Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:43])[NH:12][CH:13]([C:17]([N:19]1[CH2:23][CH2:22][CH:21]2[N:24]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[CH2:25][CH:26]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([F:36])=[CH:33][CH:34]=4)[NH:29][CH:28]=3)[CH:20]12)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:36][C:32]1[CH:31]=[C:30]2[C:35]([C:27]([CH:26]3[CH:20]4[N:19]([C:17]([CH:13]([NH:12][C:11](=[O:43])[CH:9]([NH:7][CH3:6])[CH3:10])[CH:14]([CH3:15])[CH3:16])=[O:18])[CH2:23][CH2:22][CH:21]4[N:24]([C:37]4[N:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[CH2:25]3)=[CH:28][NH:29]2)=[CH:34][CH:33]=1
Reactant: CC(C)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1)C(C)C
Reaction time: 2 h

Procedure:
To a solution containing 74 (202 mg, 0.33 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. After 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by RP-HPLC (2″ Dynamax C18, 10-70% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 125 mg (61%, 3 steps) of 75. 1H NMR (CDCl3, 300 MHz): δ8.37 (dd, J=6.0, 10.5 Hz, 2H), 8.19 (s, 1H), 8.11 (dd, J=5.4, 8.7 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 6.99-6.88 (m, 2H), 6.74-6.68 (m 1H), 6.62-6.58 (m, 1H), 4.74-4.60 (m, 1H), 4.48-4.44 (m, 1H) 4.16-4.04 (m, 2H), 3.69 (dd, J=6.0, 11.4 Hz, 1H), 3.51-3.42 (m, 1H), 3.26 (dd, J=6.6, 13.5 Hz, 1H), 2.76 (br s, 4H), 2.53-2.47 (m, 1H), 2.44-2.39 (m, 3H), 2.21-2.01 (m, 3H), 1.39-1.32 (m, 3H), 1.06-0.96 (m, 6H) ppm. 13C NMR (CDCl3, 75 MHz) δ173.9, 170.8, 160.2 (JCF=237.4 Hz), 159.8, 136.2, 123.4, 120.9 (JCF=10.1 Hz), 116.6, 110.1, 108.5 (JCF=24.5 Hz), 97.2 (JCF=26.2 Hz), 68.2, 60.3, 59.7, 55.9, 51.4, 47.2, 38.9, 34.2, 31.5, 30.7, 19.4, 18.8, 18.0 ppm. Mass spectrum, m/z [508.3] (M)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:13][NH2:14]>C(O)C>[CH3:13][NH:14][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CN
Solvent: CCO
Product: CNCc1cccc2ccccc12
Reaction time: 8 h

Procedure:
17.6 g of 1-chloromethyl-naphthalene in 40 ml of absolute ethanol is added, dropwise, at 0° to 5°, to 100 ml of a 33% solution of methylamine in absolute ethanol. The mixture is allowed to stand overnight and is then evaporated. The residue is taken up in a little chloroform and washed with 100 ml of 1 N sodium hydroxide solution and with water. The organic phase is dried and evaporated to dryness. The residue is distilled at 0.01 Torr to obtain the heading compound as main fraction, b.p. 85°-87°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.Cl[CH2:11][C:12](=O)[CH3:13]>C(O)C>[NH2:9][C:6]1[CH:5]=[CH:4][N:3]2[CH:11]=[C:12]([CH3:13])[N:1]=[C:2]2[C:7]=1[I:8]
Reactant: CC(=O)CCl
Reactant: Nc1ccnc(N)c1I
Solvent: CCO
Product: Cc1cn2ccc(N)c(I)c2n1
Temperature: 65 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
To a solution of 2,4-diamino-3-iodopyridine 22 (4.36 g, 18.6 mmol) in ethanol (100 mL) was added chloracetone (7.15 g, 77.3 mmol). The solution was stirred at 65° C. for 6 h. After cooling to room temperature, the solution was evaporated to dryness. The residue was diluted with water (75 mL) and the resulting solution made basic (pH=12-13) by the addition of a ammonium hydroxide solution. The solution was extracted with CH2Cl2 and the combinated extracts were dried (Na2SO4), filtered and evaporated under reduced pressure. The crude product was purified by chromatography using CH2Cl2/EtOAc (4/1, v/v) as eluent to afford compound 23 (3.30 g, yield: 65%); mp 185° C.; IR (KBr) 3454, 3431, 3355, 3093, 3026, 1646, 1499, 1463; 1H NMR (400 MHz, DMSO-d6) δ 2.19 (s, 3H), 5.68 (brs, 2H), 6.38 (d, 1H, J=7.1 Hz), 7.42 (s, 1H), 8.03 (d, 1H, J=7.1 Hz); 13C NMR (100 MHz, DMSO-d6) δ 14.1, 60.9, 103.8, 109.3, 126.0, 140.4, 145.6, 146.6. Anal. Calcd for C8H8IN3: C, 35.19; H, 2.95; N, 15.39. Found: C, 35.25; H, 2.92; N, 15.60.
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1.C([N:21](CC)CC)C>ClCCl>[NH2:21][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (5. 26 mL, 68 mmol) was added dropwise over 5 minutes to a stirred solution of 1,1-dimethylethyl (3R)-3-hydroxypyrrolidine-1-carboxylate (10.6 g, 56.7 mmol) and triethylamine (11.8 mL, 85 mmol) in dichloromethane (250 mL) at −10° C. After stirring for 1 hour at 0° C., the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (25:75 to 50:50), to give the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:47][C:48]([F:62])([F:61])[C:49]1[CH:54]=[CH:53][C:52]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[CH:51][CH:50]=1>C1COCC1>[CH:13]([O:12][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:7]=1[C:8]([N:58]1[CH2:57][CH2:56][N:55]([C:52]2[CH:51]=[CH:50][C:49]([C:48]([F:61])([F:62])[F:47])=[CH:54][CH:53]=2)[CH2:60][CH2:59]1)=[O:10])([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(C#N)cc1C(=O)O
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(C#N)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.6 mmol 5-cyano-2-isopropoxy-benzoic acid (compound 1.13) in 20 ml THF were added 4.0 mmol TBTU, 21.6 mmol N-ethyldiisopropylamine and 4.0 mmol 1-(4-trifluoromethyl-phenyl)-piperazine (commercial). The reaction was then stirred at RT for 16 h, concentrated in vacuo, and purified by chromatography on silica gel (eluant: ethyl acetate/heptane 1:1) to afford the title compound. MS (m/e): 418.3 (M+H+, 100%)
Reaction SMILES: C([O:8][C:9](=[O:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:19]2(=[O:34])=[O:33])[CH:13]=1)C1C=CC=CC=1.CCO.[H][H]>CCOC(C)=O.[Pd]>[C:39]([O:38][C:36]([NH:35][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[S:19]2(=[O:33])=[O:34])[CH:13]=1)[C:9]([OH:43])=[O:8])=[O:37])([CH3:40])([CH3:42])[CH3:41]
Reactant: COc1ccc(CN2C(=O)CN(c3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc4ccccc4)c3)S2(=O)=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CN(c3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c3)S2(=O)=O)cc1

Procedure:
The title D compound, (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester (187 mg, 0.307 mmol) is dissolved in a 1:1 mixture of EtOAc:EtOH (50 mL) in a 200 mL Parr bottle. 10% Palladium on carbon (52 mg) is added as a solid and the reaction mixture is hydrogenated on a Parr Shaker Apparatus at 47 psi of hydrogen for 1.33 h. The reaction mixture is filtered through celite and concentrated in vacuo to give (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid as a white foam: [M−1]−=518.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:16][C:15]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:14])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:17]
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-naphthalene is reacted with acetyl chloride and aluminium chloride in nitrobenzene to give (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) methyl ketone. Reduction of this ketone with lithium aluminium hydride in ether yields 5,6,7,8-tetrahydro-α-5,5,8,8-pentamethyl-2-naphthalene-methanol which is converted by treatment with phosphorus tribromide in ether/hexane in the presence of a small amount of pyridine into 2-bromoethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene. This bromoethyl compound is converted by treatment with triphenylphosphine in xylene while heating for 12 hours into [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide which, in a Wittig reaction with 4-ethoxycarbonyl-benzaldehyde, yields p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoic acid ethyl ester of melting point 90°-91° C. This ester is reduced with lithium aluminum hydride in ether/tetrahydrofuran to give p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzyl alcohol of melting point 123°-124° C. (from methanol).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (10.0 g, 44 mmol), 3-amino-5-methyl-1H-pyrazole (6.0 g, 62 mmol) and N,N-diisopropylethylamine (9.20 ml, 53 mmol) in 1-butanol (80 ml) was heated at 85° C. for 12 hours. The mixture was allowed to cool to ambient temperature and the resulting precipitate collected by filtration. The solid product was washed with ethanol and dried to give the sub-titled compound (10.8 g, 85%). 1H NMR (DMSO): δ 2.23 (s, 3H), 6.23 (s, 1H), 8.39 (s, 1H), 9.21 (s, 1H), 12.27 (s, 1H); MS: m/z 290 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:18][C:8]2[N:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[N:11]=[C:12](Cl)[C:7]=2[CH:6]=1)=[O:4].N#N>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:18][C:8]2[N:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(Cl)nc(S(C)(=O)=O)nc2s1
Agent: [Pd]
Agent: N#N
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc2cnc(S(C)(=O)=O)nc2s1
Reaction time: 6 h

Procedure:
To a solution of 4-chloro-2-methanesulfonyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (700 mg, 2.2 mmol) in THF/MeOH (10/10 mL) purged with N2 was added Pd/C (700 mg). The reaction mixture was purged with N2, evacuated and purged with H2 three times. After 6 h, the mixture was filtered via Celite and concentrated. The residue dissolved in MeOH/CH2Cl2 and the solid was filtered. The filtrate containing the product was concentrated and used without further purification. ESIMS calcd 273 (M++H), found 273 (M++H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][C:13]2[CH:15]=[C:16]([C:19]([NH:21][C:22]3[C:31]4[O:30][C:29]([C:32]([O:34]CC)=O)=[CH:28][C:27](=[O:37])[C:26]=4[CH:25]=[CH:24][CH:23]=3)=[O:20])[CH:17]=[CH:18][C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:38]>CO.O1CCCC1>[O:37]=[C:27]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:21][C:19]([C:16]3[CH:17]=[CH:18][C:12]4[O:11][CH:10]([CH2:9][O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:14][C:13]=4[CH:15]=3)=[O:20])[C:31]=2[O:30][C:29]([C:32](=[O:34])[NH2:38])=[CH:28]1
Reactant: N
Reactant: CCOC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc4c(c3)CC(COCc3ccccc3)O4)c2o1
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc4c(c3)CC(COCc3ccccc3)O4)c2o1
Reaction time: 1.5 h

Procedure:
In a solution of ethyl 8-(2-benzyloxymethyl-2,3-dihydrobenzofuran-5-carboxamido)-4-oxo-4H-1-benzopyran-2-carboxylate (528 mg, 1.06 mmol) in methanol (25 ml) and anhydrous tetrahydrofuran (25 ml), ammonia gas was bubbled for 30 minutes. After evaporation to dryness, the resulting solid residue was dissolved in a tetrahydrofuran:methanol 1:1 mixture (15 ml) and added with concentrated HCl (0.5 ml). The mixture was refluxed under stirring for 1.5 h, then the solvents were evaporated off under reduced pressure. The resulting crude was suspended in water and the insoluble solid was recovered by filtration, washed repeatedly with water and dried under vacuum on phosphorous pentoxyde, thereby obtaining 527 mg of the title compound (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][CH:13]1[CH2:19][C:18](=[O:20])[O:17][C:15](=[O:16])[CH2:14]1>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:18](=[O:20])[CH2:19][CH:13]([CH3:12])[CH2:14][C:15]([OH:17])=[O:16])=[CH:3][C:4]=1[O:10][CH3:11])#[N:7]
Reactant: COc1cc(N)ccc1C#N
Reactant: CC1CC(=O)OC(=O)C1
Solvent: C1CCOC1
Product: COc1cc(NC(=O)CC(C)CC(=O)O)ccc1C#N
Yield: 108.2 %

Procedure:
A solution of the compound obtained in Step 1 (670 mg, 4.52 mmol) and 3-methylglutaric anhydride (579 mg, 4.52 mmol) in THF (20 mL) was heated with reflux for 14 hr. The reaction solution was concentrated under reduced pressure to give 5-((4-cyano-3-methoxyphenyl)amino)-3-methyl-5-oxopentanoic acid (1.35 g, 4.89 mmol, quantitative) as a brownish-red oil.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:23]=[C:22]([NH:24][C:25](NC2C=C(C)N=C(C)C=2)=[O:26])[CH:21]=[C:20]([CH3:36])[N:19]=1>O1CCOCC1>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C:25]([NH:24][C:22]2[CH:23]=[C:18]([CH3:17])[N:19]=[C:20]([CH3:36])[CH:21]=2)=[O:26])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCC(Cc2ccccc2)CC1
Reactant: Cc1cc(NC(=O)Nc2cc(C)nc(C)c2)cc(C)n1
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)NCCN2CCC(Cc3ccccc3)CC2)cc(C)n1

Procedure:
A suspension of 2-(4-benzylpiperidino)-1-ethanamine (Example B1, 54.6 mg, 0.25 mmol), TEA (35 μL, 0.25 mmol) and 1,3-bis-(2,6-dimethyl-pyridin-4-yl)-urea (Example B1, 67.6 mg 0.25 mmol) in dioxane (2 mL) is heated at reflux for 24 h. The solvent is evaporated and the residue purified by HPLC to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]1COCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Reactant: C1CCOC1
Product: C=C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
(S)-3-formylpyrrolidine-1 -carboxylic acid t-butyl ester (3.0 g, 15.0 mmol, 1.0 eq.) in THF (10 mL) was slowly added and the mixture was stirred at −78° C. for 2 hours. The mixture was warmed to room temperature over 3 hours and the reaction was quenched with half saturated NH4Cl (50mL). The organic layer was washed with saturated aqueous NaCl (50 mL). The organic layer was collected, dried over MgSO4, filtered, and concentrated. The resulting oil was slurried in hexanes (50 mL) and the precipitate was filtered off The filtrate was concentrated, diluted with hexanes (25 mL), and chilled at −20° C. overnight. The precipitate was filtered off and the filtrate was purified by column chromatography (0-100% EtOAc in hexanes) to yield (R)-3-vinylpyrrolidine-1-carboxylic acid t-butyl ester as an oil (2.1 g).
Reaction SMILES: [I-].[OH:2][CH2:3][CH:4]1[CH:9]2[C:10]3[C:15]([CH2:16][CH2:17][N:8]2[CH2:7][O:6][CH:5]1SC)=[CH:14][C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=3.C(O)C.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[OH:2][CH2:3][CH:4]1[CH:9]2[C:10]3[C:15]([CH2:16][CH2:17][N:8]2[CH:7]([CH:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[NH:27])[O:6][CH2:5]1)=[CH:14][C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=3
Reactant: Nc1ccccc1
Reactant: COc1cc2c(cc1OC)C1C(CO)C(SC)OCN1CC2
Agent: [I-]
Solvent: CCO
Product: COc1cc2c(cc1OC)C1C(CO)COC(C3C=CC=CC3=N)N1CC2
Reaction time: 3 h

Procedure:
To a solution of 4.51 g (0.01 mole) of 1-(hydroxymethyl)-2-(methylthio)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1,3]oxazino[4,3-a]isoquinoline iodide in ethanol 9.3 g (0.10 mole) of aniline are added, and the reaction mixture is boiled for 3 hours. Upon cooling the product separates from the mixture in crystalline form.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:10][S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18])(=[O:13])=[O:12].N1C=CC=CC=1>O1CCCC1>[C:1]([O:6][CH2:7][CH2:8][O:9][C:17]([C:16]1[CH:15]=[C:14]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:22]=[CH:21][CH:20]=1)=[O:18])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Yield: 84.1 %

Procedure:
With stirring, a solution of 13 g (0.1 mole) of 2-hydroxyethyl methacrylate in 80 ml of tetrahydrofuran is slowly added dropwise at 0° C. to a solution of 23.9 g (0.1 mole) of 3-chlorosulfonylbenzoyl chloride and 7.9 g (0.1 mole) of pyridine in 150 ml of tetrahydrofuran. The reaction mixture is subsequently stirred for 15 hours at room temperature. The precipitated pyridine salt is removed by filtration, and the filtrate is concentrated by evaporation in vacuo. The oily residue is dried under high vacuum, affording 28 g of viscous product.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[C:11]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][C:21]3[C:22]4[C:27]([CH:18]=[CH:19][C:20]=3[CH:9]=[CH:8]2)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C#CC(O)(c1ccccc1)c1ccccc1
Reactant: Oc1cccc2ccccc12
Product: C1=CC(c2ccccc2)(c2ccccc2)Oc2c1ccc1ccccc21

Procedure:
The procedure of Step 2 of Example 1 was followed except that 1,1-diphenyl-2-propyn-1-ol was used in place of 1,1-bis(4-methoxyphenyl)-2-propyn-1-ol and 1-hydroxynaphthalene was used in place of methyl-1,4-dihydroxy-2-naphthoate to produce 2,2-diphenyl-[2H]-naphtho[1,2-b]pyran.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.Cl.Cl.[CH3:15][N:16]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:21][C@@H:18]2[CH2:19][CH2:20][N:16]([CH3:15])[CH2:17]2)=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Reactant: CN1CC[C@@H](N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC[C@@H](NC(=O)c2cc(F)c(N)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-amino-2,5-difluoro-benzoic acid (Rare Chemicals GmbH; 450 mg, 2.6 mmol), (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 473 mg, 2.73 mmol), HATU (1.08 g 2.86 mmol) and DIPEA (2.25 mL, 13 mmol) were combined in DMF (10 mL) and stirred at room temperature for 4 hours. The solvent was evaporated and the residue dissolved in MeOH and added to an SCX-2 column (20 g), pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were combined and evaporated and the resultant material dissolved in DCM and purified on a silica column eluting with 5% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to a yellow gum. Diethylether was added and re-evaporated and dried under high vacuum to yield the title compound as a yellow gum, which slowly crystallised to a cream solid (550 mg, 83%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:9][CH3:10])[NH:5][C:6]=1[CH2:7][OH:8]>C(Cl)Cl.O1CCOCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:3]=[C:4]([CH2:9][CH3:10])[NH:5][C:6]=1[CH:7]=[O:8]
Reactant: CCc1nc(Cl)c(CO)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1nc(Cl)c(C=O)[nH]1
Temperature: 25 °C
Yield: 0 %

Procedure:
A solution of (4-chloro-2-ethyl-1H-imidazol-5-yl)methanol (1.60 g, 10.0 mmol) and manganese dioxide (5.5 g, 63.3 mmol) in CH2Cl2 (30 mL) and 1,4-dioxane (15 mL) was heated under reflux for 6.5 h. The reaction mixture was cooled to RT, then filtered through Celite, which was washed thoroughly with CH2Cl2. The filtrate was concentrated and dried to provide the title compound (0.763 mg, 48%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.66 (s, 1H), 2.84 (q, 2H), 1.38 (t, 3 H).
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]2[C:13]([NH2:30])=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=2)=[CH:8][CH:7]=1.[CH3:33][C:34]1([CH3:47])[C@@H:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C@@H:35]1[C:42](OCC)=O>C(Cl)Cl>[Br:5][C:6]1[CH:32]=[CH:31][C:9]([CH2:10][N:11]2[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:14][C:13]=3[N:30]=[C:42]2[C@H:35]2[C@H:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]2([CH3:33])[CH3:47])=[CH:8][CH:7]=1
Reactant: CCOC(=O)[C@H]1[C@H](C(=O)OCC)C1(C)C
Reactant: Nc1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(Br)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)C1(C)C
Temperature: 90 °C
Reaction time: 12 h

Procedure:
A solution of trimethyl aluminum (0.2 mL, 2 M in toluene) was added to 25 mL round-bottomed flask containing N1-(4-bromobenzyl)-4-(quinolin-2-ylmethoxy)benzene-1,2-diamine (100 mg, 0.23 mmol), trans-diethyl 3,3-dimethylcyclopropane-1,2-dicarboxylate (49 mg, 0.23 mmol), and DCM (4 mL). After 12 h, the solution was partitioned between sat. NaHCO3 (30 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combine organic layers were dried with sodium sulfate, filtered, and concentrated to dryness. To the residue was added ethanol (2 mL) and concentrated HCl (0.1 mL, 12 N). The solution heated to 90° C. After 5 h, the mixture was cooled, concentrated to dryness, and purified by reverse phase HPLC to afford the title compound. MS (ESI): mass calcd. for C32H30BrN3O3, 583.15; m/z found, 584.1 [M+H]+.