Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CC=CC=1CCC(O)=O.CC1C=CC=CC=1CCC(Cl)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1.[CH3:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[CH2:58][CH2:59][C:60]([N:62]=[C:63]=[S:64])=[O:61]>C1(C)C=CC=CC=1.C(O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH:48][C:63]([NH:62][C:60](=[O:61])[CH2:59][CH2:58][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[CH3:51])=[S:64])=[CH:46][CH:45]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccccc1CCC(=O)N=C=S
Agent: Cc1ccccc1CCC(=O)Cl
Agent: Cc1ccccc1CCC(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)CCc4ccccc4C)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-(2-methylphenyl)propanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-(2-methylphenyl)propanoyl isothiocyanate was prepared using the resultant 3-(2-methylphenyl)propanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(2-methylphenyl)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (48 mg, yield 57%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[O:43]1[CH2:48][CH2:47][N:46]([CH:49]([CH3:52])[CH2:50]O)[CH2:45][CH2:44]1>>[ClH:1].[N:46]1([CH:49]([CH3:52])[CH2:50][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:47][CH2:48][O:43][CH2:44][CH2:45]1
Reactant: CC(CO)N1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OCC(C)N2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: Cl

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-morpholinopropan-1-ol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-morpholin-4-yl-propyl ester, hydrochloride. MS (ES+) m/z calcd. for C38H43Cl2F2N4O5: [(M+H)+]: 744. found: 744.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18]Cl)[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:17]=1
Reactant: Nc1nc(CCl)cs1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(CSc2ccc([N+](=O)[O-])cc2)cs1
Yield: 99.4 %

Procedure:
A mixture of 4-nitrothiophenol (9.3 g), 2-amino-4-chloromethylthiazole hydrochloride (11 g) and potassium carbonate (20 g) in N,N-dimethylformamide (200 ml) was heated at 85°-90° C. for 5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-4-(4-nitrophenylthiomethyl)thiazole (15.80 g, yield: 98.6%).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.N12CCCN=C1CCCCC2.[CH3:22][C:23]1[O:24][CH2:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1>ClCCl.[Cu](Br)Br>[CH3:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1
Reactant: COC(=O)C1COC(C)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.2 %

Procedure:
Hexamethylenetetramine (11.7 g, 5.00 mmol) and 1,8-diazabicyclo(5,4,0)undec-7-ene were added to a stirred suspension of copper bromide (18.7 g, 83.85 mmol) in dichloromethane (50 mL) at 0° C. and purged with argon gas for 20 min. To the mixture was added methyl 2-methyl-4,5-dihydrooxazole-4-carboxylate (3 g, 20.97 mmol) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for a further 12 h. The solvent was removed in vacuo and the resulting residue partitioned between ethyl acetate and 1:1 saturated aqueous ammonium chloride and ammonium hydroxide. The organic layer was separated and the aqueous layer extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with 1:1 saturated aqueous ammonium chloride and ammonium hydroxide, 10% aqueous citric acid, saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford methyl 2-methyloxazol-4-carboxylate (1.1 g, 34%) as a solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.[Cl:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][CH:20]=[C:19]2[C:23]1[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][CH:20]=[C:19]2[C:23]1[CH2:24][CH2:25][N:26]([C:10]([CH:2]2[CH2:1][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3]2)=[O:12])[CH2:27][CH:28]=1
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: Clc1cccc2c(C3=CCNCC3)c[nH]c12
Product: O=C(C1Cc2ccccc2C1)N1CC=C(c2c[nH]c3c(Cl)cccc23)CC1

Procedure:
Prepared from 9a and 7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H](C2C=CC=CC=2)C)[C@@H:10]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:24]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[OH-].[Pd+2].[OH-].CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:24]2)[C@H:11]([NH2:13])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](CN2CCC[C@@H](Cc3ccc(F)cc3)C2)[C@H](N)C1
Reaction time: 20 h
Yield: 95.3 %

Procedure:
(3S, 4S)-3-[(S)-3-(4-Fluorobenzyl)-piperidin-1-ylmethyl]-4-[(R)-1-phenyl-ethylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.201 mmol), palladium hydroxide (20 weight % on carbon, dry basis; 40 mg) and methanol (7 mL) were combined in a pressure bottle and shaken under hydrogen atmosphere (50-55 psig) for 20 h . The mixture was filtered through Celite, and the solids were rinsed with ethanol. The filtrate was concentrated to give the product as a glassy foam (75 mg, 95%), used without further purification. 1H NMR (300 mHz, CD3OD) δ7.20 (m, 2H), 6.98 (m, 2H), 3.18-2.42 (15H), 1.80-1.50 (4H), 1.41 (s, 9H); mass spec. (ES+) m/z 392.4.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[N+:13]([O-])([OH:15])=[O:14].C(O)(=O)C>C(OC(=O)C)(=O)C>[OH:1][C:2]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2c(O)cccc2N1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1CCc2c(ccc([N+](=O)[O-])c2O)N1
Temperature: 5 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
In 110 ml of acetic anhydride was dissovled 25 g of 5-hydroxy-3,4-dihydrocarbostyril, and to the solution was added dropwise a mixture of 12 g of fuming nitric acid and 75 ml of acetic acid at 5° C. After stirring at 5° C. for 2 hours, 20 g of ice was added to the reaction mixture, and the precipitated crystals were collected. The crystals were suspended in a 3N sodium hydroxide aqueous solution, followed by filtration. The filtrate was neutralized with hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 22 g of the named compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:17]=2)[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:38][CH2:39][S:40][CH3:41])[C:34]([O:36][CH3:37])=[O:35].Cl.COC(=O)[C@H](CCSC)N.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:18]2[CH:17]=[C:16]([NH:15][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[CH:24]=[CH:23][C:19]=2[C:20]([NH:32][C@@H:33]([CH2:38][CH2:39][S:40][CH3:41])[C:34]([O:36][CH3:37])=[O:35])=[O:22])=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(NC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A mixture of 4-{1-(4-fluorophenyl)-2-(imidazol-1-yl)ethylamino]-2-(4-fluorophenyl)benzoic acid (1.67 g; 4 mmol), methyl (2S)-2-amino-4-(methylsulfanyl)butanoate, (L-methionine methyl ester hydrochloride) (0.96 g; 4.8 mmol), HOBT (0.65 g; 4.8 mmol), EDC (0.925 g; 4.8 mmol) and DMAP (0.54 g; 4.4 mmol) in dichloromethane (100 ml) was stirred at ambient temperature for 5 hours. The solution was diluted with dichloromethane (200 ml), washed with 5% aqueous sodium hydrogen carbonate solution and evaporated to dryness. The residue was purified by flash chromatography eluting with dichloromethane/ethanol 95/5 to give the title compound as a solid (1.8 g; 80%).
Reaction SMILES: [Li+].[N:2]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:15]2[CH:31]=[CH:30][C:18]([O:19][CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([C:25]([C:24]2[CH:28]=[CH:29][C:21]([CH2:20][O:19][C:18]3[CH:17]=[CH:16][C:15]([C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[CH2:7][N:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)=[O:14])=[CH:31][CH:30]=3)=[CH:22][CH:23]=2)=[O:26])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNCC1
Reactant: O=C([O-])c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1
Agent: [Li+]
Product: O=C(c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1)N1CCCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure D from 4-[4-(2-(S)-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenoxymethyl]-benzoic acid lithium salt and piperidine. MS (ES+) 476.2
Reaction SMILES: CN(C)C1C=CC=CC=1.[NH2:10][C:11]1[C:12]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[N:13][C:14]([CH3:23])=[CH:15][C:16]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20].[Br:30][CH2:31][C:32](Br)=[O:33]>ClCCl.O>[Br:30][CH2:31][C:32]([NH:10][C:11]1[C:12]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[N:13][C:14]([CH3:23])=[CH:15][C:16]=1[O:17][CH2:18][C:19]([F:21])([F:22])[F:20])=[O:33]
Reactant: Cc1cc(OCC(F)(F)F)c(N)c(OCC(F)(F)F)n1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: O
Solvent: CN(C)c1ccccc1
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CBr)c(OCC(F)(F)F)n1
Yield: 85 %

Procedure:
N,N-Dimethylaniline (20.46 g, 168.8 mmol) was added to a solution of 3-amino-2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridine (42.29 g, 139.0 mmol) in dichloromethane (600 mL). While the mixture was stirred under cooling with ice, a solution of bromoacetyl bromide (28.73 g, 142.3 mmol) in dichloromethane (100 mL) was added thereto, followed by stirring for ten minutes. The reaction mixture was diluted with water and then extracted with chloroform. The organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate, followed by concentration under reduced pressure. The thus-obtained crystals were recrystallized from chloroform-hexane, to thereby yield 2-bromo-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (50.25 g, yield 85%) as colorless needles.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=1[O:34][CH3:35].O.Cl>CCO>[Br:1][C:2]1[C:3]([N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=2[O:34][CH3:35])=[N:6][CH:7]=1
Reactant: CNC(=O)C(C)(C)CN(c1nc(Cl)ncc1Br)C1CCCC1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNC(=O)C(C)(C)CN(c1nc(Nc2ccc(C(=O)OC)cc2OC)ncc1Br)C1CCCC1
Temperature: 90 °C
Yield: 23 %

Procedure:
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-N,2,2-trimethyl-propanamide (266 mg, 0.6825 mmol) and methyl 4-amino-3-methoxy-benzoate (185.5 mg, 1.024 mmol) were dissolved in EtOH (2 mL) and Water (8 mL) and treated with HCl (134.5 μL of 37% w/v, 1.365 mmol). Heat at 90° C. overnight. Cool to ambient temperature and remove solvent in vacuo. The reaction mixture was diluted with EtOAc/NaHCO3 and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filter and concentrated. The crude residue was purified by column chromatography (0 to 100% EtOAc/Petrol) to give the sub-title compound as a beige oil (84 mg, 23%); NMR (400.0 MHz, DMSO) d 0.97 (s, 6H), 1.44-1.69 (m, 8H), 2.45 (d; J=4.4 Hz, 3H), 3.58 (br s, 2H), 3.84 (s, 3H), 3.96 (s, 3H), 4.11 (quin, 1H), 7.32-7.34 (m, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.61 (d, 1H), 8.07 (s, 1H), 8.38 (s, 1H) and 8.43 (d, J=8.5 Hz, 1H); MS ES(+) 536.0, ES (−) 534.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:17])[CH3:16].Cl.CCN(CC)CC>CC#N.C(Cl)Cl>[CH2:15]([NH:17][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13])[CH3:16]
Reactant: CC(C)c1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Reactant: CCN
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNc1cc(C(C)C)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 4-chloro-6-isopropyl-3-nitro-1H-pyridin-2-one (Example 28, step 6) (500 mg, 2.31 mmol) in CH3CN at room temperature is added EtNH2.HCl (565 mg, 6.92 mmol) followed by Et3N (1.29 mL, 9.23 mmol). The reaction mixture is then stirred in a sealed tube at 100° C. for 1.5 h. After cooling, the reaction mixture is diluted with CH2Cl2 and washed with H2O (2×25 mL). The aqueous washes are reextracted once with CH2Cl2, and the combined extracts are dried over Na2SO4 and concentrated to provide 4-ethylamino-6-isopropyl-3-nitro-1H-pyridin-2-one as a yellow-orange solid. The material is sufficiently pure to be used without further purification. 1H NMR (DMSO-d6, 400 MHz) δ 11.1 (br, 1H), 8.93 (m, 1H), 5.73 (s, 1H), 3.37 (dq, J=7.4, 6.8 Hz, 2H), 2.67 (sept, J=6.8 Hz, 1H), 1.17 (t, J=7.4 Hz, 3H), 1.15 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:8])([O-:3])=[O:2].[CH3:20]C(C)([O-])C.[K+].IC.C(=O)(O)[O-].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[C:7]([N:9]([CH3:20])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(NCc1cccnc1)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(Cc1cccnc1)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 85.3 %

Procedure:
To a stirred solution of 3-nitro-N-(3-pyridylmethyl)benzamide (2.00 g) in tetrahydrofuran (40 ml) was added potassium tert-butoxide (917 mg) in one portion in an ice-cooled bath. The stirring was continued for 40 minutes and then iodomethane (0.53 ml) was added thereto. The reaction mixture was stirred at 0° C. for one hour, then at ambient temperature for five hours. Saturated sodium bicarbonate solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution. After dried over anhydrous magnesium sulfate and filtered, the solvent was removed in vacuo and the residue was purified by flash chromatography (methanol-chloroform 3%, V/V) to afford 3-nitro-N-methyl-N-(3-pyridylmethyl)benzamide (1.8 g) as an yellow oil.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][CH:22]([CH3:25])[CH2:23][SH:24].Cl>CN(C)C=O>[CH2:23]([S:24][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH:22]([CH3:25])[CH3:21]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CC(C)CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CSc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14(b)) in 6 ml N,N-dimethylformamide were added 13.8 mol cesium carbonate and 9.97 mmol 2-methyl-1-propanethiol and the mixture was stirred at 90° C. for 30 min. The reaction mixture was then cooled to room temperature and acidified to pH1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid which was used in the next step without further purification (yield 99%). MS (m/e): 287.0 ([M−H]−, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2F)[N:3]=1.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CN(C)C=O>[CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: Cc1ncc2c(F)cccc2n1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ncc2c(N3CCNCC3)cccc2n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a stirred solution of 2-methyl-5-fluoro-quinazoline (WO02003068772, Chem. Abstr. 139:197493, 2 g; 12.3 mmol) in dry dimethylformamide (10 mL) were added triethylamine (3.4 mL; 2 eq) and piperazine (11 g; 10 eq). The reaction mixture was stirred under nitrogen at 120° C. for 4 h, then cooled to room temperature, poured into water (10 mL) and extracted with ethyl acetate (5×15 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by ion-exchange chromatography [SCX-2; MeOH -1M NH3/MeOH (1:0)→(0:1)] to afford the title compound as a yellow solid (1.8 g; yield 64%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.[OH:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH:25]([N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[C:24]1=[O:41]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11].[OH:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH:25]([N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[C:24]1=[O:41]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoate (100 mg) was dissolved in 25% TFA/DCM (10 mL) and stirred on a magnetic strirrer at room temperature. The mixture was allowed to react for 4 hrs. DCM and most of TFA were removed by rotary evaporation in vacuo. The foam obtained was dissolved in DCM (50 mL). The mixture washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and filtered. 52 mg of a solid was obtained after drying in vacuo. 1H NMR (CDCl3, ppm) δ 7.80-7.90 (m, 2H), 7.70-7.80 (m, 2H), 7.10-7.35 (m, 5H), 4.95-5.12 (m, 1H), 4.35-4.45 (m, 1H), 4.15-4.25 (m, 2H), 4.00-4.15 (m, 1H), 3.65-3.72 (m, 1H), 2.95-3.10 (m, 2H), 2.75-2.90 (m, 3H), 2.12-2.20 (m, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]([C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32])[C@@H:15]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[CH2:16][C:17](OC(C)(C)C)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]([C@H:31]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH3:32])[C@@H:15]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[CH2:16][CH2:17][OH:18])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc([C@@H](CC(=O)OC(C)(C)C)N(Cc2ccccc2)[C@@H](C)c2ccccc2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc([C@@H](CCO)N(Cc2ccccc2)[C@@H](C)c2ccccc2)cn1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a solution of LiAlH4 (1.24 g, 32.79 mmol) in THF (80 mL) at 0° C., was added dropwise a solution of (R)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-3-(6-methylpyridin-3-yl)propanoate (4.7 g, 10.93 mmol) in THF and was heated to 75° C. After 4 h, the reaction mixture was quenched with EtOAc and filtered. The filtrate was washed with excess EtOAc and dried under high vacuum to afford a residue. Purification of the residue by column chromatography (neutral Al2O3, Et2O/Pet ether 15:85) afforded the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[C:13]2[NH:14][C:15]3[CH:25]=[N:24][CH:23]=[CH:22][C:16]=3/[C:17](=[N:20]/[OH:21])/[C:18](=O)[C:12]=2[CH:11]=[CH:10][CH:9]=1.[Cl:26][C:27]1[CH:34]=[C:33]([CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH:32]=[C:31]([Cl:47])[C:28]=1[CH:29]=O.C([O-])(=O)C.[NH4+:52]>C(O)(=O)C>[Cl:26][C:27]1[CH:34]=[C:33]([CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH:32]=[C:31]([Cl:47])[C:28]=1[C:29]1[N:20]([OH:21])[C:17]2[C:16]3[CH:22]=[CH:23][N:24]=[CH:25][C:15]=3[NH:14][C:13]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:18]=2[N:52]=1
Reactant: [NH4+]
Reactant: CC(C)[Si](OCc1cc(Cl)c(C=O)c(Cl)c1)(C(C)C)C(C)C
Reactant: O=c1/c(=N\O)c2ccncc2[nH]c2ncccc12
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[Si](OCc1cc(Cl)c(-c2nc3c(n2O)-c2ccncc2Nc2ncccc2-3)c(Cl)c1)(C(C)C)C(C)C
Temperature: 130 °C
Yield: 97.4 %

Procedure:
A solution of (6Z)-5H-dipyrido[2,3-b:4′,3′-f]azepine-5,6(11H)-dione 6-oxime trifluoroacetate (1.0 g, 2.82 mmol), 2,6-dichloro-4-[(triisopropylsilyl)oxy]methylbenzaldehyde (2.04 g, 5.64 mmol) and ammonium acetate (3.3 g, 42 mmol) was stirred in acetic acid (30 mL) and heated in a microwave for 5 minutes at 130° C. Evaporation gave the crude product (1.6 g, 100%) which was used without further purification in the next step. LC/MS: 582 (M+H)+.