Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH:27]=O>CO>[N:8]1([C:5]2[CH:6]=[CH:7][C:2](/[N:1]=[CH:27]/[C:26]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)=[C:3]([NH:13][C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Nc1ccc(N2CCCC2)cc1NC(=O)c1ccccc1
Solvent: CO
Product: COc1cc(/C=N/c2ccc(N3CCCC3)cc2NC(=O)c2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of N-(2-amino-5-(pyrrolidin-1-yl)phenyl)benzamide (2 mmol) and 3,4,5-trimethoxybenzaldehyde (3 mmol) in methanol was stirred at room temperature for 12 h. The suspension was filtered and the solid was washed with methanol to afford (E)-N-(5-(pyrrolidin-1-yl)-2-(3,4,5-trimethoxybenzylideneamino)phenyl)benzamide as a yellow solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([CH2:19][OH:20])[CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([CH:19]=[O:20])[CH:13]=1
Reactant: Cc1cnc(CO)cc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
A solution of dimethyl sulfoxide (0.85 mL, 12.02 mmol) in DCM (10 mL) was added dropwise over 5 minutes to a solution of oxalyl chloride (0.47 mL, 5.51 mmol) in DCM (20 mL) at −78° C. under an atmosphere of N2 (gas evolved). Stirring was continued for 10 minutes. To this solution was added (4-bromo-5-methyl-2-pyridyl)methanol [CAS: 820224-83-7](1.01 g, 5.01 mmol) in DCM (2 mL) dropwise over a period of 10 minutes. Stirring was then continued for a further 10 minutes. Triethylamine (3.13 mL, 22.54 mmol) was added dropwise and stirring continued for 5 minutes, before allowing the reaction to warm to room temperature. Water was added and the phases were separated by passing over a hydrophobic frit. The organic phase was evaporated to yield a dark brown solid which was dried under vacuum overnight (795 mg). This was purified by column chromatography on silica gel (0-100% EtOAc in isohexane) to yield 4-bromo-5-methyl-pyridine-2-carbaldehyde (D21) (619 mg, 3.0945 mmol, 61.8% yield) as an orange crystalline solid;
Reaction SMILES: [CH2:1]([C:8]([CH2:10][CH3:11])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12](Cl)[CH:13]=[CH:14][CH3:15]>>[C:2]1([CH:1]([C:8](=[O:9])[CH2:10][CH3:11])[CH2:12][CH:13]=[CH:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=CCCl
Reactant: CCC(=O)Cc1ccccc1
Product: CC=CCC(C(=O)CC)c1ccccc1

Procedure:
Ethyl benzyl ketone is reacted with crotyl chloride according to the foregoing details and there is obtained 5-phenyl-oct-2-en-6-one of boiling point 95° C./3 mmHg; nD20 =1.5102.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[S:40][C:41]([C:44]([NH:46][CH:47]2[CH2:49][CH2:48]2)=[O:45])=[CH:42][N:43]=1.ClC1SC(C(NC2CC2)=O)=CN=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:47]1([NH:46][C:44]([C:41]2[S:40][C:39]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:7]5[O:6][C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[N:9][N:8]=5)[CH:11]=4)[NH:15][CH:14]=3)=[N:43][CH:42]=2)=[O:45])[CH2:48][CH2:49]1
Reactant: O=C(NC1CC1)c1cnc(Br)s1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(-c4ncc(C(=O)NC5CC5)s4)c3c2)o1
Temperature: 130 °C

Procedure:
A mixture of N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (150 mg, 0.287 mmol), 78 mg of the 1:1 mixture of 2-bromo-N-cyclopropylthiazole-5-carboxamide and 2-chloro-N-cyclopropylthiazole-5-carboxamide, Pd2(dba)3 (Strem Chemicals, 8 mg, 8.6 μmol), Xphos (Stem Chemicals, cat #15-1152, 9 mg, 17 μmol), potassium phosphate (183 mg, 0.861 mmol) in dioxane (2.5 mL) and water (0.5 mL) was heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 130° C. for 25 min. LCMS indicated the presence of desired product (M+1=563.0), as well as a significant amount of the starting N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine. To the reaction mixture was added Pd(PPh3)4 (Strem Chemicals, cat #46-2150, 10 mg) and 50 mg of the 1:1 mixture of 2-bromo-N-cyclopropylthiazole-5-carboxamide and 2-chloro-N-cyclopropylthiazole-5-carboxamide. It was heated again at 130° C. for 15 min in an Initiator microwave reactor. The reaction mixture was treated with water (5 mL) and extracted with EtOAc (2×25 mL). The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 20-100% EtOAc in hexanes to give N-cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)thiazole-5-carb oxamide (60 mg, in 75% purity) as a brown amorphous solid. MS (ESI, pos. ion) m/z: 563.0 (M+1).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:55])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([N:51]=[N+:52]=[N-:53])[CH:47]([OH:54])[CH2:46]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].[CH3:58]I>[Ag]=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:55])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([N:51]=[N+:52]=[N-:53])[CH:47]([O:54][CH3:58])[CH2:46]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CI
Agent: O=[Ag]
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
A suspension of 17-ethyl-20-fluoro-1-hydroxy-12-[2'-(4"-azido-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (20 mg) and silver oxide (20 mg) in 1.5 ml of methyl iodide is refluxed in a gas-tight bottle for 4 days. The yellow solid is filtered off and the excess methyl iodide is removed. Purification of crude material by preparative tlc on silica gel gives the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:25]([O:27][CH3:28])=[O:26].O>O1CCCC1.C(OCC)(=O)C>[CH3:28][O:27][C:25]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[O:9])[CH2:3][CH2:2]1)=[O:26]
Reactant: O=C(Nc1ccc(F)cc1)NC1CCNCC1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N1CCC(NC(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(piperidin-4-yl)-N′-(4-fluorophenyl)urea (0.3 g) in tetrahydrofuran (4 ml) were added in turn pyridine (0.28 ml), methyl chloroformate (98 μl) and catalytic amount of N,N-dimethylaminopyridine at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give N-(1-methoxycarbonylpiperidin-4-yl)-N′-(4-fluorophenyl)urea (0.312 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:28]([NH2:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:28]([NH:30][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:29]
Reactant: CCN
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide (77 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100 mg), ethylamine (2 M in THF, 254 uL), HBTU (116 mg), and DIEA (67 uL). LC/MS: m/z 421.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.46 (bs, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.74 (s, 2H), 7.64 (d, 1H), 7.48 (d, 1H), 3.66 (bs, 3H), 3.30 (q, 2H), 1.13 (t, 3H).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].N1C=CN=C1>CO.CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[O:22])[CH2:15][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1)[CH3:21]
Reactant: O=[N+]([O-])c1ccc2nc(S)[nH]c2c1
Reactant: CCOC(=O)C(=O)CBr
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CSc1nc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 2-mercapto-5-nitrobenzimidazole (195 mg, 1.0 mmol) and ethyl 3-bromopyruvate (0.150 mL, 1.19 mmol) in methanol (2.5 mL) and acetone (2 mL) was added imidazole (68 mg, 1.0 mmol). The resulted solution was shaken at 20° C. for 4 hour. After the removal of solvents under vacuum, the residue was triturated with ethyl ether. The ether phase was discarded. The residue was treated with sodium bicarbonate aqueous solution and ethyl ether. The ether phase was washed successively with sodium bicarbonate aqueous solution, water, and dried over magnesium sulfate. Evaporation to dryness under vacuum gave 200 mg (65% of yield) of the expected product, 3-(5-nitro-1H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester. Proton NMR showed the product was sufficiently pure to be used without further purification. 1H-NMR (D3COD, 300 MHz) δ (ppm): 8.35 and 8.08 (2 br. s, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.50 and 7.28 (2 br. s, 1H), 4.42 (q, J=7.1 Hz, 2H), 4.41 (br. s, 1H), 4.06 (br. s, 1H), 1.30 (t, J=7.1 Hz, 3H). MS (ESI) m/z: 310 (M+1, 100).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[NH2:16][C@H:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>C(#N)C>[CH3:21][O:20][C:18](=[O:19])[C@H:17]([N:16]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:22]
Reactant: COC(=O)[C@@H](C)N
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@@H](C)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Potassium carbonate (49.5 g, 358 mmol) and benzyl bromide (42.5 mL, 358 mmol) were each added to a partial solution of (R)-methyl 2-aminopropanoate hydrochloride (10 g, 71.6 mmol) in acetonitrile (200 mL) and the reaction was allowed to stir at 60° C. overnight. The reaction was filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography using hexane (to elute the excess benzyl bromide) followed by 5:1 hexane:ethyl acetate to elute the product. After concentration and drying of the fractions containing the major product, the title compound (20.13 g, 71.0 mmol, 99% yield) was obtained as a colorless oil. HPLC (condition B): retention time=2.80 min. LCMS (condition B): m/z 284.2. 1H NMR (500 MHz, MeOD) δ ppm 7.38-7.44 (4 H, m), 7.34 (4 H, t, J=7.63 Hz), 7.22-7.30 (2 H, m), 3.84 (2 H, d, J=13.87 Hz), 3.77 (3 H, s), 3.65 (2 H, d, J=13.87 Hz), 3.52 (1 H, q, J=7.12 Hz), 1.35 (3 H, d, J=7.21 Hz).
Reaction SMILES: [C:1]1([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[C:7]([C:9]1[S:13][C:12]([NH:14][C:22](=[O:23])[C:21]([OH:20])([CH3:26])[CH3:25])=[N:11][C:10]=1[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)C(=O)Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
Compound 136 (150 mg, 0.555 mmol) was dissolved in DMF (2.5 mL), and 2-hydroxy-2-methylpropanoic acid (116 mg, 1.11 mmol), EDC hydrochloride (313 mg, 1.11 mmol) and 1-hydroxybenzotriazole monohydrate (170 mg, 1.11 mmol) were added thereto, followed by stirring at 50° C. for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 137 (158 mg, 80%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].Cl.[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:5][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[CH2:2][C:3]#[CH:4]
Reactant: C#CCCO
Reactant: C1=COCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: C#CCCOC1CCCCO1
Reaction time: 16 h

Procedure:
A solution of 3-butyn-1-ol (74.5 g, 1.06 mol) in carbon tetrachloride (225 ml) is cooled in an ice bath, and treated with concentrated hydrochloric acid (1 ml). Dihydropyran (157 g, 1.86 mol) is then added via a dropping funnel. After stirring 16 hours the reaction mixture is treated with solid sodium bicarbonate for 30 minutes and filtered. The reaction mixture is concentrated and the residue is distilled in vacuo to give the title compound.
Reaction SMILES: CO.O.[CH3:4][C:5]1([C:10]2[CH:11]=[C:12]([CH:16]3[N:21]4[CH:22]=[CH:23][N:24]=[C:20]4[NH:19][C:18]([CH3:25])=[C:17]3[C:26]([O:28][CH3:29])=[O:27])[CH:13]=[CH:14][CH:15]=2)OCC[O:6]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:5]([C:10]1[CH:11]=[C:12]([CH:16]2[N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[NH:19][C:18]([CH3:25])=[C:17]2[C:26]([O:28][CH3:29])=[O:27])[CH:13]=[CH:14][CH:15]=1)(=[O:6])[CH3:4]
Reactant: COC(=O)C1=C(C)Nc2nccn2C1c1cccc(C2(C)OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)Nc2nccn2C1c1cccc(C(C)=O)c1
Temperature: 60 °C
Yield: 69.8 %

Procedure:
In a mixture of 50 ml of acetone, 30 ml of methanol and 20 ml of water is dissolved 1.8 g of 5-[3-(2-methyl-1,3-dioxolan-2-yl)phenyl]-6-methoxycarbonyl-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine. The mixture is adjusted to pH 1 with p-toluenesulfonic acid and then heated at 60° C. for 3 hours. The solvent is distilled off and the residue is neutralized with sodium bicarbonate solution. The resulting white precipitations are collected by filtration and recrystallized from a mixture of ethanol and acetone to give 1.1 g of 5-(3-acetylphenyl)-6-methoxycarbonyl-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 227°-229° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15]C(C)=O.C(=O)([O-])[O-].[K+].[K+].CI>O.C(OCC)(=O)C>[C:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:15])=[O:11])=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cn1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)(C)C)nc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a mixed liquid of 2163 mg of 6-tert-butoxynicotinic acid and 32 ml of acetone were added 2297 mg of potassium carbonate and 0.97 ml of methyl iodide, followed by stirring at 35° C. overnight. Ethyl acetate and water were added thereto to carry out liquid separation, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.191 g of methyl 6-tert-butoxynicotinate.
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:14]([OH:16])=O.FC1C(F)=C(F)C(F)=C2C(=O)OC(=O)C=12.[F:32][C:33]1[C:38]([CH2:39]C(O)=O)=[C:37]([F:43])[C:36]([F:44])=[C:35]([F:45])[C:34]=1[F:46].C(N(CC)CC)C>C(N(CC)CC)C.C(OC(=O)C)(=O)C>[OH:11][C:10]1[C:2]([F:1])=[C:3]2[C:4](=[C:8]([F:13])[C:9]=1[F:12])[C:5](=[O:7])[O:16][C:14]2=[CH:39][C:38]1[C:37]([F:43])=[C:36]([F:44])[C:35]([F:45])=[C:34]([F:46])[C:33]=1[F:32]
Reactant: O=C(O)Cc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)c1c(F)c(O)c(F)c(F)c1C(=O)O
Agent: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=Cc2c(F)c(F)c(F)c(F)c2F)c2c(F)c(O)c(F)c(F)c21

Procedure:
A process for preparing 3,5,6-trifluoro-4-hydroxyphthalic acid used here as the starting material is described in Osadchii, S. A., Bakahash, V. A.; Zh. Org. Khim., Vol. 6 (8), p. 1636 (1970) (Chemical Abstract, 73, 109544p). According to this litrature, when tetrafluorophthalic anhydride and pentafluorophenylacetic acid are reacted in triethylamine-acetic anhydride, a triethylamine salt of 5-hydroxy-4,6,7-trifluoro-3-(pentafluorobenzylidene)phthalide is obtained. And, by treatment of the by-products of this reaction, 3,5,6-trifluoro-4-hydroxyphthalic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Br:14]N1C(=O)CCC1=O>C(O)(=O)C>[Br:14][C:4]1[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)c(Cl)cc1C(C)=O
Solvent: CC(=O)O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Temperature: 100 °C
Yield: 38 %

Procedure:
To a stirred solution of 1-(5-chloro-2-methoxy-4-methylphenyl)ethanone (5.00 g, 25.2 mmol, from Oakwood) in acetic acid (100 mL) was added N-bromosuccinimide (4.93 g, 27.7 mmol) and the resulting mixture heated at 100° C. for 18 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo, then neutralized with sat. sodium bicarbonate, filtered off insoluble succinimide. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexanes, to give the desired products (2.66 g, 38%). LCMS calculated for C10H11BrClO2(M+H)+: m/z=277.0; found: 277.0. 1H NMR (DMSO-d6, 300 MHz): δ 7.70 (1H, s), 3.77 (3H, s), 2.57 (3H, s), 2.50 (3H, s) ppm.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][N:14]4[C:18](=[O:24])[CH2:19][NH:20][C:21](=O)[CH:22]=[C:13]4[C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.ClCCCl.[CH:29]([C:32]1[N:33]=[CH:34][NH:35][CH:36]=1)([CH3:31])[CH3:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][N:14]4[C:18](=[O:24])[CH2:19][N:20]=[C:21]([N:35]5[CH:36]=[C:32]([CH:29]([CH3:31])[CH3:30])[N:33]=[CH:34]5)[CH:22]=[C:13]4[C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c[nH]cn1
Reactant: O=C1C=C2c3nccc(-c4ccc(F)nc4)c3CCN2C(=O)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)c1cn(C2=NCC(=O)N3CCc4c(-c5ccc(F)nc5)ccnc4C3=C2)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
EXAMPLE 94. To a stirred solution of 4-(6-fluoropyridin-3-yl)-5,6,9,10-tetrahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione (31 mg, 0.096 mmol) in 1,2-dichloroethane (2 mL) POCl3 (29.3 mg, 0.19 mmol) was added and the resulting suspension was stirred at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCl3 the residue was taken up in toluene and evaporated twice again and dried under high vacuo. The resulting crude chloro compound was dissolved in 1,2-dichloroethane (5 mL), 4-isopropyl-1H-imidazole (53 mg, 0.48 mmol) was added and the mixture was stirred at 100° C. for 1 h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by SFC (column: DEAP 5 μm, 250×30 mm, 60A, Princeton; eluent: from 6% MeOH/CO2 to 11% MeOH/CO2 in 11 min; flow 100 mL/min; UV detection at 220 nm) and yielded the title compound as beige powder (11 mg). UPLC-MS: MS 417.2 (M+H+); UPLC rt 0.87 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17-1.34 (m, 6 H), 2.81-2.98 (m, 3 H), 4.05 (br. s., 2 H), 4.40 (s, 2 H), 7.09 (dd, J=8.3, 2.8 Hz, 1 H), 7.22-7.36 (m, 2 H), 7.77 (td, J=7.9, 2.1 Hz, 1 H), 7.96 (s, 1 H), 8.03 (s, 1 H), 8.23 (d, J=1.5 Hz, 1 H), 8.68 (d, J=4.8 Hz, 1 H).
Reaction SMILES: [CH2:1]([N:8]([CH3:39])[S:9]([CH:12](C#N)[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][O:23][C@H:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])[CH3:25])[CH:17]=[C:16]2[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][N:32]1[CH3:36])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:1]([N:8]([CH3:39])[S:9]([CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][O:23][C@H:24]([Si:26]([CH3:27])([CH3:28])[CH3:29])[CH3:25])[CH:17]=[C:16]2[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][N:32]1[CH3:36])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](OCn1cc(CC2CCCN2C)c2cc(C(C#N)S(=O)(=O)N(C)Cc3ccccc3)ccc21)[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](OCn1cc(CC2CCCN2C)c2cc(CS(=O)(=O)N(C)Cc3ccccc3)ccc21)[Si](C)(C)C
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a stirred solution of N-benzyl-1-cyano-N-methyl-1-[(R)-3-(1-methyl-2-pyrrolidinylmethyl)-1-trimethylsilylethyloxymethyl-1H-indol-5-yl]methanesulfonamide (from step (b), 1.56 g, 2.8 mmol) in ethanol (12 ml) at ambient temperature was added 2N potassium hydroxide solution (6.24 ml, 12.5 mmol). The dark brown solution was then brought to reflux and maintained at this temperature for 15 hr. The oily reaction mixture was then cooled to ambient temperature and extracted with ethyl acetate (3×25 ml). The organic extracts were combined and evaporated in vacuo to yield the crude product as a dark brown oil. This was purified by flash column chromatography (ethyl acetate:hexane:dietiylamine 1:1:0.1 as eluant) to yield the title compound (1.49 g, 75%) as a brown oil.