Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C([Li])CCC.CCCCCC.O=[C:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]1>O1CCCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[C:45]2[CH2:46][CH2:41][CH2:42][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:44]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(=Cc2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a stirring solution of (4-fluorophenylmethyl)-triphenylphosphonium chloride (17.68 g, 43.5 mmol) in dry tetrahydrofuran (60 mL) at −78° C. was added 2.5 M n-butyllithium in hexane (14.6 mL, 36.5 mmol). The reaction was warmed to 0° C. for 1 hr and t-Butyl 3-oxo-1-piperidinecarboxylate (3.46 g, 17.4 mmol) in tetrahydrofuran (60 mL) was added. The mixture was stirred at room temperature for 1 hr and the heated to reflux for 16 hr. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride. The reaction was extracted with ethyl acetate three times (100 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to a pale yellow oil. The oil was purified by flash chromatography (silica gel, hexane:ethyl acetate 9:1) to yield 3.82 g of a mixture of E and Z isomers as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.22-7.14 (m, 2H), 7.04-6.98 (m, 2H), 6.36 (s, 0.33H), 6.28 (s, 0.67H), 4.14 (s, 1.34H), 4.00 (s, 0.66H) 3.50 (t, J=5, 2H), 2.47 (t, J=5, 0.66H), 2.39 (t, J=5, 1.34H), 1.75-1.68 (m, 1.34H), 1.65-1.57 (m, 0.66H), 1.48 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([F:9])[CH:8]=1)#[CH:2].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([F:9])[CH:8]=3)[O:28][N:27]=2)=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: C#Cc1cc(F)cnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncc(F)cc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Temperature: 55 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a tetrahydrofuran (10 mL) mixture of 3-ethynyl-5-fluoro-pyridin-2-ylamine (129 mg, 0.95 mmol) described in Manufacturing Example 173-1-2 and 4-benzyloxy-phenyl-acetohydroximoyl chloride (314 mg, 1.14 mmol) described in Manufacturing Example 1-1-3 was added triethylamine (264 μL, 1.90 mmol) at room temperature, which was stirred for 1 hour at 55° C., and then for another hour at 60° C. This reaction mixture was cooled to room temperature, and then partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (212 mg, 60%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=2[O:2]1.Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:14]3[CH:15]=[C:16]([NH2:17])[CH:18]=[CH:19][CH:20]=3)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1ccc2c(c1)OCO2
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: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
3,4-methylenedioxyphenyl boronic acid (0.115 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.057 g in 58% yield.
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([O:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)OC[C@H]1COc2c(O)cccc2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)OC[C@H]1COc2c(OCc3ccccc3)cccc2O1
Yield: 1.5 %

Procedure:
A mixture of methanesulfonic acid (R)-5-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (0.6 g, 1.69 mmol), benzyl bromide (0.4 g, 2.30 mmol) and potassium carbonate (1.14 g, 8.30 mmol) in acetone (30 ml) was refluxed under nitrogen atmosphere for 5 h. The crude product was crystallized from 2-propanol to yield 8.8 mg of the pure title compound.
Reaction SMILES: C(N(CC)CC)C.[I:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23]>ClCCl>[I:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](=[O:14])[NH:23][CH2:22][C:21]([O:20][CH3:19])=[O:24])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1ccc(I)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Triethylamine (5.4 ml) was added to a solution of 4-iodobenzoyl chloride (5.06 g) in dichloromethane (30 ml) at 5° C. Glycine methyl ester hydrochloride (2.4 g) was then added to the reaction mixture and the mixture was stirred at 5° C. for 2 hours. The mixture was then stirred at ambient temperature overnight. Dichloromethane (100 ml) was added and the mixture was washed with water (2×100 ml), dried (MgSO4) and evaported. The residue was triturated with pentane to give a solid which was collected by filtration to give methyl 4-iodohippurate, m.p. 166-168° C. NMR: 3.65(3H,s), 4.0(2H,d), 7.65(2H,m), 7.88(2H,m) and 9.0(1H,m); m/z 320(M+H).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=2[CH:4]=1)[NH2:2].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:15]1(=[N:2][NH:1][C:3]2[N:8]=[N:7][C:6]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=3[CH:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: NNc1cc2c(nn1)CCCCCC2
Product: c1c(NN=C2CCCCC2)nnc2c1CCCCCC2

Procedure:
A solution of 10.0 g of 3-hydrazino-5,6,7,8,9,10-hexahydrocyclooct[c]pyridazine in 100 cc of cyclohexanone is boiled at reflux at a bath temperature of 180° for 1 hour and 45 minutes. The mixture is concentrated in a vacuum, whereby the crystalline title compound is obtained and is recrystallized from isopropanol. M.P. 160°-162° (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][CH:25]=[O:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S([CH2:37][N:38]=[C:39]=O)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][C:25]3[O:26][CH:39]=[N:38][CH:37]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCC=O)CC[C@H]2c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2C(CCc3cnco3)CCC2c2ccc(F)cc2)cc1
Yield: 24 %

Procedure:
A stirred mixture of (2RS,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionaldehyde (375 mg, 1.0 mmol, prepared from the corresponding alcohol by oxidation in accordance with the general method of example 29a), tosylmethyl-isocyanate (199 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol) and MeOH (10 ml) was heated under reflux conditions for 35 h, evaporated and purified by column chromato-graphy on silica gel (ethyl acetate/hexane 4:1) to give the title compound (100 mg, 24%) as a light yellow oil, MS: m/e=415.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[C@H:21]1[CH2:22][CH2:23][C@H:24]([O:27][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)[CH2:25][CH2:26]1
Reactant: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](O)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](OC2CCCCO2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9-(trans-4-hydroxycyclohexyl)-7H-purin-8(9H)-one (0.8 mmol) and dihydropyran (15 equiv.) in anhydrous chloroform/THF (30 mL/15 mL) containing p-TsOH (0.1 equiv.) was stirred at 50° C. for 1 day (LCMS indicative of complete reaction). The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on neutral alumina to give the desired product. MS (EI) m/z 487.3 (MH)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:7][CH:6]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:2][CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:10]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCCCCCc1ccc(CCN)cc1
Agent: Cl
Product: O=C(O)CCCCCCCc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1

Procedure:
By the reaction of ethyl 7-[4-(2-aminoethyl)-phenyl]-heptane-carboxylate hydrochloride with 4-chlorobenzoyl chloride, there is obtained 7-{4-[2-(4-chlorobenzamido)-ethyl]-phenyl}-heptane-carboxylic acid; m.p. 145°-148° C., after recrystallization from diethyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C2CCC(=O)CC2)cc1
Yield: 32 %

Procedure:
A solution of 4-(4-nitro-phenyl)-cyclohexanone (0.512 g, 2.34 mmol, as prepared in the previous step) in EtOH (50 mL) was hydrogenated under the following conditions on an H-cube apparatus fitted with a 30 mm CatCart™ 5% Pd/C cartridge: 40° C., 40 bar H2, flow rate 1 mL/min. The solvent was evaporated in vacuo. Silica gel chromatography of the residue with 25% EtOAc-hexane on a 20-g Isolute SPE column (FlashMaster system) afforded the title compound (0.140 g, 32%) as a colorless glassy solid. Mass spectrum (ESI, m/z): Calcd. for C12H15NO, 190.1 (M+H). found 190.2.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:4]=[N:5][CH:6]=[C:7]([Cl:10])[C:8]=1Cl>C(O)C>[NH2:1][C:8]1[C:7]([Cl:10])=[CH:6][N:5]=[N:4][C:3]=1[Cl:2]
Reactant: N
Reactant: Clc1cnnc(Cl)c1Cl
Solvent: CCO
Product: Nc1c(Cl)cnnc1Cl
Temperature: 25 °C

Procedure:
Dry ethanol is saturated with ammonia gas and placed in a sealed tube with 8.0 grams of 3,4,5-trichloropyridazine. The reaction mixture is heated at 120°-130° C. for five hours. The tube is opened and the reaction mixture concentrated under reduced pressure. The residue is dissolved in 20 ml of chloroform and the solution heated under reflux for 20 minutes. The solution is allowed to cool to ambient temperature for several hours in place. A solid precipitate is collected by filtration and repeatedly recrystallized from water to yield 2.8 grams of 4-amino-3,5-dichloropyridazine; m.p. 176°-178° C. The filtrate is concentrated under reduced pressure and the residue recrystallized from water to yield 2.0 grams of 4-amino-5,6-dichloropyridazine; m.p. 150°-151° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:28]1(I)[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOC(C)=O>CN(C)C=O>[CH:28]1([N:16]2[CH:17]=[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)=[N:15]2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: IC1CCCC1
Reactant: CC(C)(C)OC(=O)c1c[nH]nc1-c1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cn(C2CCCC2)nc1-c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
To tert-Butyl 3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate (156 mg, 0.46 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride, 60% in mineral oil (20.8 μg, 0.52 mmol). After the gas evolution ceased (about 5 minutes), cyclopentyl iodide (59 μL, 0.51 mmol) was added dropwise and the mixture was stirred for 16 hours at room temperature. EtOAc was added and the crude mixture was washed with a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc (3 times). The combined organic extracts were washed with water and brine. The organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with petroleum ether/DCM) to afford the title compound as a white solid (0.131 g, 69% yield). MS (ES+) m/e=405. 1H NMR (CDCl3) δH 1.51 (9H, s), 1.70-1.80 (2H, m), 1.85-2.00 (2H, m), 2.02-2.13 (2H, m), 2.18-2.30 (2H, m), 4.71 (1H, quint.), 7.06 (4H, d), 7.12 (1H, t), 7.35 (2H, t), 7.76 (2H, d), 7.95 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:22][CH2:23][O-:24].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([O:24][CH2:23][CH3:22])[N:12]=[C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CC[O-]
Reactant: Clc1nc(N2CCNCC2)c2[nH]c3cc(Br)ccc3c2n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N2CCNCC2)c2[nH]c3cc(Br)ccc3c2n1

Procedure:
200 mg (0.55 mmol) 7-bromo-2-chloro-4-(piperazin-1-yl)-5H-pyrimido[5,4-b]indole and 1.64 ml (1.64 mmol) 1 M NaOEt solution (EtOH) in 6 ml EtOH were heated in a microwave oven to 130° C. for 3 h. Then, the solvent was removed and the residue was suspended in water and sucked off. 200 mg (97%) of the title substance was obtained. ESI-MS [m/z]: 376, 378 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:8])=[CH:5][C:4]=1[CH3:23])#[N:2].[H-].[Na+].I[CH3:27]>CN(C=O)C>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[CH3:27])=[O:8])=[CH:5][C:4]=1[CH3:23])#[N:2]
Reactant: CI
Reactant: Cc1cc(C(=O)Nc2ccccc2-c2ccco2)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N(C)c2ccccc2-c2ccco2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-cyano-N-(2-furan-2-ylphenyl)-3-methylbenzamide from Example 21B (222 mg, 0.734 mmol) in DMF (8.0 ml) was added sodium hydride (60%, 44 mg, 1.10 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 45 min. Iodomethane (68 μl, 1.10 mmol) was added and the mixture was stirred for 18 h. The mixture was evaporated in vacuo and the residue was taken up in EtOAc, washed with brine, dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant pet.ether:EtOAc 80:20) to give a brown solid; yield 198 mg, 85%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:31]1[S:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>CN1C(=O)CCC1>[S:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[NH:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: Clc1nc2ccccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=c1c(CNc2nc3ccccc3s2)cn(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (40 mg, 0.140 mmol), N,N-diisopropylethylamine (74.0 mg, 100 μL, 0.567 mmol) and 2-chlorobenzothiazole (31 mg, 0.181 mmol) in NMP (0.5 mL) was heated at 115° C. in a sealed tube. After 2 hr., LCMS indicated the desired product to be present with some remaining starting material and minor impurities. Heating continued overnight. In the morning, more 2-chlorobenzothiazole (12 mg, 0.070 mmol) was added. Heating continued for another 24 hr. The reaction mixture was concentrated under a stream of nitrogen, and the crude product was purified by preparative reverse phase HPLC. The desired product 3-(benzothiazol-2-ylaminomethyl)-7-chloro-1-phenyl-1H-quinolin-4-one (13 mg, 22%) was obtained an off-white solid. MS calcd. for C23H16ClN3OS [(M+H)+] 418.1, obsd. 418.
Reaction SMILES: [C:1]1(=[C:6]([C:9]2[N:10]=[N:11][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:13]=2)[C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CO.C1COCC1.O=[Pt]=O>[CH:1]1([CH:6]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC(=C1CCCC1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=[Pt]=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCC(c1nnn[nH]1)C1CCCC1
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of cyclopentylidene-(2-trityl-2H-tetrazol-5-yl)-acetonitrile (2.05 g, 4.91 mmol) in 50 mL MeOH:THF (1:1) was added PtO2 (0.2 g), concentrated HCl (1.49 g), and the mixture was hydrogenated in a Parr shaker at 48 psi for 8 h. The mixture was filtered and concentrated. Flash chromatography of the residue on silica gel (0.25:1.25:3.5 conc. NH4OH (aq):MeOH:CH2Cl2), followed by a second column using the same conditions, provided 0.54 g (61%) of 2-cyclopentyl-2-(1H-tetrazol-5-yl)-ethylamine as a colorless solid. 1H NMR (D2O) δ 3.22 (m, 2H, —CH2NH2), 3.06 (m, 1H, —CHCH2NH2), 1.99 (m, 1H, —CHCHCH2NH2), 1.72 (m, 1H), 1.03-1.38 (m, 6H), 0.87 (m, 1H). 13C NMR (CD3OD) □ 161.11, 42.78, 42.56, 40.48, 30.61, 30.11, 24.96, 24.53. LRMS: m/z 180.1 (M−1). Anal. Calc'd for C8H15N5: C, 53.02; H, 8.34; N, 38.64. Found: C, 51.59; H, 8.18; N, 37.96.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.5 gms, 1.41 mmole) was dissolved in 20 mL methylene chloride and 0.5 mL pyridine, and the mixture was cooled in an ice bath. Methanesulfonyl chloride (0.16 g, 1.41 mmol) was added dropwise, and the reaction mixture was stirred for five minutes at ice bath temperature, then allowed to warm to room temperature. The reaction mixture was quenched by addition of water, and was extracted with methylene chloride. The organic layer was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 0.39 g of (R)-N-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methanesulfonamide, M+H=398.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[O:22])[C:17]=3[CH:28]=2)[C:3]1=[O:29].S(OC)(O[CH3:34])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([N:23]([CH3:34])[S:24]([CH3:27])(=[O:26])=[O:25])=[O:22])[C:17]=3[CH:28]=2)[C:3]1=[O:29]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)NS(C)(=O)=O)c3c2)c1=O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12)S(C)(=O)=O
Yield: 74.9 %

Procedure:
To a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-N-(methylsulfonyl)-1,2-benzisothiazole-3-carboxamide (0.300 g, 0.000670 mol) in acetone is added dimethyl sulfate (0.180 g, 0.00140 mol) followed by potassium carbonate (0.250 g, 0.00180 mol). The resultant mixture is stirred one hour at reflux and concentrated in vacuo. The residue is partitioned between methylene chloride and water. The organic layer is saved and the aqueous layer is extracted with methylene chloride. The combined organic layers are washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate:hexanes to give the title compound as a white solid (0.232 g, 74.9%, mp 120-122° C.).
Reaction SMILES: [C:1]([NH:9][C:10](=[S:28])[NH:11][C:12]1[S:20][C:15]2[CH2:16][O:17][CH2:18][CH2:19][C:14]=2[C:13]=1[C:21]([O:23]C(C)(C)C)=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([NH:9][C:10](=[S:28])[NH:11][C:12]1[S:20][C:15]2[CH2:16][O:17][CH2:18][CH2:19][C:14]=2[C:13]=1[C:21]([OH:23])=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccccc2)sc2c1CCOC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(=S)Nc1sc2c(c1C(=O)O)CCOC2)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.3 %

Procedure:
To a solution of tert-Butyl 2-(3-benzoylthioureido)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.104 g, 0.25 mmol, 1 equiv.) in DCM (10 mL) was added TFA (2 mL, 26 mmol, 100 equiv.), and the reaction was stirred at rt for 16 h. The solvent was removed and the product was triturated with 1:1 Et2O/hexanes (25 mL) and filtered. The product was purified by mass-directed reverse-phase chromatography and isolated as a white solid (3 mg, 3% yield). 1H NMR (400 MHz, CDCl3) δ 14.92 (br s, 1H), 9.02-9.09 (m, 1H), 7.83-7.91 (m, 1H), 7.55-7.66 (m, 2H), 7.41-7.50 (m, 2H), 7.19-7.23 (m, 1H), 4.69-4.76 (m, 2H), 3.92-3.98 (m, 2H), 2.88-3.03 (m, 2H). LCMS retention time: 2.955 min; LCMS purity at 215 nm=100%. HRMS m/z calculated for C16H15N2O4S2 [M++1]: 363.0468. found 363.0464.