Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][CH2:6][NH:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:29][CH2:30][C:31](Cl)=[O:32]>O>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][CH2:6][N:7]([CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)[C:31](=[O:32])[CH2:30][Br:29])[CH3:2]
Reactant: O=C(Cl)CBr
Reactant: CCOC(CCNCC1OCCO1)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(CCN(CC1OCCO1)C(=O)CBr)OCC

Procedure:
N-(3,3-Diethoxypropyl)-N-(1,3-dioxolan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and bromoacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(1,3-dioxolan-2-ylmethyl)-α-bromoacetamide as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[O:9][CH:10]([CH:11]=[CH:12]2)[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]3[C:19]([O:21][CH3:22])=[O:20])=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ccco2)cc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C(=O)OC)C2(c3ccc(Cl)cc3)C=CC1O2
Reaction time: 8 h

Procedure:
A mixture of 2-(4-chlorophenyl)furan (prepared according to A.W. Johnson, J. of Chem. Soc. 1946, p 895-99) (0.105 g), and dimethyl acetylenedicarboxylate (0.07 mL) in distilled water (0.25 mL) was placed in a closed vial and subjected to ultrasonic vibration overnight. The reaction temperature at the end of the reaction was between 40 and 50° C. After cooling the Diels-Alder adduct was isolated by extraction with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and evaporated to dryness in-vacuo to provide almost pure product which was further purified by chromatography on silica gel using 5-10% acetone in n-hexane. The title compound (0.16 g) m.p. 84° C. was isolated from some of the combined fractions: PMR δH (CDCl3): 3.7(s,3H), 3.84 (s, 3H), 5.76 (d, 1H, J=1.2Hz), 7.58-7.29 (m, 5H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[C:13]=2[F:20])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:21]([C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32]I)[CH2:28][CH2:27]1)[CH2:22][CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:32][C@H:29]3[CH2:30][CH2:31][C@H:26]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28]3)=[C:14]([F:19])[C:13]=2[F:20])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](CI)CC1
Reactant: CCCCCc1ccc(-c2ccc(O)c(F)c2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCc1ccc(-c2ccc(OC[C@H]3CC[C@H](CCCCC)CC3)c(F)c2F)cc1

Procedure:
0.1 mol of 4'-n-pentyl-2,3-difluorobiphenyl-4-ol and 0.1 mol of trans-4-n-pentylcyclohexylmethyl iodide and heated in the presence of 0.12 mol of anhydrous K2CO3 in dimethylformamide (DMF) until the mixture boils gently. When the reaction has ended, the mixture is worked up in the customary manner and the product is purified by chromatography and crystallization. Trans-4-n-pentylcyclohexylmethyl 4'-pentyl-2,3-difluorobiphenyl-4-yl ether is obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][O:9][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: CC(C)(CO)CCCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CCCCCBr)COC1CCCCO1
Yield: 46.5 %

Procedure:
According to the method described for the synthesis of 207d, 206g (36.0 g, 161 mmol) was treated with 3,4-dihydro-2H-pyran (18.5 g, 220 mmol) and p-toluenesulfonic acid hydrate (0.28 g, 1.5 mmol) in CH2Cl2 (60 mL). After filtration through neutral aluminum oxide (200 g) and concentration, the crude product was purified by column chromatography (silica gel; hexanes/ethyl acetate=50/1), affording 207g (23.0 g, 46%) as an oil. 1H NMR (CDCl3): δ 4.54 (t, 1H, J=3.0), 3.84 (m, 1H), 3.51-3.39 (m, 4H), 2.98 (d, 1H, J=9.3), 1.89-1.80 (m, 3H), 1.70-1.40 (m, 7H), 1.29-1.22 (m, 4H), 0.89 (s, 6H). 13C NMR (CDCl3): δ 99.3, 76.6, 62.1, 39.3, 34.3, 34.2, 33.0, 30.8, 29.2, 25.7, 24.7, 23.2, 19.6. HRMS (LSIMS, gly): Calcd for C14H28BrO2 (MH+): 307.1272, found: 307.1245.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[CH3:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][N:19]=1.NC1C(C(O)=O)=NC(C2C=CC(F)=CC=2)=C(C(F)(F)F)C=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:21]2[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=2)[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][C:10]=1[NH2:11])=[O:4]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: Nc1cc(C(F)(F)F)c(-c2ccc(F)cc2)nc1C(=O)O
Product: COC(=O)c1nc(-c2ccc(C)nc2)c(C(F)(F)F)cc1N

Procedure:
This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) and 2-methylpyridine-5-boronic acid analogously to 3-amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate G); LC-MS Rt 0.96 min [M+H]+ 312 (Method 2minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 8.41 (1H, s), 7.79 (1H, s), 7.69 (1H, dd), 7.32 (1H, d), 7.10 (2H, s), 3.82 (3H, s), 2.52 (3H, s).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:3]=1.C([O-])(=[O:25])C.[Cs+]>CN(C=O)C>[OH:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:3]=1
Reactant: C[C@@H](COc1cc(Cl)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc(O)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A mixture of tert-butyl ((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)carbamate (4.83 g), cesium acetate (6.99 g) and DMF (40 mL) was stirred at 80° C. for 1 hr. The mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.84 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[N:16][NH2:17])[CH2:11]1)=[O:9].C(N(CC)CC)C.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]2[C:30]([C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)=[N:17][N:16]=[C:12]2[CH2:11]1)=[O:9]
Reactant: NN=C1CN(C(=O)c2ccccc2Cl)CCN1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)N1CCn2c(nnc2-c2ccco2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-[(2-chlorophenyl)carbonyl]-2-piperazinone hydrazone (140) (715 mg, 2.83 mmol) and triethylamine (0.986 mL, 7.08 mmol) were dissolved in Dichloromethane (DCM) (10 mL). 2-furancarbonyl chloride (0.306 mL, 3.11 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Acros) was added and the solution stirred at 25° C. for 4 hr. Solvents were removed in vacuo and the residue was dissolved in n-butanol (10.00 mL). The solution was heated at reflux for 4 hours and the solvents were removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was extracted with ethyl acetate (3×25 mL), the combined extracts were washed with water (3×50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated to a crude solid in 925 mg. The product was purified by flash chromatography (Isolera, 100 g, 0-100% Methanol:Dichloromethane (1:9)/Dichloromethane) to afford product in 260 mg. This was further purified by MDAP to afford product in 85 mg.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C:8]([C:11](=[O:31])[NH:12][C:13]1[S:14][C:15]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:17]=1)([CH3:10])[CH3:9])(C)(C)C.Cl.CCO[C:37]([CH3:39])=O>>[CH:37]1([CH2:39][C:6]([NH:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C:13]2[S:14][C:15]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:17]=2)=[O:31])=[O:5])[CH2:19][CH2:18][CH2:16][CH2:15]1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1
Agent: Cl
Product: CC(C)(NC(=O)CC1CCCC1)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1

Procedure:
{1-[4-(4-Fluoro-phenyl)-5-morpholin-4-yl-thiazol-2-ylcarbamoyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester was stirred overnight in freshly prepared HCl (g)/EtOAc solution. Evaporation to dryness afforded the desired product as the hydrochloride salt. 1H NMR (400 MHz, DMSO-D6) 1.63 (s, 6H) 2.81-2.89 (m, 4H) 3.70-3.78 (m, 4H) 7.23-7.29 (m, 2H) 8.10-8.16 (m, 2H) 8.62 (s, 3H) 12.46 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]([CH:21]([CH2:27][CH2:28][CH2:29]Cl)[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ClC1C=CC=CC=1>O>[C:14]1([C:13]2[N:1]([CH2:2][CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[NH:6][CH:5]=3)[CH2:29][CH2:28][CH2:27][C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(CCCCl)C(=O)c1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: Clc1ccccc1
Solvent: O
Product: CCOC(=O)C1=C(c2ccccc2)N(CCc2c[nH]c3ccccc23)CCC1

Procedure:
0.273 g. (0.0017 mole) of tryptamine are added to a solution of 0.229 g. (0.00085 mole) of (±)-ethyl 2-benzoyl-5-chloro-valerate prepared according to Example 29 in 5 ml. of chlorobenzene, and the reaction mixture is heated on an oil bath of 150° C. for 5 hours, with stirring, while the water formed is allowed to distill off slowly together with chlorobenzene. After cooling the precipitate is filtered off, washed with chlorobenzene, and the combined chlorobenzene solution is evaporated from a bath of 40° C. on a rotating evaporator. The title compound is obtained by subjecting the residue to column chromatography on 40 g. of silica gel (Geduran Si 60, 0.063-0.200 mm.) using toluene containing 10% of diethyl amine as an eluting agent.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[CH3:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1>>[CH3:16][N:15]([CH3:17])[C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:6]2[CH:19]=[CH:20][C:21]3[NH:22][C:31]([C:30]4[CH:33]=[CH:34][C:27]([N:26]([CH3:35])[CH3:25])=[CH:28][CH:29]=4)=[N:1][C:4]=3[CH:5]=2)=[O:18])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc(N(C)C)cc4)nc3c2)cc1

Procedure:
Compound 206 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and 4-dimethylaminobenzaldehyde. 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.39 (s, 1H), 8.11 (d, J=8 Hz, 2H), 7.90 (d, J=9 Hz, 2H), 7.81 (d, J=9 Hz, 2H), 7.68 (d, J=9 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 6.78 (d, J=9 Hz, 2H), 3.07 (s, 6H), 2.99 (s, 6H).
Reaction SMILES: C1C=C(C2SC(C3SC=CC=3)=CC=2)SC=1.ClS([N:20]=[C:21]=O)(=O)=O.[C:23]([C:25]1[S:29][C:28]([C:30]2[S:31][C:32]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)=[CH:33][CH:34]=2)=[CH:27][CH:26]=1)#[N:24]>C(Cl)Cl>[C:23]([C:25]1[S:29][C:28]([C:30]2[S:31][C:32]([C:35]3[S:36][C:37]([C:21]#[N:20])=[CH:38][CH:39]=3)=[CH:33][CH:34]=2)=[CH:27][CH:26]=1)#[N:24]
Reactant: N#Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Reactant: O=C=NS(=O)(=O)Cl
Agent: c1csc(-c2ccc(-c3cccs3)s2)c1
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(-c3ccc(C#N)s3)s2)s1

Procedure:
α-Terthienyl (2.46 g, 0.01 m) was treated with two equivalents of chlorosulfonyl isocyanate (0.02 m) in methylene chloride as described in the preparation of 5-cyano-2,2':5',2"-terthienyl. Work-up as in that procedure gave crude product (2.4 g), m.p. 165°-170° C., contracting around 140° C. m/z 298(m+);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[F:55][C:56]([F:67])([F:66])[O:57][C:58]1[CH:59]=[C:60]([NH2:65])[C:61]([NH2:64])=[CH:62][CH:63]=1.CN(C)C=O>>[NH2:65][C:60]1[CH:59]=[C:58]([O:57][C:56]([F:55])([F:66])[F:67])[CH:63]=[CH:62][C:61]=1[NH:64][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH:37]([CH3:39])[CH3:38])[CH2:31]1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(OC(F)(F)F)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N,N′,N-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.19 g, 3.14 mmol) added to a solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoic acid (1.3 g, 2.1 mmol) and N,N-Diisopropylethylamine (1.20 mL, 6.90 mmol) and 4-(trifluoromethoxy)benzene-1,2-diamine (0.482 g, 2.51 mmol) in N,N-Dimethylformamide (13.0 mL, 167 mmol). The reaction was stirred overnight at RT and was partially concentrated to ca. 2 mls and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4 filtered and concentrated. The residue was purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to the desired amide (1.4 g) as a solid.
Reaction SMILES: [CH:1]1([C:7]2([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:40])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[CH:17]1([C:7]2([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:11]3[CH2:12][N:13]([C:32]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:40])[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C1OC(C2CCCCC2)(C2CCCCC2)C2CNCCN12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)N1CCN2C(=O)OC(C3CCCCC3)(C3CCCCC3)C2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.1 %

Procedure:
To a solution of 1,1-dicyclohexyl-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.13 g, 0.42 mmol) in tetrahydrofuran (1 mL) were sequentially added diisopropylethylamine (0.5 mL) and phenyl chlorocarbonate (0.10 g, 0.64 mmol), and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=7:3), crystallized from diisopropyl ether and dried to obtain the title compound (88 mg, yield 49%).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.[NH2:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15].C(=O)=O.CC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:8]=[C:7]1[NH:9][C:2]([C:1]([NH:12][CH:13]([CH:14]([CH3:16])[CH3:15])[C:17]([OH:19])=[O:18])=[O:10])=[CH:3][C:4](=[O:5])[NH:6]1
Reactant: O=C(Cl)c1cc(=O)[nH]c(=O)[nH]1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)C(NC(=O)c1cc(=O)[nH]c(=O)[nH]1)C(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the orotoyl chloride solution, 6.56 g (56 mmol) of Valine is suspended, with stirring, in 50 mL of dry DCM. To this suspension a catalytic amount (˜0.1 mmol) of DMAP is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of about −15° C. When the target temperature is reached the drop wise addition of orotoyl chloride is commenced. Addition of orotoyl chloride continues, with constant cooling and stirring, until all of the orotoyl chloride is added, after which the reaction is allowed to warm to room temperature with constant agitation. The solution is then filtered to remove any remaining Valine and the volatile DCM is removed from the filtrate under reduced pressure, the remainder is then purified by flash chromatography (ethyl acetate/hexanes; 1/6), yielding 2-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-3-methylbutanoic acid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:24]1[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=1>COCCOC.O.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>[O:7]([C:14]1[CH:19]=[CH:18][C:17]([C:24]2[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A mixture of sodium carbonate (1.905 g), tetrakis(triphenylphosphine)palladium(0) (519 mg), 4-phenoxyphenylboronic acid (2.5 g) and 3-bromopyridin-2-amine (1.555 g) in 1,2-dimethoxyethane (60 mL) and water (12 mL) was stirred overnight at 80° C. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.289 g) as a pale-yellow solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([CH:32]([O:35][CH3:36])[O:33][CH3:34])=[N:9][C:10]2[N:11]([C:17](=[O:31])[NH:18][C:19]3[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[C:22]([C:29]#[N:30])=[CH:21][N:20]=3)[CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)(=O)=O.[CH3:37][NH2:38]>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:29]([C:22]1[C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:24][C:19]([NH:18][C:17]([N:11]2[C:10]3[C:15](=[CH:16][C:7]([CH2:6][NH:38][CH3:37])=[C:8]([CH:32]([O:33][CH3:34])[O:35][CH3:36])[N:9]=3)[CH2:14][CH2:13][CH2:12]2)=[O:31])=[N:20][CH:21]=1)#[N:30]
Reactant: COC(OC)c1nc2c(cc1COS(C)(=O)=O)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(OC(C)C)c(C#N)cn1)CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of (8-((5-cyano-4-isopropoxypyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl methanesulfonate (intermediate 167, 2.59 g, 4.98 mmol) in THF (83 ml) was added methylamine 2 M in THF (37.4 ml, 74.70 mmol) at ambient temperature and the reaction mixture was stirred at room temperature for approximately 4 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined and dried using Na2SO4, filtered and concentrated to yield the title compound as a light yellow solid. (UPLC-MS 3) tR 0.88 min, ESI-MS 455.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 14.00 (s, 1H), 8.37 (s, 1H), 7.95 (s, 1H), 7.61 (s, 1H), 5.51 (s, 1H), 4.88-4.79 (m, 1H), 4.06-4.01 (m, 2H), 3.86 (s, 2H), 3.50 (s, 6H), 2.88-2.80 (m, 2H), 2.49 (s, 3H), 2.03-1.96 (m, 2H), 1.43 (d, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([O:10][CH2:11][C@H:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][O:15][C@@H](C3C=CC(OC)=CC=3)[O:13]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C1COCC1.C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][C@H:12]([OH:13])[C:17]([CH3:18])([CH3:19])[CH2:16][OH:15])=[O:9])=[CH:28][CH:29]=1)([O-:3])=[O:2]
Reactant: COc1ccc([C@@H]2OCC(C)(C)[C@H](COC(=O)c3ccc([N+](=O)[O-])cc3)O2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(CO)[C@@H](O)COC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of compound obtained in Step C (4.4 g, 10.96 mmol) in THF (5 ml) and acetic acid (70%) (50 ml) was heated at 60° C. for 4 hours. The solvent was concentrated under reduced pressure and dissolved in EtOAc. The organic layer was washed with NaHCO3 and brine. The organic phase was concentrated under reduced pressure and the crude was crystallized from Et2O and n-Hexane at 0° C. to give a white solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:19])[C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:22]=[C:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24](OCC)=[O:25]>O1CCCC1>[CH2:1]([S:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH:13]([C:24](=[O:25])[C:23]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:22])[C:12](=[O:19])[C:11]=2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2cnc(SCc3ccccc3)nc21
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C(=O)C1CCc2cnc(SCc3ccccc3)nc2C1=O)c1ccccc1
Yield: 68 %

Procedure:
To a solution of 0.22 g (0.81 mmol) of 2-(benzylthio)-6,7-dihydroquinazolin-8(5H)-one in 5 mL of dry tetrahydrofuran cooled to −50° C., 0.10 g of sodium hydride 60% in mineral oil were added. The resulting suspension was maintained at the same temperature for 30 minutes and then 0.59 mL of ethyl α-oxobenzeneacetate (PhCOCOOEt) were added and the reaction mixture allowed to come to room temperature. After 16 hours the mixture was partitioned between water and ethyl acetate and the organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by chromatography on a silica gel column (eluant hexane/ethyl acetate 7/3) giving 0.22 g (68% yield) of the title compound.