Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([Cl:14])=[C:4]([NH:15][C:16]2[CH:20]=[C:19]([O:21][CH3:22])[NH:18][N:17]=2)[N:3]=1.Cl.[F:24][C:25]1[CH:26]=[N:27][C:28]([C@@H:31]([NH2:33])[CH3:32])=[N:29][CH:30]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:14][C:5]1[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[N:7][C:2]([NH:33][C@H:31]([C:28]2[N:29]=[CH:30][C:25]([F:24])=[CH:26][N:27]=2)[CH3:32])=[N:3][C:4]=1[NH:15][C:16]1[CH:20]=[C:19]([O:21][CH3:22])[NH:18][N:17]=1
Reactant: COc1cc(Nc2nc(Cl)nc(N(C)S(C)(=O)=O)c2Cl)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N(C)S(C)(=O)=O)c2Cl)n[nH]1
Temperature: 160 °C
Yield: 76.8 %

Procedure:
A microwave reaction vessel was charged with N-{2,5-dichloro-6-[(5-methoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide (Method 25, 63.8 mg, 0.174 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 61.7 mg, 0.348 mmol), and DIPEA (0.122 ml, 0.693 mmol). Anhydrous n-BuOH (1 ml) was added, and the tube was sealed and heated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexane) to afford the title compound as a white solid (63.1 mg, 77%). LC-MS: 472 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 11.71 (s, 1H), 9.40 (s, 1H), 8.77 (s, 2H), 7.91 (s, 1H), 5.65 (s, 1H), 5.07-5.10 (m, 1H), 3.79 (s, 3H), 3.01 (s, 6H), 1.54 (d, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][NH:4][CH2:5][C:6]1[S:10][C:9](B(O)O)=[CH:8][CH:7]=1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:9]4[S:10][C:6]([CH2:5][NH:4][CH2:3][CH:2]([CH3:1])[CH2:14][CH3:15])=[CH:7][CH:8]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CCC(C)CNCc1ccc(B(O)O)s1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Temperature: 150 °C
Reaction time: 0.13 h
Yield: 20 %

Procedure:
To a CEM microwave tube containing the crude (5-{[(2-methylbutyl)amino]methyl}-2-thienyl)boronic acid (43 mg, 0.188 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), dioxane (1.5 mL), H2O (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (9 mL) and a 2 M solution of NH3/MeOH (6 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40° C., and the crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 50° C. to give 16.2 mg of the title compound (17%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6](SC)[C:5]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.[CH2:19]([O:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH2:19]([O:26][N:27]=[C:6]1[C:5]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CSC1=Nc2ccc(Br)cc2C12CCCCC2
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CO
Product: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Temperature: 45 °C

Procedure:
5′-Bromo-2′-(methylthio)spiro[cyclohexane-1,3′-[3H]indole] (9.0 g, 28.98 mmol) and O-benzylhydroxylamine hydrochloride (13.8 g, 86.9 mmol) were combined in methanol (150 mL) and heated to 45° C. for 6 hours. Methanol was evaporated in vacuo. Ethyl acetate was added to the residue and this mixture was washed with ammonium chloride solution. Ethyl acetate was dried over magnesium sulfate, ethyl acetate collected evaporated in vacuo and the residue was flash chromatographed on alumina 90 (9:1 Hexane/EtOAc) to the desired product (6.5 g, 60%). 1H NMR (DMSO-d6, 300 MHz) δ 1.38-1.70 (m, 8H), 1.92-2.06 (m, 2H), 5.06 (s, 2H), 6.71 (d, 1H, J=8.26 Hz), 7.22-7.43 (m, 7H), 9.62 (s, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH2:6].Br[CH2:15][C:16]([CH3:18])=[CH2:17].O>C1COCC1>[Br:3][C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH:6][CH2:17][C:16]([CH3:18])=[CH2:15]
Reactant: C=C(C)CBr
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)CNc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
To a suspension of NaH 60% dispersion in oil (97 mg, 0.0023 mol) in 2 mL of anhydrous THF at 0° C. was added 2-bromo-5-nitroaniline (500 mg, 0.0023 mol) in 2 mL of THF dropwise, the temperature was raised to rt to complete deprotonation then lowered to 0° C. 3-bromo-2-methylpropene (232 mL, 0.0023 mol) was added very slowly and the reaction mixture was stirred at 0° C. for 3 h then neutralized with water (5 mL). The mixture was extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and concentrated in vacuo to an oil that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 8:2) to give 200 mg (32%) of 2-bromo-N-(2-methyl-2-propenyl)-5-nitroaniline (structure 55A of Scheme XLVII, where R1 =methyl, R2 =H). Data for 2-bromo-N-(2-methyl-2-propenyl)-5-nitroaniline: 1H NMR (400 MHz, CDCl3) 7.55 (d,J=8.5, 1H), 7.40 (dd,J=8.5, 2.8, 1H), 7.39 (d,J=2.8, 1H), 4.96 (s, 2H), 4.95 (bs, 1H), 3.82 (d,J=5.9, 2H), 1.81 (s, 3H).
Reaction SMILES: [F-].[K+].[F:3][C:4]([Si](C)(C)C)([F:6])[F:5].[Br:11][C:12]1[CH:13]=[N:14][C:15](I)=[N:16][CH:17]=1.N>CN1C(=O)CCC1.CN(C)C=O>[Br:11][C:12]1[CH:13]=[N:14][C:15]([C:4]([F:6])([F:5])[F:3])=[N:16][CH:17]=1
Reactant: Brc1cnc(I)nc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: N
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ncc(Br)cn1

Procedure:
A mixture of potassium fluoride (1.77 g) and cuprous iodide (5.79 g) was stirred and heated together using a heat gun under vacuum (˜1 mm) for 20 min. After cooling, dimethyl formamide (20 ml) and N-methyl pyrrolidinone (20 ml) were added followed by (trifluoromethyl)trimethylsilane (4.1 ml) and 5-bromo-2-iodopyrimidine (6.5 g). The mixture was stirred at rt for 5 h and then the brown solution was poured into 6N ammonia solution. The product was extracted into ethyl acetate and the extracts were washed with sodium bicarbonate solution and brine and then dried (Na2SO4) and evaporated. Chromatography on silica gel (elution with 20-50% dichloromethane in pentane) gave the title compound (D30) as a white solid (2.4 g). 1H NMR (CDCl3): 8.97 (2H, s).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Br:12])=[CH:7][CH:8]=2)[CH:3]=1.Cl.N([O-])=O.[Na+].[F:18][B-](F)(F)F.[Na+]>C(OC)(C)(C)C.C(OCC)C>[Br:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][CH:2]=[C:3]2[F:18])=[CH:8][CH:7]=1
Reactant: Nc1ccc2ccc(Br)cc2c1
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Fc1cccc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
A solution of the product from Step A (5 g, 21 mmol) in methyl tert-butyl ether (20 ml) was treated with a solution of hydrogen chloride in diethyl ether (16.9 ml, 2 M) and the resulting mixture was stirred at room temperature. After 30 minutes, solids had precipitated and were filtered and washed with methyl tert-butyl ether. These solids were added to 6 M HCl (57.7 ml) and the resulting suspension was cooled to 0° C. Sodium nitrite (4.7 g, 70 mmol) followed by sodium tetrafluoroborate (7.4 g, 70 mmol) were added portionwise keeping the temperature at 0° C. The mixture was stirred at 0° C. for 30 minutes, then filtered. The filtrate was washed with ice cold water and extracted with ice cold methyl tert-butyl ether to give 7-bromo-1-fluoronaphthalene (4 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=1.8 Hz, 1H), 7.97 (dd, J=9.0, 1.8 Hz, 1H), 7.80 (d, J=8.1 H), 7.72 (dd, J=8.7, 2.1 Hz, 1H), 7.55 (td, J=7.8, 5.4 Hz, 1H), 7.39 (ddd, J=10.8, 7.8, 0.9 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:14]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][S:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(CCCl)c1ccc(O)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: ClCCl
Product: O=S(=O)(CCN1CCC(Cc2ccccc2)CC1)c1ccc(O)cc1
Reaction time: 16 h
Yield: 38.7 %

Procedure:
To a solution of 40.0 g 4-(2-chloro-ethanesulfonyl)-phenol (181 mmol) in 600 ml CH2Cl2 were added 69.9 g 4-benzylpiperidine (399 mmol). After stirring for 16 h at r. t. the reaction mixture was concentrated to 100 ml and directly purified by chromatography over silica gel (CH2Cl2/MeOH/NH3 19/1/0.1). Recrystallization from ethyl acetatelhexane (2:1) yielded 25 g product (70 mmol, 38%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:7][C:6]=12.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].CCN(CC)CC>C1COCC1>[F:12][C:11]([F:14])([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[C:6]2[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(Br)c3n2)cc1
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-bromo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (Example C.1 step 2a) (12.30 g, 30 mmol), trimethylsilylacetylene (8.3 mL, 60 mmol) and Et3N (6.3 mL, 45 mmol) in THF (30 mL) was stirred for 10 min at 23° C. while being purged with Argon, then PdCl2(PPh3)2 (105 mg, 0.5 mol %), PPh3 (20 mg, 0.25 mol %) and CuI (17 mg, 0.3 mol %) were added. Stirring was continued at 75° C. for 38 h. After 22 h, trimethylsilylacetylene (2.1 mL) and Et3N (2.1 mL) was added. Cooled to 23° C., diluted with ethyl acetate (100 mL), filtered through celite, washed with ethyl acetate. Removal of the solvent in vacuum left the 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (13.65 g, 106%) as an orange solid, which can directly be used in the subsequent step. An analytical sample was obtained by silica gel column chromatography with heptane/EtOAc. MS (ISP) 427.0 [(M)+]; mp 136° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[OH:23])=[O:11])([CH3:8])[CH2:6][CH3:7])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38]O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][O:23][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]([Cl:22])=[CH:21][C:12]=2[C:10](=[O:11])[NH:9][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:24])([CH3:8])[CH2:6][CH3:7])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1O
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 0.95 g of 2-[(4-chloro-1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-butyric acid ethyl ester, 0.76 g 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester and 1.43 g triphenylphosphine in 30 mL of dry THF, 1.10 g of diisopropylazodicarboxylate were added. After 18 h at room temperature 1.43 g of triphenylphosphine and 1.10 g of diisopropylazodicarboxylate were added, and after 3 h again 1.43 g of triphenylphosphine and 1.10 g of diisopropylazodicarboxylate were added. After an additional 24 h the reaction was concentrated. After chromatography on silica (ethyl acetate/heptane) 1.17 g of 4-[4-chloro-2-(1-ethoxycarbonyl-1-methyl-propylcarbamoyl)-naphthalen-1-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH3:14])[C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O>[CH2:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:3]=[C:4]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[CH3:14]
Reactant: CCSc1ncnc2c(N3CCCCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CCSc1ncnc2c(N3CCCCC3)nc(N3CCNCC3)nc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-8-ethylthio-4-piperidino-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.
Reaction SMILES: C(N(CC)CC)C.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:17]=[C:18]1[C:27]([C:28]#[N:29])=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([C:36]([C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)=[O:37])[CH2:32][CH2:31]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19]1>ClCCl>[O:17]=[C:18]1[C:27]([C:28]#[N:29])=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([C:36]([C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)=[O:37])[CH2:32][CH2:31]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:19]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc2[nH]c1=O
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
Cupric acetate (497 mg, 2.74 mmol), triethylamine (380 μL, 2.74 mmol), and phenyl boronic acid (335 mg, 2.74 mmol) were added successively to a solution of Compound 116 (500 mg, 1.37 mmol) in dichloromethane. The solution was stirred at room temperature for 48 h. The solution was filtered through celite and washed successively by saturated NaHCO3 solution, water, and brine. The organic phase was dried over Na2SO4 and evaporated to yield a residue which was purified by flash chromatography eluting with 0–1% MeOH in dichloromethane gradient to get 187 mg (31%) of white solids. M.P. 289° C. 1H NMR (DMSO-d6): δ 3.78 (m, 4H), 4.02 (m, 4H), 6.60 (d, J=7.6 Hz, 1H), 7.22 (m, 1H), 7.38 (m, 3H), 7.57–7.71 (m, 5H), 7.88 (dd, J=0.8, 4.8 Hz, 1H), 8.02 (d, J=7.2 Hz, 1h). EIMS m/z 441 (M+1). Anal. (C25H20N4O2S) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH:12]=O.[Br:14]CC1C2C(=CC=CC=2)C=CC=1>>[Br:14][CH2:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Reactant: BrCc1cccc2ccccc12
Product: Clc1ccc2nccc(CBr)c2c1

Procedure:
4-(Bromomethyl)-6-chloroquinoline was prepared from 6-chloroquinoline-4-carbaldehyde following the procedure described in the preparation of 1-(bromomethyl)naphthalene.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:13][C:14]1[N:23]=[C:22]2[C:17]([C:18](=[O:30])[C:19]([C:27]([OH:29])=[O:28])=[CH:20][N:21]2[CH:24](O)[CH3:25])=[CH:16][CH:15]=1)[CH3:12]>N1C=CC=CC=1>[CH2:11]([O:13][C:14]1[N:23]=[C:22]2[C:17]([C:18](=[O:30])[C:19]([C:27]([OH:29])=[O:28])=[CH:20][N:21]2[CH2:24][CH2:25][O:2][CH:1]=[O:3])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1ccc2c(=O)c(C(=O)O)cn(C(C)O)c2n1
Reactant: O=CO
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCOc1ccc2c(=O)c(C(=O)O)cn(CCOC=O)c2n1
Reaction time: 0.75 h

Procedure:
Formic acid (1 ml) was added to acetic anhydride (2 ml) which was cooled to 0°. The mixture was warmed to 50° for 15 minutes, cooled to 0° and added to a suspension of 7-ethoxy-1,4-dihydro-1-hydroxyethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.78 g) in dry pyridine (10 ml). The mixture was stirred at 0° for 45 minutes and then for 1 hour at room temperature. The solid was collected and washed with water and dried, m.p. 208.5°-210° (d). (71%).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:38][C:39]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:42]=[CH:41][N:40]=1>C(Cl)Cl.C(N(CC)CC)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:14]([N:48]1[CH2:49][CH2:50][N:45]([C:43]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:38])[CH:44]=2)[CH2:46][CH2:47]1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: Cc1cc(N2CCNCC2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC2)ccn1
Yield: 90.1 %

Procedure:
To a solution of Boc-D-tert-leucine (0.23 g) in methylene chloride (5 ml) were added HOBt (0.20 g), WSC (0.29 g) and triethylamine (0.28 ml) under ice-cooling, and the reaction mixture was mixed at 0° C. for 15 minutes. Then, 1-(2-methyl-4-pyridinyl)piperazine (0.18 g) obtained in Example 114b) was added thereto, and further mixed at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The reaction mixture was washed with an aqueous potassium carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified with basic silica gel column (ethyl acetate) to obtain the title compound as a colorless solid (0.35 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H]>O1CCCC1.CO.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[CH:4][C:3]=1[NH2:19]
Reactant: [H][H]
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2Cl)cc1OC(F)F
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(-c2cc(N)c(Cl)cc2Cl)cc1OC(F)F

Procedure:
1.5 g (4.2 mmol) of 2,4-dichloro-5-(5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)nitrobenzene were dissolved in a mixture of 50 ml of tetrahydrofuran and 50 ml of methanol and admixed with 4 g of Raney nickel. The mixture was stirred at room temperature under a gage pressure of 0.3 bar of hydrogen for 4 h and then filtered through kieselguhr. The filtrate was dried using magnesium sulfate and then evaporated to dryness. This gave 1.3 g of the aniline.
Reaction SMILES: [C:1]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].Cl.[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH3:19])[CH2:3][CH2:2][C:1]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: CNC
Reactant: C=CC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CN(C)CCC(=O)N(C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from N-acryloyl-N-methyl-4-nitro-aniline and dimethylamine hydrochloride
Reaction SMILES: [NH:1]([C:25]([O:27][CH:28]1[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:30]([CH3:46])([CH3:45])[CH2:29]1)=[O:26])[NH:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([CH3:24])([CH3:23])[CH2:7]1)=[O:4].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>>[N:2]([C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([CH3:23])([CH3:24])[CH2:7]1)=[O:4])=[N:1][C:25]([O:27][CH:28]1[CH2:29][C:30]([CH3:46])([CH3:45])[N:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:32]([CH3:34])([CH3:35])[CH2:33]1)=[O:26]
Reactant: CCCCCCCCON1C(C)(C)CC(OC(=O)NNC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)N=NC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C

Procedure:
The procedure of Example 4 is repeated using 4.6 g of bis(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl) hydrazine-1,2-dicarboxylate and 2.3 g of iodobenzene diacetate to afford 3.3 gg of the title compound as a pale yellow oil. NMR, IR and mass spectra analyses are consistent with the desired structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:27]1(I)[CH2:31][CH2:30][CH2:29][CH2:28]1>O>[CH:27]1([N:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:15])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: IC1CCCC1
Reactant: COC(=O)c1c[nH]c(=O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(C2CCCC2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
To a solution of methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate (780 mg, 3.8 mmol, Bionet), potassium carbonate (650 mg, 4.7 mmol, Aldrich), and 6 mL of DMF was added cyclopentyl iodide (0.52 mL, 4.5 mmol, Aldrich). The solution was stirred at RT for 4 h, then diluted with 50 mL of water. The solids were filtered and washed with CH2Cl2 and EtOAc. The filtrate was concentrated in vacuo and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 15% EtOAc:hexane to give 240 mg (23%) of methyl 2-cyclopentyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate as an off-white solid. MS m/z: 272.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]3C(=O)C4=CC=CC=C4C3=O)=[N:19][N:18]=[C:17]2[CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]3[C:17]([CH2:33][N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])=[N:18][N:19]=[C:20]3[CH2:21][N:22]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: CCN(CC)Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN(CC)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 27, 5chloro-2-[3-[(diethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.