:12]4[CH2:13][CH2:14][CH2:15][N:11]4[C:9](=[O:10])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:27])=[CH:25][N:24]3[CH:23]=2)=[CH:47][CH:48]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cn3cc(NC(=O)[C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)nc3s2)cc1
Yield: 5 %

Procedure:
Compound A37 was synthesized from compound 23 (0.100 mmol) and 4-(Boc-amino)benzeneboronic acid pinacol ester (0.150 mmol), following the procedure as described for compound A1, as a white lyophilized powder in 5% yield. MS (ESI, EI+) m/z=661.27 (MH+)
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[NH:32][CH:33]=[CH:34][N:35]=2)=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.Cl.[CH3:37][C:38]1([OH:42])[CH2:41][NH:40][CH2:39]1>CC(O)C>[OH:42][C:38]1([CH3:37])[CH2:41][N:40]([C:11]2[C:30]([C:31]3[NH:32][CH:33]=[CH:34][N:35]=3)=[CH:29][C:14]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=3)=[O:16])=[CH:13][N:12]=2)[CH2:39]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ncc[nH]2)c1
Reactant: CC1(O)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ncc[nH]2)C1
Temperature: 140 °C

Procedure:
DIPEA (0.139 mL, 0.794 mmol) was added to a mixture of 6-chloro-5-(1H-imidazol-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 69.1, 76 mg, 0.199 mmol) and 3-methylazetidin-3-ol HCl (27 mg, 0.218 mmol) in iPrOH (1 mL) and the RM was stirred at 140° C. 4.5 h. The solvent was evaporated off under reduced pressure and the residue was treated with water, extracted with EtOAc and the combined extracts were washed with water and brine, dried over MgSO4/charcoal and the solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 15 g, EtOAc/EtOH from 95:5 to 9:1) and crystallized from n-hexane/EtOAc to give the title product as white crystals. UPLC-MS (Condition 3) tR=0.7 min, m/z=434.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.32 (s, 3H) 3.54-3.67 (m, 4H) 5.47 (s, 1H) 7.05 (s, 1H) 7.26 (s, 1H) 7.35 (d, J=8.66 Hz, 2H) 7.87 (d, J=9.03 Hz, 2H) 8.15 (d, J=2.07 Hz, 1H) 8.76 (d, J=2.07 Hz, 1H) 10.25 (s, 1H) 12.39 (br. s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:4]=2[N:3]=1.N1CCOCC1.Cl.C(OCC)C>C1COCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: CCOCC
Product: CC(C)CCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Yield: 56.1 %

Procedure:
A solution of 8-chloro-3-(3-methylbutyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.074 g, 0.25 mmol) in THF (2 ml) was treated with morpholine (0.035 ml, 4.0 mmol) and the mixture degassed by the repeated alternate application of vacuum and nitrogen to the reaction vessel. The mixture was then treated with a solution of tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.026 mmol) in degassed THF (0.5 ml). After 2 hours the mixture was treated with 2M aqueous hydrochloric acid (2 ml) and diethyl ether (3 ml). The precipitated product was filtered off, washed with diethyl ether and dried. This yielded the title compound as a white solid (0.036 g, 56%). NMR δH (400 MHz, d6-DMSO); 0.91 (d, 6H, J=6.3 Hz), 1.47-1.62 (m, 3H), 3.87 (t, 2H, J=7.5 Hz), 11.19 (br. s, 1H), 14.83 (br. s, 1H); m/z 257, 259[MH+].
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15]>>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[S:14]([NH:2][CH3:1])(=[O:16])=[O:15]
Reactant: CN
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Product: CNS(=O)(=O)c1cc(C(F)(F)F)ccc1Br

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate EU using methylamine and 2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. 1H NMR (500 MHz, CDCl3) δ 8.46-8.29 (d, J=2.4, 1H), 7.99-7.79 (d, J=8.3, 1H), 7.79-7.59 (dd, J=8.3, 2.3, 1H), 5.20-5.01 (d, J=6.4, 1H), 2.80-2.56 (d, J=5.3, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]2[O:17][C:16](=[O:18])[C:15]3[CH2:19][CH2:20][CH2:21][C:14]=3[C:13]=2[CH:22]=1)(=O)=O.[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(=O)/C=C/C([O-])=O>C(O)(C)C.C(O)C>[CH3:24][O:23][C:10]1[C:9]([O:8][CH2:7][CH2:6][N:34]2[CH2:35][CH2:36][CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[CH:22][C:13]2[C:14]3[CH2:21][CH2:20][CH2:19][C:15]=3[C:16](=[O:18])[O:17][C:12]=2[CH:11]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCOS(C)(=O)=O)CCC3
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OCCN1CCC(c2ccccc2)CC1)CCC3
Yield: 93 %

Procedure:
Method B (16 h at 60° C.); starting materials: 2,3-dihydro-8-[2-(methanesulfonyloxy)ethoxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 81) and 4-phenylpiperidine; yield 93%; fusion point 150°-152° C. (from isopropanol). Fumarate: method E; yield 84%; fusion point 185°-187° C. (from ethanol and isopropanol).