Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:23][CH3:24])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=O)C.[OH-:25].[Na+].[NH2:27]O.Cl>CCO.O>[OH:25][NH:27][C:4]([C:6]1[C:7]([CH2:23][CH3:24])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:3]
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CC
Reactant: [OH-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1c(C(=O)NO)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-ethyl-1-(4-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (57 mg, 0.175 mmol) in EtOH (2 mL), was added a 10% wt/wt solution of NaOH in water (0.5 mL) and a 50% wt/wt solution of hydroxylamine in water (1 mL). The reaction was stirred at room temperature for 18 hours, and then 1 N HCl was added till a pH of 7 was reached. The reaction was concentrated by rotary evaporation, and then purified by preparative HPLC to give the desired product. Yield 10 mg, 18%. 1H NMR (400 MHz, CDCl3) δ 1.36 (t, J=7.58 Hz, 3H), 3.47 (q, J=7.41 Hz, 2H), 5.38 (s, 2H), 6375 (d, J=3.28 Hz, 1H), 7.02 (m, 2H), 7.13 (m, 2H), 7.30 (m, 1H), 8.43 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(C)o1
Temperature: 0 °C
Yield: 89.6 %

Procedure:
To a solution of methyl 5-methyl-2-furancarboxylate (1.5 g, 10.70 mmol) and aluminum trichloride (2.14 g, 16.06 mmol) in chloroform (21 ml) at 0° C. was added bromine (0.77 ml, 14.99 mmol). The resulting solution stirred at 0° C. and warmed to RT over 12 h. This reaction was run in batches (1.5 g and 1 g) and the batches were combined, added to ice and partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (0.5-10% EtOAc in hexanes) affording the title compound (2.1 g, 54%) as a white solid; LCMS (ES) m/z=219, 221 (M, M+2)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7]2.[C:15](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2cccc(Br)c2n1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cccc(Br)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 8-bromoquinoline-2-carboxylic acid (Princeton Biomolecular Research, Monmouth Junction, N.J.; 2.65 g, 10.51 mmol) in DCM (25 mL) at 0° C. was treated with oxalyl chloride, 2.0 M solution in DCM (10.51 mL, 21.0 mmol), followed by 12 drops of DMF. The ice bath was removed, the mixture was stirred at RT for 1 h, becoming completely soluble during that time. The reaction mixture was then concentrated in vacuo and the residue was dissolved in DCM (50 mL) and cooled to 0° C. MeOH (1.7 mL, 42.1 mmol) and TEA (1.7 mL, 12.6 mmol) were added, the ice bath was removed, and the mixture was stirred at RT for 1 h. The reaction mixture was then diluted with DCM (50 mL), washed sequentially with 0.5 N HCl (25 mL), water (25 mL), 0.5 N NaOH (25 mL) and brine (25 mL), then dried over MgSO4, filtered, and concentrated to give methyl 8-bromoquinoline-2-carboxylate as a brown oil. This material was used without further purification, assuming the theoretical yield: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (d, J=8.4 Hz, 1H), 8.24 (d, J=7.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.11 (d, J=8.2 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 3.98 (s, 3H). m/z (ESI, +ve ion) 266.0/268.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([NH:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[N:8][C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:5]=2[CH2:4][NH:3]1.[I:34]N1C(=O)CCC1=O>C(Cl)Cl>[I:34][C:10]1[C:5]2[CH2:4][NH:3][C:2](=[O:1])[C:6]=2[C:7]([NH:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[N:8][C:9]=1[NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(I)c3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a screw-top vial was added tert-butyl (1S,2R)-2-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (73 mg, 0.162 mmol) and 1-iodopyrrolidine-2,5-dione (36.4 mg, 0.162 mmol) in DCM (1.6 mL) to give a yellow solution. The reaction was stirred 0.5 h at RT. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aq NaHCO3 (10 mL), water (10 mL), and brine (10 mL). The collected organic layers were dried with sodium sulfate and concentrated to give the title compound as a brown solid, which was used without further purification (85.7 mg, 92%). [M+H] calc'd for C25H32IN5O3, 578. found, 578.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]=[CH:21][N:22]=4)=[CH:14][CH:13]=3)=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH2:51][C:50](=[O:52])[CH2:49][CH2:48][N:47]2[C:53](Cl)=[O:54])=[CH:42][CH:41]=1>O1CCCC1.C(OCC)(=O)C>[F:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH2:51][C:50](=[O:52])[CH2:49][CH2:48][N:47]2[C:53]([N:4]2[CH2:5][C:6]3[CH:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([C:18]5[N:19]([C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]=[CH:21][N:22]=5)=[CH:16][CH:17]=4)[CH:9]=[CH:8][C:7]=3[O:1][CH2:2][CH2:3]2)=[O:54])=[CH:42][CH:41]=1
Reactant: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Reactant: O=C1CCN(C(=O)Cl)C(c2ccc(F)cc2)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CN(C(=O)N2CCC(=O)CC2c2ccc(F)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution 2-methylpropyl 2-[4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)phenyl]-1H-imidazole-1-carboxylate (0.22 g, 0.56 mmol) and diisopropylethylamine (0.50 mL, 2.81 mmol) in dimethylfomamide (10 mL) at 0° C. a solution of 2-(4-fluorophenyl)-4-oxopiperidine-1-carbonyl chloride (reagent preparation 37) (0.15 g, 0.59 mmol) in tetrahydrofuran (5 mL) was added and the reaction mixture was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate (250 mL) and partitioned with water (100 mL). The organic layer was separated and washed with water (50 mL), 10% aqueous citric acid (50 mL), brine then dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (hexane-acetone 4:1 to 7:3) provided 2-methylpropyl 2-[4-(4-{[2-(4-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)phenyl]-1H-imidazole-1-carboxylate (0.28 g, 80%). 1H NMR (400 MHz, d6-DMSO): 7.73 (d, 1H), 7.68-7.61 (m, 4H), 7.62 (d, 1H), 7.54 (dd, 1H), 7.30 (m, 1H), 7.15 (d, 1H), 7.10 (m, 3H), 7.04 (d, 2H), 5.20 (t, 1H), 4.62 (s, 2H), 4.24 (m, 2H), 4.04 (d, 2H), 3.68 (m, 3H), 3.40 (m, 1H), 2.86 (m, 2H), 2.61 (m, 1H), 2.32 (2t, 1H), 1.86 (m, 1H), 0.76 (m, 6H). MS (EI) for C35H35FN4O5: 611 (MH+).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C([O:11][C:12]([C:14]1[S:18][C:17]([Cl:19])=[N:16][CH:15]=1)=O)C>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:12]([C:14]1[S:18][C:17]([Cl:19])=[N:16][CH:15]=1)=[O:11])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1cnc(Cl)s1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)c1cnc(Cl)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a stirred solution of isopropylamine (123 mg, 2.08 mmol) in dioxane (5 mL) under argon and at room temperature was added trimethylaluminium (1.04 mL of a 2M solution in toluene, 2.08 mmol). After 1 h, a solution of 2-chloro-thiazole-5-carboxylic acid ethyl ester (100 mg, 0.522 mmol) in dioxane (5 mL) was added and the reaction mixture warmed to 90° C. After 6 h, the reaction mixture was cooled, quenched with Seignettes's salt solution and water, then extracted with dichloromethane. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 30% ethyl acetate in heptane) gave the title compound (100 mg, 94%) as a white solid. MS: m/e=203.4 [M+H]+.
Reaction SMILES: CO.[CH3:3][O:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])O[C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:6].[CH2:22]([NH2:24])[CH3:23].Cl>O.C(O)(=O)C>[CH2:22]([N:24]1[C:10]([CH3:14])=[CH:11][C:12](=[O:13])[C:7]([C:5]([O:4][CH3:3])=[O:6])=[C:8]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH3:23]
Reactant: CCN
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)oc(C)cc1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCn1c(C)cc(=O)c(C(=O)OC)c1-c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
A 1000 ml flask is fitted with a magnetic stirring bar and a sidearm addition funnel. 500 ml of methanol, 30 ml of glacial acetic acid and 60 g of 3-methoxycarbonyl-6-methyl-2-(4'-chlorophenyl)-4-pyrone are added. 120 ml of 70% aqueous ethylamine is placed in the addition tunnel and added very slowly (4 hr. addition time). 50 ml of water is then added followed by 100 ml of concentrated HCl (cooling required). The reaction mixture is allowed to stand undisturbed for 30 minutes. The bulk of the methanol is then removed in vacuo leaving 46.1 g of methyl 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate. mp (methylene chloride/ether)=217°-219° C.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].CO>C(Cl)Cl>[CH3:14][N:15]([CH:17]=[C:11]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]1=[O:10])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: O=C1CCCc2ccccc21
Solvent: CO
Solvent: ClCCl
Product: CN(C)C=C1CCc2ccccc2C1=O
Temperature: 25 °C

Procedure:
The 3,4-dihydro-2-(dimethylaminomethylene)-1(2H)-naphthalenone starting material was prepared by heating a mixture of α-tetralone (5.85 g, 40 mmol) and N,N-dimethylformamide dimethyl acetal (32 ml, 240 mmol) at 110° for 3 h. The reaction was allowed to cool to room temperature and excess reagent removed in vacuo to give a thick oil. This crude material was subjected to column chromatography (silica, 5% methanol in CH2Cl2) to afford the desired product as a thick orange oil (3.50 g). δH (CDCl3) 8.02 (1 H, dd, J 7.7, 1.5 Hz), 7.72 (1 H, s), 7.36 (1 H, td, J 7.3, 1.6 Hz), 7.28 (1H, td, J 7.6, 1.5 Hz), 7.15 (1H, dm, J 7.3 Hz), 3.12 (6H, s) and 2.98-2.80 (4H, m). MS (ES+) 202 (MH+, 90%), 175 (MH+−HCN, 100%).
Reaction SMILES: [C:1]([C@@H](C)C(N)(N)C(O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.O[C:24]1[C:32]2[N:31]=N[NH:29][C:28]=2C=C[CH:25]=1.C1C[O:36]CC1>>[C:4]([O:3][C:1](=[O:2])[NH:31][C@H:32]1[CH2:24][CH2:25][NH:29][C:28]1=[O:36])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@H](C(=O)OC(C)(C)C)C(N)(N)C(=O)O
Reactant: Oc1cccc2[nH]nnc12
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
(S)-Boc-Diaminobutyric acid (25 g, 115 mmol), triethyl amine (35 g, 344 mmol), and hydroxybenzotriazole (19.3 g, 143 mmol) are dissolved in 300 mL of THF. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiiimide hydrochloride (27.4 g, 143 mmol) is added to the solution. The solution is heated to 60° C. over 15 minutes. A white precipitate forms and the solution is kept at 60° C. for 4 hours. After this time, the solution is filtered and the collected liquid is concentrated. The crude product is purified by column chromatography in a gradient of 1% MeOH/CH2Cl2 to 3% MeOH/CH2Cl2 to afford the title compound (19.6 g, 98 mmol) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:22][CH3:23])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]#[N:33]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:31][C:32]#[N:33])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:22][CH3:23])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: COc1ccc2c(c1)c1c(O)cccc1n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c(OCC#N)cccc1n2Cc1ccccc1
Temperature: 120 °C
Yield: 31.4 %

Procedure:
To a mixture of 9-benzyl-6-methoxy-9H-carbazol-4-ol (1.21 g, 4.0 mmol) in DMF (25 mL) is added potassium carbonate (2.07 g, 15 mmol) and bromoacetonitrile (0.7 mL) 10 mmol). The mixture is heated at 120° C. overnight. The mixture is partitioned between water and Et2O. The organic layer is washed twice with water (100 mL) and dried over anhydrous sodium sulfate. The residue is dissolved in CH2Cl2 and passed through a silica gel plug. The filtrates are concentrated to dryness to give 0.43 g (31%) of the title compound; IR (drift) 1487, 1469, 1449, 1439, 1291, 1275, 1211, 1181, 1170, 1147, 1120, 775, 745, 705, 697 cm−1. 1H NMR (CDCl3) δ3.94, 5.06, 5.48, 6.7, 7.09, 7.24, 7.36, 7.81; Anal. Calcd for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C, 76.68; H, 5.31; N, 8.08.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](OC)[N:21]=1.Cl>C1COCC1>[OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[N:21]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1
Reactant: COc1cccc(OC)n1
Reactant: OCC1CCC2CNCCN2C1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(N2CCN3CC(CO)CCC3C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
According to the procedure reported by Wynberg (J. Org. Chem. 1993, 58, 5101), a solution 0.50 g (2.9 mmol) of racemic (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 10 mL of dry THF at 0° C. was treated with 2.59 mL (6.5 mmol) of n-butyl lithium (2.5 M in hexane). The mixture was kept at 0° C. for 30 min and at room temperature for 1 h, and 0.39 mL (2.94 mmol) of 2,6-dimethoxypyridine was added and the solution refluxed for 16 h. After cooling to room temperature, the mixture was poured into 1 M HCl and washed with toluene (3×). The aqueous layer was basified with 1 M NaOH and extracted with toluene (1×) and ethyl acetate (1×). The combined organic layers were dried (magnesium sulfate), filtered, and evaporated to give a yellow oil. Purification by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.304 g (37%) of (7RS,9aSR)-7-hydroxymethyl-2-(6-methoxypyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:34]([O:37][CH2:38][C:39](Cl)=[O:40])(=[O:36])[CH3:35]>>[C:34]([O:37][CH2:38][C:39]([N:31]1[CH2:32][CH2:33][CH:28]([C:25]2[N:24]=[C:23]([NH:22][C:10]3[C:9]([O:8][C:7]4[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:14][C:13]([S:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:12][N:11]=3)[S:27][N:26]=2)[CH2:29][CH2:30]1)=[O:40])(=[O:36])[CH3:35]
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCNCC2)ns1
Reactant: CC(=O)OCC(=O)Cl
Product: CC(=O)OCC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3cccnc3C)n2)CC1
Yield: 96.5 %

Procedure:
Following the procedure in Example 1, Step G, and using N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (Example 193, step F; 150 mg, 0.314 mmol) and 2-chloro-2-oxoethyl acetate (42.9 mg, 0.314 mmol) provided 2-(4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)-2-oxoethyl acetate (175 mg, 0.303 mmol, 96.5% yield).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([O:20][CH3:21])=[N:18][C:17]([C:22]([O:24]C)=O)=[CH:16][N:15]4[C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[NH3:33]>>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:13]=[C:14]4[C:19]([O:20][CH3:21])=[N:18][C:17]([C:22]([NH2:33])=[O:24])=[CH:16][N:15]4[C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c(OC)n1
Reactant: N
Product: COc1nc(C(N)=O)cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12

Procedure:
A solution of methyl 2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo-[1,2-a]pyrazine-6-carboxylate [Example 7] (65 mg, 0.09 mmol, 80% purity (UPLC area-%), 1.0 eq) in 1.73 mL ammonia (7 M solution in methanol, ˜100 eq) was heated to 130° C. for 2 h in a single mode microwave oven. The volatile components were removed by the use of a rotary evaporator. The solvent was using a rotary evaporator and the crude material was purified via MPLC (Biotage Isolera, 10 g Snap-cartridge; eluent: DCM→DCM/ethanol (8/2)) to deliver 22 mg (43%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:12])[CH2:11][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH:5]2[CH2:4]1.Cl[C:14]1[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][CH2:2][C:3]1([CH3:12])[CH2:11][N:6]2[CH2:7][CH2:8][N:9]([C:14]3[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=3)[CH2:10][CH:5]2[CH2:4]1
Reactant: CC1(CO)CC2CNCCN2C1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC1(CO)CC2CN(c3ncc(F)cn3)CCN2C1
Yield: 47.3 %

Procedure:
A mixture of (7RS,8aSR)-7-hydroxymethyl-7-methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (1.08 g, 6.35 mmol), 0.925 g (6.98 mmol) of 2-chloro-5-fluoropyrimidine (Dunaiskis, A. et., Org. Prep. Proc. Int., 1995, 27, 600-602), and 1.48 g (13.96 mmol) of sodium carbonate and 65 mL of water was heated at 90° C. for 72 hours. The solution was cooled and extracted with chloroform (3×). The combined organic layers were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography eluting with chloroform:methanol (95:5) gave 0.80 g (47%) of the title compound. 13C NMR (CDCl3): δ 25.5, 39.5, 41.7, 43.3, 48.7, 51.2, 62.3, 63.8, 71.0, 144.9, 145.2, 149.8, 153.1, 158.9. m/z (MH+) 267.
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19]O)[CH3:17].[OH2:25]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:13][C:5]1[C:4]([Br:14])=[C:3]([Br:15])[C:2]([Br:1])=[C:7]([C:8]([O:9][CH2:11][CH:6]([CH2:7][CH3:8])[CH2:5][CH2:4][CH2:3][CH3:2])=[O:25])[C:6]=1[C:11]([O:10][CH2:19][CH:18]([CH2:16][CH3:17])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:12]
Reactant: CCCCC(CC)CO
Reactant: O
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCCCC(CC)COC(=O)c1c(Br)c(Br)c(Br)c(Br)c1C(=O)OCC(CC)CCCC

Procedure:
Tetrabromophthalic anhydride (1391.1 grams; 3.0 moles), 2-ethyl-1-hexanol (1171.8 grams; 9.0 moles) and titanium (IV) isopropoxide (7 ml.; 0.5 volume percent on tetrabromophthalic anhydride) were charged into a 3,000 ml. reaction flask maintained under a nitrogen atmosphere. The reaction flask was fitted with a mechanical stirrer. thermometer. nitrogen inlet tube, and a Dean-Stark water trap connected to a Friedrich condensor. The reaction mixture was heated with agitation at a temperature equal or less than about 200° C. for eight hours. The resulting product (2.497 grams) was an amber thick clear liquid having an acidity of 1.4 meq. per 100 grams.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:42].[Mg+2]>C(Cl)Cl.CO>[CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][C:26]3[CH:27]=[CH:28][N+:29]([O-:42])=[CH:30][CH:31]=3)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(-c2cccc(C#Cc3ccncc3)c2)c2ncccc2c1=O
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)NC(=O)c1cn(-c2cccc(C#Cc3cc[n+]([O-])cc3)c2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-Isopropyl-1-[3-(4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 3 in methylene chloride (36 mL/mmol) and methanol (3 mL/mmol) was added magnesium monoperoxyphthalate hexahydrate (MMPP, 3.6 eq) and the mixture was stirred at room temperature overnight. A further amount of MMPP (2 eq) was added and stirring was continued for 24 hours. The resulting mixture was filtered through a bed of celite, the filtrate was diluted with methylene chloride and washed with aqueous sodium bicarbonate and water. After drying, the organic phase was evaporated and the crude product was purified by chromatography on silica gel eluting with 10% methanol in methylene chloride to afford the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH:3]1[CH3:9].[C-:10]#[N:11].[Na+].[NH4+:13].[Cl-]>N.CO>[NH2:13][C:5]1([C:10]#[N:11])[CH2:6][CH2:7][N:2]([CH3:1])[CH:3]([CH3:9])[CH2:4]1
Reactant: CC1CC(=O)CCN1C
Reactant: [C-]#N
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1CC(N)(C#N)CCN1C
Reaction time: 2 h

Procedure:
1,2-Dimethyl-4-piperidone (1.23 g, 9.67 mmol, 1.0 equiv) was dissolved in 39 mL of 2 M NH3 in MeOH (8 equiv NH3). To this solution was added NaCN (0.52 g, 10.6 mmol, 1.1 equiv) and NH4Cl (0.57 g, 10.6 mmol, 1.1 equiv). The resulting mixture was refluxed for 2 h at which time an additional 39 mL of 2 M NH3 in MeOH was added followed by an additional 2 h of reflux. The reaction was cooled and filtered. The filtrate was concentrated and taken up in 100 mL of CH2Cl2 giving more salt precipitate which was removed by a second filtration. The filtrate was then concentrated to thick orange oil (1.32 g, 89%). 1H NMR showed a 3 to 1 mixture of diastereomers of unknown configuration. The crude product was used without further purification; MS, m/z 154=M+1.
Reaction SMILES: [Cl:1][C:2]1[S:26][C:5]2NC(C(NC3CC4C(=CC=CC=4)N(CCO)C3=O)=O)=C[C:4]=2[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.ClC1SC2[NH:53][C:54]([C:56]([NH:58][CH:59]3[CH2:68][C:67]4[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=4)[N:61]([CH2:69][C:70]([O:72][CH3:73])=[O:71])[C:60]3=[O:74])=[O:57])=[CH:55]C=2C=1.C(Cl)[Cl:77]>O>[Cl:1][C:2]1[S:26][C:5]2[CH:55]=[C:54]([C:56]([NH:58][CH:59]3[CH2:68][C:67]4[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=4)[N:61]([CH2:69][C:70]([O:72][CH3:73])=[O:71])[C:60]3=[O:74])=[O:57])[NH:53][C:4]=2[C:3]=1[Cl:77]
Reactant: O=C(NC1Cc2ccccc2N(CCO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reactant: COC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reactant: ClCCl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Product: COC(=O)CN1C(=O)C(NC(=O)c2cc3sc(Cl)c(Cl)c3[nH]2)Cc2ccccc21
Reaction time: 18 h

Procedure:
5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method 8; 595 mg, 2.52 mmol), HOBt (340 mg, 2.52 mmol), DCM (100 mL) and finally EDCI (483 mg, 2.52 mmol) were added to methyl (3-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (Method 1, 590 mg, 2.52 mmol) and the reaction was stirred for 18 hours The reaction was then diluted with water (50 mL) and stirred vigorously for 30 min. The resultant precipitate was filtered and washed with Et2O (2×20 mL). After filtration the resultant solid was then triturated with refluxing Et2O (25 mL) and after cooling the title compound (528 mg, 46%) was collected again by filtration as a white solid.