Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[N:25]=[CH:24][N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=2)=[N:10]1.C1C(=O)N([Br:39])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:39])[NH:12][C:11]([C:21]2[N:25]=[CH:24][N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cn1cnc(C2=NC(c3ccc(F)cc3Br)C(C(=O)OCC)=C(C)N2)n1
Product: CCOC(=O)Cn1cnc(C2=NC(c3ccc(F)cc3Br)C(C(=O)OCC)=C(CBr)N2)n1
Yield: 69 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (0.45 g, 0.91 mmol) was reacted with NBS (0.16 g, 0.91 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.36 g, 69%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][N:20]([CH3:31])[C:21]1[S:22][C:23]2[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=2[N:25]=1>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:30][C:28]3[CH:27]=[CH:26][C:24]4[N:25]=[C:21]([N:20]([CH2:19][CH2:18][N:17]([CH3:16])[CH3:32])[CH3:31])[S:22][C:23]=4[CH:29]=3)=[O:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(C4CCCCC4)cc3)cc2s1

Procedure:
The title compound is prepared by following General Method A, using 4-cyclohexyl-benzoic acid (0.16 g, 0.78 mmol), and N*2*-(2-Dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.15 g, 0.60 mmol) to afford a white solid (0.076 g, 29%). LC/MS: Retention time 5.00 min; (m/z): calcd for C25H32N4OS (M+H)+: 437.6; found: 437.0.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[CH:8]=1.[CH3:16][C:17]([CH3:40])([CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1)[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:27]2[C:28]([CH3:30])=[CH:29][C:24]([O:23][CH2:22][C:17]([CH3:16])([CH3:40])[C:18]([O:20][CH3:21])=[O:19])=[N:25][CH:26]=2)=[CH:8][C:9]=1[F:15])#[N:12]
Reactant: COC(=O)C(C)(C)COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: N#Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(C#N)c(F)c2)cn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 104.8 %

Procedure:
N,N-dimethylformamide (30 mL) was added to 4-bromo-2-fluorobenzonitrile (2000 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate (4191 mg) and palladium chloride (dppf) methylene chloride complex (408 mg), and after adding 2N aqueous sodium carbonate solution (15 mL) to the mixture, the atmosphere was replaced with nitrogen and the resulting mixture was stirred at 60° C. for 7 hours. Ethyl acetate and water were added to the reaction mixture, and the liquids were separated. The organic layer was separated, washed with a saturated brine, and the residue obtained by concentrating the mixture under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 80:20) to obtain methyl 3-{[5-(4-cyano-3-fluorophenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate (3587 mg).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[NH2:12].[CH2:18]([CH:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=O)[CH3:19]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[NH:12][C:21]1[CH2:22][CH2:23][C:24](=[O:25])[C:20]=1[CH2:18][CH3:19]
Reactant: COc1ccc(N)cc1OC1CC2CCC1C2
Reactant: CCC1C(=O)CCC1=O
Product: CCC1=C(Nc2ccc(OC)c(OC3CC4CCC3C4)c2)CCC1=O
Yield: 100 %

Procedure:
According to the same procedure as in Example 1(3), using 3-[(1RS,2RS,4SR)-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyaniline produced in Example 8(2) instead of 3-cyclopentyloxy-4-methoxyaniline, and using 2-ethyl-1,3-cyclopentanedione instead of 1,3-cyclopentanedione, the title compound (yield 100%) was obtained as a dark brown oil.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[S+:11]=1)([CH3:9])([CH3:8])[CH3:7].[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(OCC)C>C(OC(=O)C)(=O)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([C:10]1[CH:15]=[C:14]([CH:16]=[CH:27][C:26]2[CH:29]=[CH:30][C:23]([N:22]([CH3:31])[CH3:21])=[CH:24][CH:25]=2)[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[S+:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1cc(C(C)(C)C)[s+]c(C(C)(C)C)c1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C=Cc2cc(C(C)(C)C)[s+]c(C(C)(C)C)c2)cc1
Temperature: 100 °C

Procedure:
319 mg of 2,6-di-tert-butyl-4-methylthiopyrylium perchlorate and 150 mg of 4-dimethylaminobenzaldehyde were heated in 5 ml of acetic anhydride for 40 minutes on an oil bath maintained at 100° C. After allowing to cool, diethyl ether was added to precipitate crystals and then the crystals were recrystallized from ethanol. Yield: 210 mg; m.p.: 240° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:19])[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[Br-:20]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:20][CH:10]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:19]
Reactant: [Br-]
Reactant: COc1ccc(C(=O)CCCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C(Br)CCc2ccccc2)cc1
Yield: 89.4 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 1-(4-methoxy-phenyl)-4-phenyl-butan-1-one prepared in the step 2 and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst. The crude product obtained was recrystallized with a mixture of petroleum ether and ethyl acetate (2:1) to give a product as a white solid in a yield of 89.4%, mp: 65-66 └. 1H-NMR (CDCl3, 400 MHz) δ: 2.38˜2.52 (2H, m, CH2), 2.75˜2.90 (2H, m, CH2), 3.88 (3H, s, OCH3), 5.03 (1H, t, J=8.00 Hz, CHBr), 6.93 (2H, d, J=9.2 Hz, ArH), 7.18˜7.32 (5H, m, ArH), 7.91 (2H, d, J=9.20 Hz, ArH); ESI-MS m/e (%): 334.0 (M+2, 1), 332.0 (M, 1), 229.9 (53), 227.9 (53), 135.0 (100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>O.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:18][C:19](=[O:21])[CH3:20]
Reactant: Sc1ccccc1Br
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CSc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
20 g (105.7 mmol) of 2-bromothiophenol, 19 g (137.5 mmol) of potassium carbonate, 27.8 g (165.5 mmol) of potassium iodide, 200 ml of dimethylformamide and 14.68 g (158.6 mmol) of chloroacetone are introduced into a 500 ml three-necked flask. The mixture is stirred for 2 hours at room temperature and is then poured into 800 ml of water. Extraction is carried out with ethyl acetate (3×400 ml). The organic phases are combined, washed with a molar sodium hydroxide solution (2×400 ml), dried over magnesium sulphate and concentrated. The residue is purified by chromatography on a silica column (elution solution: 10% ethyl acetate in cyclohexane). 24.1 g (Yield: 93%) of (2-bromothiophenoxy)acetone are obtained (yellow oil).
Reaction SMILES: S(=O)(=O)(O)O.COC[O:9][C:10]1[C:11]([CH3:34])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH3:33])([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1)[CH2:14][CH2:13]2.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[OH:9][C:10]1[C:11]([CH3:34])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH3:33])([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1)[CH2:14][CH2:13]2
Reactant: COCOc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc([N+](=O)[O-])cn1)O2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc([N+](=O)[O-])cn1)O2
Temperature: 0 °C

Procedure:
1 g of 10% w/v aqueous sulfuric acid was added to 45 ml of acetic acid containing 5.2 g of 6-methoxymethoxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman prepared as described in Preparation 34), and the resulting mixture was heated at 55°-58° C. for 15 minutes. The reaction mixture was cooled, poured into a mixture of 75 g of sodium bicarbonate and 75 g of ice, and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue gave the title compound as a light-brown oil.
Reaction SMILES: CCN(CC)CC.N1C=CC=CC=1.[CH2:14]([O:16][C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1)=[CH:23][CH:22]=2)=[O:18])[CH3:15].[CH:38]([O:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)([CH3:40])[CH3:39]>CC([O-])=O.CC([O-])=O.[Cu+2].C(Cl)Cl>[CH2:14]([O:16][C:17]([C:19]1[N:20]([C:45]2[CH:46]=[CH:47][C:42]([O:41][CH:38]([CH3:40])[CH3:39])=[CH:43][CH:44]=2)[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][N:29]=1)=[CH:23][CH:22]=2)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2[nH]1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1
Reaction time: 30 h

Procedure:
Anhydrous CH2Cl2 (10 mL), followed by Et3N (92 μL, 0.66 mmol), pyridine (54 μL, 0.66 mmol) and 3 Å molecular sieves (1 g) were added to a mixture of 5-(5-(trifluoromethyl)pyrid-2-yl)indole-2-carboxylic acid ethyl ester (110 mg, 1.33 mmol; see step (b)), Cu(OAc)2 (120 mg, 0.66 mmol), and 4-isopropoxyphenylboronic acid (119 mg, 0.66 mmol). The mixture was stirred vigorously at ambient temperature for 18 h after which additional Cu(OAc)2 (59.9 mg, 0.33 mmol), 4-isopropoxyphenylboronic acid (59.4 mg, 0.33 mmol), Et3N (46.4 μL, 0.33 mmol) and pyridine (27 μL, 0.33 mmol) were added. After a further 30 h of stirring, the mixture was filtered through Celite®. The filter cake was washed with EtOAc and the solvents concentrated and purified by chromatography to give the sub-title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[NH:14][C:13]2[N:12]=[C:11]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:10]=[C:9](N)[C:8]=2[N:7]=1)=[O:5])[CH3:2].C(Br)(Br)[Br:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[NH:14][C:13]2[N:12]=[C:11]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:10]=[C:9]([Br:29])[C:8]=2[N:7]=1)=[O:5])[CH3:2]
Reactant: BrC(Br)Br
Reactant: CCOC(=O)c1nc2c(N)nc(SCc3cccc(F)c3F)nc2[nH]c1=O
Product: CCOC(=O)c1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]c1=O

Procedure:
The sub-titled compound was prepared from the product of example 36, step (a) (2 g) and bromoform (40 ml) using the method of Example 3, step (b).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:17])[CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Cl.C([O-])(O)=O.[Na+].N12CCN(CC1)CC2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:21])([F:22])[F:20])[C:16](=[O:17])[C:10]2([CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)C2C1
Reactant: ClCc1ccccn1
Agent: C1CN2CCN1CC2
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)C2(Cc2ccccn2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In flame-dried glassware, 1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydroimidazo[1,5a]pyrazine-7-carboxylic acid tert-butyl ester (prepared as described in Step 4, 10.11 g, 30 mmol) was dissolved in 150 mL of DMF/30 mL of THF and cooled to −78° C. Potassium bis(tnimethylsilyl)amide (KHMDS, 0.5 M solution, 90 mL, 45 mmol) was added dropwise and allowed to stir for 1 h at −78° C. In separate glassware, 2-picolyl chloride-HCl (14.76 g, 90 mmol) was reacted with saturated aqueous NaHCO3 (150 mL), extracted with CH2Cl2 (3×150 mL), dried with MgSO4, evaporated and added 50 mL of dry THF with some molecular sieves. The resulting solution of 2-picolyl chloride free base was added to the reaction mixture at −78° C. via syringe and allowed to warm to room temperature overnight. The toluene and THF were evaporated and resulting DMF solution was partitioned with 150 mL of H2O/150 mL of IPE. 1,4-Diazabicyclo[2,2,2]octane (7.3 g, 65 mmol) and K2CO3 (12 g, 90 mmol) were added to the solution and the solution was stirred for one hour to remove excess 2-picolyl chloride. The organic solvents were separated and were removed by evaporation to give 11.45 g (89%) of essentially pure title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O-:18])=O)=[O:9].Cl.[NH2:20][OH:21].[OH-].[Na+].Cl>CO.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[NH:20][OH:21])=[O:9]
Reactant: NO
Reactant: O=C([O-])CCCCCNC(=O)/C=C/c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1ccco1)NCCCCCC(=O)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a solution of 6-{[(E)-3-(2-furyl)-2-propenoyl]amino}hexanoate (0.200 g, 0.75 mmol) in methanol (2 ml) a solution of hydroxylamine hydrochloride (0.210 g, 3.02 mmol) in methanol (3 ml) and NaOH (242 mg, 6.04 mmol) in H2O (1 ml) were added. The mixture was stirred for 30 min at room temperature and acidified with 1N HCl to pH 3 of the reaction medium. The mixture was extracted with ethyl acetate (3×25 ml), the organic phase was washed with brine and dried (Na2SO4). The solvent was evaporated and the residue (0.172 g) was crystallized from acetonitrile (5 ml) to give the title compound (0.117 g, 58%). M.p. 151-152.5° C. 1H-NMR (DMSO-d6, HMDSO), δ: 1.15-1.62 (m, 6H); 1.94 (t, J=7.2 Hz, 2H); 3.14-3.22 (m, 2H); 6.40 (d, J=15.5 Hz, 1H); 6.57 (dd, J=1.6 and 3.2 Hz, 1H); 6.74 (d, J=3.2 Hz, 1H); 7.21 (d, J=15.5 Hz, 1H); 7.75 (s, 1H); 8.11 (t, J=5.6 Hz, 1H); 8.67 (d, J=1.6 Hz, 1H); 10.34 (s, 1H). HPLC analysis on Zorbax SB-C18 column: impurities 1% (column size 4.6×150 mm; mobile phase acetonitrile+0.1% H3PO4, gradient from 25 to 100%; detector UV 270 nm; sample concentration 1.0 mg/ml; flow rate 1.5 ml/min). Anal. Calcd for C13H18N2O4, %: C, 58.64; H, 6.81; N, 10.52. Found, %: C, 58.64; H, 6.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:30][NH:31][C:32]([NH:34][OH:35])=[NH:33].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:30][NH:31][C:32](=[NH:33])[NH:34][OH:35])[CH2:8]1
Reactant: N=C(NN)NO
Reactant: Cc1ccnc2c1C(=O)CC(c1ccsc1Cl)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1ccsc1Cl)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 118.5 %

Procedure:
A mixture of 7-(2-chlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (222 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (314 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (4 ml) was stirred at 90° C. (bath temperature) for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (20 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (15 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (0.8 ml), and the mixture was concentrated under reduced pressure. To the residue was added ether (3 ml), and the mixture was stirred at 90° C. (bath temperature) for 3 hours and cooled to give crystals, which were filtered, washed with ethanol and dried to give 7-(2-chlorothiophen-3-yl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 104) (183 mg) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1)([O-])=O.O.C1CCCCC=1.[ClH:26]>C(O)C.[Pd]>[ClH:26].[ClH:26].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1
Reactant: O=C(O)CCCCCNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: C1=CCCCC1
Solvent: O
Solvent: CCO
Product: Nc1ccc(NCCCCCC(=O)O)cc1
Yield: 81 %

Procedure:
2 g (7.9 mmol) of 6-[N-(4-nitrophenyl)amino]caproic acid are partially dissolved in 40 ml of ethanol and 2 ml of water in a 150 ml three-necked flask equipped with a thermometer and a reflux condenser. 2 g of palladium-on-charcoal (10% active and 50% moisture) are then introduced, followed by 20 ml of cyclohexene. The mixture is brought to reflux for 2 hours and is then cooled, before being filtered through celite. After having run 4 ml (2.5 eq) of 5N hydrochloric acid onto the filtrate, the latter is evaporated to dryness and the residue is taken up in ethanol and precipitated from acetone. After filtration, 1.9 g of a white product are obtained, i.e. a final yield of 81%.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][NH:20]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][N:20]2[C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: Cc1[nH]c2ncnc(Cl)c2c1C
Product: Cc1[nH]c2ncnc(N3CCc4ccc(Cl)cc43)c2c1C

Procedure:
This product is prepared in a manner analogous to that described in Example 1 from 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine and 6-chloro-2,3-dihydroindole (1.1 equi-valents, see J. Org. Chem. 55(2), 580-584 (1990); CAS Reg. No. 52 537-00-5).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:31][CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: O=C(N[C@@H]1CCCNCC1)OCc1ccccc1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@@H](NC(=O)OCc6ccccc6)CC5)n4)nn(C4CCCCO4)c3cn2)cn1
Yield: 90.5 %

Procedure:
Following the procedure of Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and (R)-benzyl azepan-4-ylcarbamate were reacted to give benzyl (4R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate as a solid (90.5%). LC/MS: m/z 607.3 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[S:30][C:11]3=[N:12][C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:14][C:15](=[O:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31]([NH:38][CH2:39][C:40](O)=[O:41])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(Cl)CCl>CN(C=O)C.O.C(OCC)(=O)C>[C:34]([O:33][C:31]([NH:38][CH2:39][C:40]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[S:30][C:11]3=[N:12][C:13]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]4)=[CH:14][C:15](=[O:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:41])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc(N)c4)sc3n2)CC1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2nn3c(=O)cc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3s2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Crude tert-butyl 4-(2-(3-aminophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (60 mg, 0.140 mmol) is taken up in DMF (1.5 mL) and to it is added the Boc-glycine (37 mg, 0.210 mmol) then EDC (40.3 mg, 0.210 mmol). The mixture is stirred at room temperature for 24 hours and the reaction mixture is then taken up in water and ethyl acetate. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are then washed with water twice, then brine, dried over MgSO4, and concentrated in vacuo to give a yellow solid which is purified via column chromatography with 2-7% MeOH/DCM gradient to give tert-butyl 4-(2-(3-(2-(tert-butoxycarbonylamino)acetamido)phenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (crude material confirmed by LCMS analysis). The residue is then taken up in 2 mL of dichloromethane and trifluoroacetic acid (1 ml, 13.0 mmol) is added and the mixture is stirred for 18 hours. The solution is then concentrated in vacuo and washed with dichloroethane to give a crude yellow solid that is dissolved in methanol and purified by preparative HPLC to give 2-amino-N-(3-(5-oxo-7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)phenyl)acetamide (40 mg, 49%) as a tan solid after HPLC purification.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[NH:8][C:7]=1[Si](CC)(CC)CC)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[F:17][C:15]([F:16])([F:18])[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][NH2:1]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCN=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1c[nH]c2ccc(C(F)(F)F)cc12

Procedure:
2-(5-(trifluoromethyl)-1H-indol-3-yl)ethanamine was prepared according to method D Step V with 3-(2-azidoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole (0.400 g; 1.09 mmol) and triphenyl phosphine (0.427 g; 1.63 mmol) in methanol (5 mL) and tetrabutylamonium fluoride (3.26 mL, 1M) in THF (stirred for 36 hours).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].[CH3:21][S:22](Cl)(=[O:24])=[O:23].CCN(C(C)C)C(C)C.C(OC1C=CC(/C=C2/C(=O)N(CCNC(=O)C)C(=O)S/2)=CC=1)C>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:22]([CH3:21])(=[O:24])=[O:23])[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: CS(=O)(=O)Cl
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNS(C)(=O)=O)C2=O)cc1

Procedure:
The title compound 27a was prepared from compound 76 (101 mg, 0.25 mmol), methylsulfonyl chloride (21 μL, 028 mmol) and DIPEA (131 μL, 0.75 mmol) in a manner similar to that described for 25a in 96.2% (89 mg) yield as a yellow solid.