Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:7]2[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH:6]12)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH:7]2[CH2:20][CH2:21][NH:22][CH:6]12)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)OC(C)(C)C)C12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCNC12
Reaction time: 1.25 h
Yield: 84.6 %

Procedure:
A solution of 14 (480 mg, 1.2 mmol) in DCM (10 mL) was treated with TFA (3 mL) at ambient temperature. After 75 min, the solution was concentrated, diluted with EtOAc, washed with saturated NaHCO3, brine. The aqueous washes were back extracted with DCM and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to afford crude 15 (309 mg) as an orange-colored oil that was used without further purification. Mass spectrum, m/z [305.2] (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (14 g, 42.7 mmol) in dichloroethane (150 mL) was added acetaldehyde (3.75 g, 85.2 mmol) and acetic acid (15.3 g, 256 mmol). The resulting reaction mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0° C. and sodium triacetoxyborohydride (27 g, 128 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Upon completion of the reaction as determined by TLC, aqueous sodium bicarbonate solution was added to the reaction mixture until a pH 7-8 was obtained, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with ethyl acetate: hexane to afford the desired compound as a viscous liquid (14 g, 93%). 1H NMR (DMSO-d6, 400 MHz) δ 7.62 (s, 1H), 7.52 (s, 1H), 3.80 (bs, 5H), 3.31 (t, 2H), 2.97-3.05 (m, 2H), 2.87-2.96 (m, 1H), 2.38 (s, 3H), 1.52-1.61 (m, 2H), 1.37-1.50 (m, 2H), 0.87 (t, 3H, J=6.8 Hz).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NNc1ccc(N=Cc2ccccc2)cc1
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)NNc1ccc(NCc2ccccc2)cc1

Procedure:
1-Acetyl-2-(4-benzalaminophenyl)hydrazine (5.1 g, 0.02 mole) and platinum oxide (catalytic amount) were suspended in ethanol (200 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until hydrogen uptake ceased. The reaction mixture was filtered and the solvent was evaporated from the filtrate leaving a white crystalline powder. Yield 4.7 g (92%), m.p. 118°-120° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[F:17].CN([CH:21]=[O:22])C.O>C1COCC1>[Br:9][C:10]1[C:11]([F:17])=[C:12]([C:13]([Cl:16])=[CH:14][CH:15]=1)[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: Fc1cc(Cl)ccc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccc(Br)c1F
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
Add a 2M LDA in THF (22 mL, 44 mmol) to 1-bromo-4-chloro-2-fluorobenzene (9.2 g, 44 mmol) in THF (100 mL) at −78° C. Stir for 10 minutes. Add DMF (10 mL, 132 mmol) and warm up to room temperature. Add the reaction mixture to ice and water. Extract the mixture with ethyl acetate (100 mL). Wash the organic layer with aqueous LiCl (20 mL, 10%), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure to obtain 5 g (48%) of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[C:8]2[C:13]([C:14]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([S:34]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][N:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14]([C:15]4[S:16][CH:17]=[CH:18][CH:19]=4)=[C:6]3[C:4]([OH:3])=[O:5])=[CH:22][CH:23]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C(O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc(NS(=O)(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from 1-(4-amino-benzyl)-3-thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester and benzenesulfonyl chloride followed the procedure of Example 3 Step 2 as a light brown solid: 1H NMR (DMSO-d6) δ 5.67 (s, 2H), 6.95-7.05 (m, 4H), 7.14-7.23 (m, 3H), 7.30-7.35 (m, 1H), 7.49-7.75 (m, 8H), 10.26 (br s, 1H), 13.24 (br s, 1H); MS (ESI) m/z 489 (MH+); HRMS calcd for C26H21N2O4S2: 489.0940; found (ESI+): 489.0935.
Reaction SMILES: [CH:1]1([C:7]2(O)[C:11]3[C:12]([CH3:26])=[C:13]([NH:18][C:19](=[O:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=3[O:9][C:8]2([CH3:28])[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.CCCCCC>[CH:1]1([CH:7]2[C:11]3[C:12]([CH3:26])=[C:13]([NH:18][C:19](=[O:25])[CH2:20][C:21]([CH3:22])([CH3:23])[CH3:24])[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=3[O:9][C:8]2([CH3:28])[CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(O)(C1CCCCC1)C(C)(C)O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(C1CCCCC1)C(C)(C)O2
Yield: 48 %

Procedure:
Using N-(3-cyclohexyl-3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 256, the title compound was synthesized in the same manner as in Example 271. Yield: 48%. Melting point: 198-199° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:8]=[C:9]([F:11])[CH:10]=1.[CH2:27]([N:34]=[C:35]=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[C:35]([NH:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(F)cc(CC(=O)OC)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(F)cc(CC(=O)OC)c1)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2′-ethylaminomethyl-5-fluoro-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl isocyanate.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].CC1(C)C(C)(C)OB([C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:24]1[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:26][CH:25]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
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: [Cs+]
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(OCCN2CCOCC2)cc1
Yield: 33.5 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1, using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.36 g, 1.35 mmol), 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)-morpholine (0.45 g, 1.35 mmol), Pd(PPh3)4 (0.078 g, 0.068 mmol) and Cs2CO3 (0.53 g, 1.6 mmol). The crude was filtered, diluted with 1M HClaqueous (3 ml) and purified via reverse phase chromatography with a Biotage C18 SNAP 120 g column (Phase A, water 95%, ACN 4.9%, formic acid 0.1%); Phase B ACN 99.9%, formic acid 0.1%) to afford the title compound (0.179 g, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=S)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]2[NH:18][C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:27][N:26]=2)=[CH:22][CH:21]=1
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nnc(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 71c) starting with [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (250 mg, 0.95 mmol) and 4-fluoro-benzohydrazide (162 mg, 0.95 mmol). Obtained as a brownish solid (41 mg, 12%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([OH:13])=O)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:38][C@@H:39]1[NH:44][CH2:43][CH2:42][N:41]([S:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)(=[O:47])=[O:46])[CH2:40]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([N:44]2[CH2:43][CH2:42][N:41]([S:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:57])([F:55])[F:56])=[CH:52][CH:53]=3)(=[O:46])=[O:47])[CH2:40][C@@H:39]2[CH3:38])=[O:13])[CH:7]=1
Reactant: O=C(O)c1cnn2cc(Br)cnc12
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cnn2cc(Br)cnc12
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
To a solution of 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (may be prepared as described in Description 17) (471 mg, 1.946 mmol) in N,N-Dimethylformamide (10 mL) under a flush of argon was added HATU (740 mg, 1.946 mmol) and the reaction stirred for 10 minutes. (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (600 mg, 1.946 mmol) was then added followed by N,N-diisopropylethylamine (0.680 mL, 3.89 mmol) and the reaction stirred for 18 h. The reaction mixture was partitioned between ethyl acetate (60 mL) and water (40 mL). The organic layer was washed with further water (20 mL) and brine (20 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The crude material was purified by silica chromatography, 40 M cartridge, eluting 0-75% EtOAC in isohexane and the solvent evaporated to give the title compound (587 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([S:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[S:21](Cl)(=[O:23])=[O:22])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:21]([C:17]1[S:18][CH:19]=[CH:20][C:16]=1[S:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1sccc1Sc1ccccc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2sccc2Sc2ccccc2)c1Br
Yield: 83 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-(phenylthio)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 using 5-amino-4-bromo-3-methylisoxazole (192 mg, 1.1 mmol) and 3-phenylthio-thiophene-2-sulfonyl chloride (300 mg, 1.0 mmol). Purification by column chromatography using 10% MeOH/CHCl3 yielded 358 mg (83%) of the pure sulfonamide as a brown oil.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[C:3]1([CH2:2][CH2:1][N:9]=[C:11]=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: NCCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=NCCc1ccccc1
Temperature: 25 °C

Procedure:
40 grams of phenethyl amine in 300 ml of dry toluene saturated with dry HCl gas was mixed until a heavy white precipitate formed. An additional 200 ml of dry toluene was added with 50 ml of phosgene (12.5% in benzene). The mixture was refluxed (10 min.) and then 450 ml of phosgene was slowly added over 30 minutes and the mixture refluxed for 4 hours. The reaction mixture was allowed to cool to room temperature slowly and the solvent removed in vacuo leaving a yellow oil. Vacuum distillation of the oil at 82° to 83° C./0.1 mm yield 1.8 g of end product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[OH:23][CH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:29]3[CH:30]=[C:25]([CH2:24][OH:23])[CH:26]=[CH:27][CH:28]=3)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: OCc1cccc(B(O)O)c1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Product: CC(On1ccc2ncc(-c3cccc(CO)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and [3-(hydroxymethyl)phenyl]boronic acid according to the procedure described in example 4.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:21]>N1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:20]([O:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)=[O:21])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: O=C(Cl)Oc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)Oc2ccc(C(F)(F)F)cc2)N(c2nnc(C(C)(C)C)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C and 4-trifluoromethylphenyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(4-trifluoromethylphenoxycarbonyloxy)-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.C([Li])CCC.[CH:34](N1CCCCC1)=[O:35]>C1COCC1>[CH:34]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=[CH:11][C:10]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:35]
Reactant: O=CN1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(-c2ccccc2)cc1C=O
Temperature: -72 °C
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
A solution of 3B (3.3 g, 12.21 mmol) in dry THF (50 mL) and TMEDA (4.6 mL, 30.53 mmol) under argon was cooled to −72° C. and treated dropwise with n-butyllithium (2.5 M in hexanes, 12.2 mL, 30.53 mmol) at such a rate so that the temperature did not exceed −65° C. Upon completion of the addition, the reaction was stirred at −72° C. for an additional 15 min and then at −20° C. for 1.5 h. The reaction was cooled again to −72° C., and N-formyl piperidine (2.7 mL, 24.4 mmol) was added while the temperature was maintained below −65° C. The mixture was allowed to stir at RT for 30 min. After this time, no starting material was detected by LC-MS. The solution was cooled to 0° C. and quenched by the addition of 1 M aqueous HCl to bring the pH to 6-8. The reaction was stirred at RT for 15 min, extracted with EtOAc (3×100 mL). The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel (110 g) column chromatography, eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as a yellow solid (1.6 g, 44%). LC/MS (method A): retention time=2.79 min, (M+MeOH+H)+=331.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[C:13]([CH3:22])=[N:14][C:15]4[C:20]([N:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:11]=[C:4]2[N:3]=1.[CH3:23][NH:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:24]([CH3:23])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:5]2[N:9]=[C:10]([C:12]3[C:13]([CH3:22])=[N:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:21]=3)[CH:11]=[C:6]2[CH:7]=1
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(Cl)cc(Cl)n2n1
Reactant: CNC1CCOCC1
Product: Cc1nc2ccccc2nc1-c1cc2cc(Cl)nc(N(C)C3CCOCC3)n2n1

Procedure:
The preparation was performed in a similar manner as Example 1.001 (g) from 3-(5,7-dichloropyrazolo[1,5-a]pyrimidin-2-yl)-2-methylquinoxaline (200 mg, 0.606 mmol) and N-methyl-4-aminotetrahydropyran (84 mg, 0.729 mmol) to give 5-chloro-N-methyl-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]pyrimidin-7-amine. MS (APCI): m/z 409/411 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][C:15]([CH3:17])=[CH:16][C:6]=3[C:5]=2[CH:4]=1.[Br:18]N1C(=O)CCC1=O>>[Br:18][C:4]1[C:5]2[C:6]3[CH:16]=[C:15]([CH3:17])[S:14][C:7]=3[C:8](=[O:13])[NH:9][C:10]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc2[nH]c(=O)c3sc(C)cc3c2c1
Reactant: O=C1CCC(=O)N1Br
Product: COc1ccc2[nH]c(=O)c3sc(C)cc3c2c1Br
Yield: 40 %

Procedure:
Following Step 4 from General Procedure A, 8-methoxy-2-methylthieno[2,3-c]quinolin-4(5H)-one (1.4 g, 5.7 mmol) was reacted with N-bromosuccinimide (1.2 g, 6.9 mmol) to afford the desired product (740 mg, 40%) as a brown solid: ESI MS m/z 325 [C13H10BrNO2S+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][N:11]2[CH:14]=[C:15]([CH3:17])[N:16]=[C:10]2[C:9]=1[I:18].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>C(Cl)Cl>[I:18][C:9]1[C:10]2[N:11]([CH:14]=[C:15]([CH3:17])[N:16]=2)[CH:12]=[CH:13][C:8]=1[NH:7][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)Cl
Reactant: Cc1cn2ccc(N)c(I)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Nc1ccn2cc(C)nc2c1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.2 %

Procedure:
A mixture of sodium carbonate (0.57 g, 5.38 mmol) and amine 23 (1.47 g, 5.38 mmol) in 50 mL of dry CH2Cl2 was treated, under argon, over a period of 15 min with ethyl chloroformate (2.34 g, 22.6 mmol). The reaction mixture was stirred at room temperature for 24 h. Then, water (50 mL) was added and organic layer was recovered, the aqueous layer was extracted with additional CH2Cl2 (3×50 mL). The organic extracts were dried (Na2SO4), filtered and evaporated under vacuum. The residue was purified by chromatography using CH2Cl2/EtOAc (4/1, v/v) as eluent to afford in order of elution: Compound 24 (820 mg, yield: 44%); mp 148° C.; IR (KBr) 3380, 3124, 3049, 2988, 1738, 1642, 1541; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (t, 3H, J=7.1 Hz), 2.31 (s, 3H), 4.13 (q, 2H, J=7.1 Hz), 6.93 (d, 1H, J=7.1 Hz), 7.78 (s, 1H), 8.35 (d, 1H, J=7.1 Hz), 8.93 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.1, 14.5, 60.7, 81.8, 110.1, 111.5, 125.7, 137.2, 142.7, 144.5, 153.9. Anal. Calcd for C11H12IN3O2: C, 38.28; H, 3.50; N, 12.18. Found: C, 38.04; H, 3.55; N, 12.08.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH3:19])[CH:13]=[C:12](Cl)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CCO.[Pd]>[NH:1]([C:8]1[N:9]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH3:19])[CH:13]=[CH:12][N:11]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccnc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Yield: 97.6 %

Procedure:
A solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (95.0 mg, 0.263 mmol), TEA (0.65 mmol), and 10% Pd/C in EtOAc (2.5 mL) and EtOH (2.5 mL) was stirred under H2 (1 atm) for 3.5 h. The reaction mixture was filtered through a pad of Celite using EtOH and EtOAc to rinse. The combined filtrates were concentrated in vacuo, and purified with Biotage silica gel chromatography using 1:1 EtOAc:Hex to afford 2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (84 mg, 98%) as a pale yellow solid. LCMS RT: 2.26 min, MH+: 328.4, Rf=0.1 (1:1 EtOAc:Hex),
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N:11]2[C:15](=[O:16])[NH:14][C:13](=O)N2)=[C:5]([F:18])[CH:4]=1>CO>[Cl:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N:11]2[C:15](=[O:16])[N:11]3[CH:6]=[CH:5][CH:4]=[CH:3][CH2:13][N:14]3[C:15]2=[O:16])=[C:5]([F:18])[CH:4]=1
Reactant: COc1cc(-n2[nH]c(=O)[nH]c2=O)c(F)cc1Cl
Agent: [Na]
Solvent: CO
Product: COc1cc(-n2c(=O)n3n(c2=O)CC=CC=C3)c(F)cc1Cl
Reaction time: 4 h
Yield: 25.9 %

Procedure:
To a solution of metallic sodium (0.46 g) in methanol (20 ml), 2-(4-chloro-2-fluoro-5-methoxyphenyl)urazol (2.6 g) was added, and the resultant mixture was concentrated under reduced pressure. The residue was dissolved in dimethylformamide (20 ml), 1,5-dibromopentane (2.3 g) was added thereto, and the resulting mixture was stirred at 100° to 120° C. for 4 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized from methanol to give 0.42 g of 2-(4-chloro-2-fluoro-5-methoxyphenyl)-1H,5H-[1,2,4]triazolo[1,2-a][1.2]diazepine-1,3(2H)-dione (Compound No. 3). M.P., 121.5°-123° C. IR νmax (cm-1) 1750, 1680. NMR δ (ppm): 1.8 (6H, m), 3.9 (3H, s).