Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:9](=[O:10])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3]1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:8]1[C:4]2[CH2:3][CH:2]([CH3:1])[C:9](=[O:10])[C:5]=2[S:6][CH:7]=1
Reactant: BrBr
Reactant: CC1Cc2ccsc2C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC1Cc2c(Br)csc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A total of 129 g (0.85 mol) of 5-methyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one in 130 ml of CHCl3 were added to a suspension of 250 g (1.89 mol) of AlCl3 (anhydrous powder) in 350 ml of CHCl3 at 0° C. over 0.5 h. The reaction mixture was stirred for 10 min at this temperature; then a solution of 46.7 ml of Br2 (0.91 mol) in 90 ml of CHCl3 was added dropwise for 1 h. The resulting mixture was stirred for 1 h at room temperature and, then, poured over 2000 cm3 of ice. The organic layer was separated. The aqueous layer was extracted with 4×200 ml of CH2Cl2. The combined organic fractions were washed with 1000 ml of the saturated aqueous Na2CO3, dried over K2CO3, passed through a short Silica Gel 60 column (40-63 μm, d 40 mm, 1 50 mm), and evaporated to dryness. Fractional distillation gave white crystalline product, b.p. 128° C./0.8 mm Hg. Yield 185 g (94%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].C(N(CC)CC)C.[C:23]([O:27][C:28]([N:30]1[CH2:37][CH:36]2[CH:32]([CH2:33][NH:34][CH2:35]2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH:32]2[CH:36]([CH2:35][N:34]([C:9](=[O:11])[CH2:8][N:5]3[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4]3)[CH2:33]2)[CH2:37]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
A solution of (4-Chloro-5-methyl-3-trifluoromethylpyrazol-1-yl)acetic acid (97 mg), triethylamine (0.2 mL) and compound 5 (76 mg) in DMF (2 mL) was stirred at 0° C. and 1-propanephosphonic acid cyclic anhydride (0.55 mL, 50% in EtOAc) was added dropwise. The reaction mixture was stirred another 30 min at 0° C. and directly purified by preparative HPLC to provide the title compound 6 as a pale yellow oil (146 mg, 93%). LCMS: Rf: 4.495 min, M+H+: 459.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1.OO.CC[O:32]CC.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:18][CH2:19]2)=[O:16])=[N:11][CH:10]=1)=[O:32]
Reactant: COc1ccc(C2(C(=O)Nc3ncc(Sc4ccccc4Cl)s3)CC2)cc1
Reactant: CCOCC
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C2(C(=O)Nc3ncc(S(=O)c4ccccc4Cl)s3)CC2)cc1
Temperature: 85 °C
Yield: 40.2 %

Procedure:
1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid [5-(2-chloro-phenylsulfanyl)-thiazol-2-yl]-amide (50.0 mg, 0.120 mmol) was dissolved in 3 mL of acetic acid containing hydrogen peroxide (30% aqueous solution, 40.8 mg, 0.360 mmol). The mixture was warmed to 85° C. for 1 hour. Ether (1.5 mL) and water (1.5 mL) was added and the layers were separated. the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude reaction mixture was then separated by reverse-phase preparative liquid chromatography to yield the pure product (20.9 mg, 0.0483 mmol, 40.2%). ESI-MS m/z calc. 432.0. found; 433.3 (M+1)+ Retention time 3.34 minutes.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.Cl.[NH3:13]>>[C:10]([C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8])(=[O:11])[NH2:13]
Reactant: N
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Agent: Cl
Product: NC(=O)[C@@H]1CCCC[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
To 40 ml of aqueous conc. ammonia were added 10.0 g of trans-1,2-cyclohexanedicarboxylic acid anhydride with stirring at room temperature, and the mixture was stirred at room temperature for 4 hours and 15 minutes. The pH of the reaction mixture was adjusted to 1 with conc. hydrochloric acid with stirring under ice-cooling and the precipitated crystalline solid was collected by filtration and washed with water. The crystalline solid was recrystallized from ethanol to obtain 6.93 g of the desired compound as a colorless crystalline solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](Br)[C:22]#[CH:23]>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]23[CH2:17][CH:16]([CH2:18]2)[C:15](=[O:19])[N:14]([CH2:23][C:22]#[CH:21])[C:13]3=[O:20])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 0.97 ml of propargyl bromide dissolved in 10 ml of N,N-dimethylformamide is then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate and, after concentration by evaporation and subsequent recrystallisation from ethyl acetate/petroleum ether, the product is obtained having a melting point of 166°-168°.
Reaction SMILES: [CH2:1]([N:4]1[C@H:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:15][C@H:7]2OS1(=O)=O)[C:2]#[CH:3].[F-:18].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:18][C@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:8]1[NH:4][CH2:1][C:2]#[CH:3]
Reactant: [F-]
Reactant: C#CCN1[C@H]2c3ccccc3C[C@H]2OS1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: C#CCN[C@H]1c2ccccc2C[C@@H]1F
Reaction time: 1.5 h

Procedure:
To a stirred solution of 100 mg (0.4 mmol) 8b in 2 ml dry THF was added 139 mg (0.44 mmol) tetrabutylammonium fluoride at 0° C. The reaction mixture was stirred for 90 min and concentrated. 2 ml 3N sulphuric acid was added and the solution was heated in microwave oven for 10 min. The solution was poured into 20 ml ice-cold and vigorously stirred 0.35 N sodium hydroxide solution. The aqueous phase was extracted with dichloromethane-isopropyl alcohol mixture (10:1) and the organic phase was dried over magnesium sulphate and concentrated. The residue The residue was purified by preparative HPLC to obtain the compound 8d as 14 mg amount batch
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=O)[CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[N:8]=1)[CH3:2].[Cl-].[NH4+]>C1COCC1.C(O)C.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[CH:6]=1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1nc(OC)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2nc(OC)ccc2[nH]1

Procedure:
To a suspension of 3-(6-methoxy-3-nitropyridin-2-yl)-2-oxopropionic acid ethyl ester (Preparation 34, 276 mg, 1.03 mmol) in THF (12 mL) and ethanol (5 mL) was added saturated aqueous ammonium chloride solution (5 mL) and iron powder (346 mg, 6.18 mmol) in one portion. The reaction mixture was heated under reflux for 1 h then filtered whilst still hot through a celite plug, washing with hot ethyl acetate. The filtrate was cooled and washed with brine (20 mL), dried (MgSO4), filtered and adsorbed onto silica gel in vacuo. Purification via flash column chromatography (SiO2, ethyl acetate/hexanes, 1:9) gave the title compound as a beige solid. δH (CDCl3): 1.40 (3H, t), 3.99 (3H, s), 4.41 (2H, q), 6.74 (1H, d), 7.20 (1H, m), 7.62 (1H, d), 9.27 (1H, s).
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)C1C=CC=CC=1.C1CCCCC=1>CCO.[Pd]>[CH2:15]([C@@H:12]1[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]1)[CH2:16][CH3:17]
Reactant: CCC[C@H]1CC[C@@H](NCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCC[C@H]1CC[C@@H](N)CC1

Procedure:
To a solution of cis-1-benzylamino-4-propylcyclohexane (Preparation 52) (1.59 g, 6.87 mmol) in EtOH (90 mL) was added cyclohexene (10 mL) and 10% palladium-on-carbon (550 mg). The mixture was refluxed for 12 h. After cooling the mixture was filtered through celite. Solvent was removed in vacuo to give the title compound: δH (CD3OD): 0.95 (3H, t), 1.28-1.74 (13H, m), 2.95 (1H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:16]([CH3:15])[C:10](=[O:12])[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Product: CN(Cc1ccccc1)C(=O)COc1ccc([N+](=O)[O-])cc1

Procedure:
MP 95°-96°. Prepared from (4-nitrophenoxy) acetic acid and N-methylbenzylamine according to the method used in Intermediate 34(a) in EP-A-494623.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1.[Na].[N+:16]([C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[OH:27])([O-:18])=[O:17]>>[CH3:14][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:27][C:20]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])[O:13][N:12]=1
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Reactant: Cc1cc(CCCCCCCBr)on1
Agent: [Na]
Product: COc1ccc(OCCCCCCCc2cc(C)no2)c([N+](=O)[O-])c1

Procedure:
[I; R is CH3, n is 7, X is O, Ar is 2--O2N--4--CH3OC6H3 ] was prepared from 4.0 g of 5-(7-bromoheptyl)-3-methylisoxazole (Example 37a) and 2.94 g of the sodium salt of 2-nitro-4-methoxyphenol according to the procedure of Example 37, part (b), and was obtained in the form of a yellow solid (4.0 g), m.p. 51° C. when recrystallized from an ether-hexane mixture; MIC vs. rhinovirus Type 2 in vitro=0.3 μg/ml; and vs. polio-2 virus=0.17 μg/ml.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([NH2:37])[C:31]=3[CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[O:19]1[C:20]2[C:12]([C:2]([CH3:11])([CH3:1])[CH2:3][C:4]([CH2:6][NH:37][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]4[C:31]=3[CH:30]=[N:29][N:28]4[C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)([OH:5])[C:7]([F:8])([F:10])[F:9])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Reactant: Nc1cccc2c1cnn2-c1ccc(F)cc1
Product: CC(C)(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)c1cccc2c1OCC2

Procedure:
Prepared similarly to Example 1 from racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (which may be prepared according to WO 04/063163) and 1-(4-fluorophenyl)-1H-indazol-4-amine (Intermediate 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18](OC(=O)CC)(=O)[CH2:19][CH3:20].Cl>C(N(CC)CC)C>[CH2:19]([C:20]1[O:17][C:5]2[C:6]([C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:18]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(Cc1ccccc1)c1cc(F)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(F)cc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
Intermediate 50 (3.0 g, 13.63 mmoles) was taken in a RB flask and to this triethylamine (30 ml) and propionic anhydride (5.30 g, 40.78 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (2.27 g, 65% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 7.79(dd, J=7.1, 4.4 Hz, 1H), 7.73(dt, J=7.7,3.1 Hz, 2H), 7.46(t, J=8.2 Hz, 2H), 7.40(m, 1H), 7.27 (dd, J=8.2,1.4 Hz, 2H), 2.55(q, J=7.5 Hz, 2H), 1.19(t, J=7.6 Hz, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[O:30]([NH2:32])[CH3:31]>C(O)C>[CH3:31][O:30][N:32]=[C:21]([C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[CH:20][CH:19]=1)[CH3:22]
Reactant: CON
Reactant: CC(=O)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CON=C(C)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared as a ca. 9.5:0.5 mixture of two isomers by using a procedure similar to the one described for example 216 from example 208 (0.070 g, 0.230 mmol), ethanol (1.5 ml), sodium acetate (0.018 g, 0.230 mmol) and methoxylamine hydrochloride (0.019 g, 0.230 mmol). Off-white solid (0.020 g. 26%). M.P.: 155-157° C. 1H-NMR (δ ppm. DMSO-d6, 400 MHz): 8.88 (d, J=2.6 Hz, 1H), 8.61 (d, J=8.8 Hz, 0.05H), 8.55 (d, J=8.8 Hz, 0.95H), 8.36 (d, J=8.4 Hz, 1H), 8.02 (m, 3H), 7.81 (dd, J=8.8, 1.7 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.16 (s, 2H), 4.01 (s, 2.85H), 3.79 (s, 0.15H), 2.32 (s, 2.85H), 2.24 (s, 0.15H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:12])[O:15][C:14](=[O:16])[CH2:13]2)=[CH:6][CH:7]=1)(=[O:19])[CH3:18]
Reactant: O=C(O)CC(CC(=O)O)c1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C2CC(=O)OC(=O)C2)cc1

Procedure:
A solution of 3-(4-hydroxyphenyl)glutaric acid (800 mg) in acetic anhydride (15 ml) is heated at 100° C. for 2.5 hours and evaporated to dryness in vacuo. The residual solid is crystallized from chloroform-hexane to afford 600 mg of 3-(4-acetyloxyphenyl)glutaric anhydride, melting point 140°-143° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[N:23]=3)[N:18]=[CH:17][C:16]=2[C:26]([O:28]CC)=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-].Cl>O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[N:23]=3)[N:18]=[CH:17][C:16]=2[C:26]([OH:28])=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(C(=O)O)cnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Crude ethyl 4-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-6-chloro-1,5-naphthyridine-3-carboxylate (54) (240.8 g, 554 mmol) was suspended in a 1:1:1 mixture of MeOH:THF:H2O (500 mL each) and LiOH (39.8 g, 1.66 mol, 3 eq) was added. The mixture was maintained at rt and monitored by LCMS. After consumption of starting material, the volatiles were removed under vacuum and the resultant solution was neutralized by the addition of 6N HCl (˜3 eq). The mixture was then carefully acidified to pH 3-5 with 5N HCl (aq). The resultant slurry was then filtered and the precipitate was rinsed with water and then methanol. The resultant precipitate was dried in a vac-oven overnight, to give 203.6 g (83%, over two steps) of 4-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-6-chloro-1,5-naphthyridine-3-carboxylic acid (55).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]3[C:26]4=[N:27][CH:28]=[C:29]([CH2:31][NH2:32])[CH:30]=[C:25]4[N:24]=[CH:23]3)[CH:18]=[CH:17][C:15]=2[N:16]=1)(=O)C.N1C=CC=CC=1.[C:39](Cl)([CH3:41])=[O:40]>C(Cl)Cl>[OH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]3[C:26]4=[N:27][CH:28]=[C:29]([CH2:31][NH:32][C:39](=[O:40])[CH3:41])[CH:30]=[C:25]4[N:24]=[CH:23]3)[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(CN)cnc43)cc2s1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((6-(aminomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (50 mg, 0.12 mmol) from Example 91 in DCM (2 mL) were added pyridine (40 μL, 0.48 mmol) and AcCl (27 μL, 0.36 mmol). The resulting mixture was stirred at rt for 3 h before it was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford N-((3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)methyl)acetamide (45 mg, 82%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.40 (br s, 1H), 8.31 (s, 1H), 7.84-8.10 (m, 2H), 7.65 (s, 1H), 7.24-7.41 (m, 1H), 7.10-7.24 (m, 1H), 5.47 (s, 2H), 4.37 (d, J=5.5 Hz, 2H), 3.34 (d, J=8.7 Hz, 2H), 1.97-2.16 (m, 1H), 1.89 (br s, 1H), 1.86 (s, 3H), 1.61 (br s, 2H), 0.99-1.39 (m, 4H). LCMS (ESI) m/z 451 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C=O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]1)=[O:33])=[CH:26]2
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1)c1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.6 %

Procedure:
A mixture of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one (Intermediate 140, 130 mg, 0.448 mmol), 5-fluoro-1H-indole-2-carboxylic acid (96.3 mg, 0.538 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) (124 mg, 0.645 mmol) and 1-Hydroxybenzotriazole hydrate (HOBT) (87 mg, 0.645 mmol) in dichloromethane/DMF (4:1, 10 mL) was stirred for 2.5 hours at room temperature. The solvent was removed under reduced pressure and the residue was suspended in methanol, stirred for 45 minutes and then filtered to give title compound (161 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([OH:14])[CH:10]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:14][C:11]1[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[O:13][N:12]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Oc1cc(-c2ccc(F)cc2F)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(F)cc2F)on1
Yield: 85 %

Procedure:
5-(2,4-difluorophenyl)-3-hydroxyisoxazole (0.3 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.27 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.44 g, 85%) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1)([O-])=O.[Cl-].[Cl-].[Ca+2]>C(O)C.O.[Zn]>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2Sc2ccccc21
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CC(=O)c1ccccc1S2

Procedure:
To a solution of 2-nitro-10-oxo-dibenzo[b,f]thiepine (2.40 g, 9.30 mmol) (Coll. Czech. Chem. Commun. 1977, 42:2231) in 78% ethanol, was added a solution of CaCl2 (0.66 g, 5.90 mmol) in water (1.00 mL) followed by zinc dust (19.9 g, 30.4 mmol). The reaction mixture was refluxed for 2 h, filtered through celite and washed extensively with hot ethanol. The ethanol filtrate was concentrated to 5.00 mL and water was added to precipitate out the product. The product was filtered and dried under vacuum, purification was performed by recrystallization from EtOAc and hexane, yield 1.97 g (92.3%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][N:31]3[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: C1CNCCNC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCNCC3)c2c1

Procedure:
The title compound was prepared as a solid by the method of Example 59 step iv) using product of Example 59 step iii) and 1,4-diazepane.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[C:11]([C:13](=[C:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9])[C:14]([NH2:16])=[O:15])#[N:12]
Reactant: N#CCC(N)=O
Reactant: CC(=O)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(Cc1ccccc1)=C(C#N)C(N)=O

Procedure:
A mixture of (phenyl)acetone (5 g), cyanoacetamide (3.15 g), ammonium acetate (0.29 g) and acetic acid (0.45 mL) was refluxed in toluene (50 mL) using a Dean and Stark head to remove water for 6 h. The mixture was cooled and the crystalline product was filtered off (3 g) and used without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:12]1[N:17]=[N:16][C:15]([N:18]([CH2:26][C:27]2([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:30][CH2:29][CH2:28]2)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=1)#[N:11].[SH2:38]>CN1C(=O)CCC1>[C:10]([C:12]1[N:17]=[N:16][C:15]([N:18]([CH2:26][C:27]2([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:30][CH2:29][CH2:28]2)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=1)(=[S:38])[NH2:11]
Reactant: S
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(C#N)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(C(N)=S)nn1

Procedure:
NMP (40 mL) and DIPEA (10 mL) were added to t-butyl 6-cyanopyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (3.9 g, 10 mmol), and hydrogen sulfide was bubbled through the reaction mixture for 2 h. The reaction was diluted with water, and the resultant yellow solid was filtered and dried under vacuum to give 2.1 g of t-butyl 6-carbamothioylpyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a yellow solid.