Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][NH:12][CH2:11][CH2:10]3)=[CH:3]1.[C:17]([O:20][C@@H:21]([C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1)[CH3:22])(=[O:19])[CH3:18].C(N(CC)CC)C>C(O)(C)C>[C:17]([O:20][C@@H:21]([C:23]1[N:24]=[C:25]([N:12]2[CH2:11][CH2:10][C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:4]4[CH:5]=[CH:6][S:2][CH:3]=4)[CH:8]=3)[CH2:13]2)[CH:26]=[CH:27][N:28]=1)[CH3:22])(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: c1cc(-c2ccc3c(c2)CCNC3)cs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)O[C@H](C)c1nccc(N2CCc3cc(-c4ccsc4)ccc3C2)n1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of 6-thiophen-3-yl-3,4-dihydro-1H-isoquinoline hydrochloride (prepared according to the method of Example 248, Step B, 170 mg, 0.68 mmol) in isopropanol (6 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five, 136 mg, 0.68 mmol) followed by triethylamine (0.28 mL, 2.04 mmol). This mixture was stirred at reflux for 7 h, cooled to room temperature overnight, evaporated, and purified by flash column chromatography (0.5→1% methanol/chloroform) to give 253 mg (98%) of the title compound of Example 248, Step C as a yellow solid. 1H NMR (CDCl3, 250 MHz) δ 8.26 (d, 1H), 7.52-7.36 (c, 6H), 6.43 (d, 1H), 5.73 (q, 1H), 4.76 (s, 2H), 3.96-3.82 (c, 2H), 3.02 (t, 2H), 2.21 (s, 3H), 1.63 (d, 3H); MS (TS) 380 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([CH3:35])[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 16.5 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (75 mg, 0.18 mmol) in dichloromethane (2 mL) was added formaldehyde (37% solution in water) (80 μL, 1.06 mmol) and sodium triacetoxyborohydride (113 mg, 0.53 mmol). The reaction was stirred (rt) for 17 h. The mixture was diluted with dichloromethane and was washed with H2O (1×10 mL). The organic phase was washed with brine, and was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water to obtain 13 mg (17%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.88 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.37-7.28 (m, 5 H), 7.14 (dd, 1 H), 6.58 (s, 1 H), 5.65 (s, 2 H), 3.11-2.97 (m, 1 H), 2.85 (d, 2 H), 2.18 (s, 3 H), 2.04-1.94 (m, 4H), 1.77-1.61 (m, 2 H); ES-MS m/z 438.3 [M+H]+, HPLC RT (min) 2.11.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[N:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[S:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:21][C:22]1[CH:23]=[C:24]([N:27]=[C:28]=[O:29])[S:25][CH:26]=1>C(N(CC)CC)C.C(Cl)Cl>[CH2:14]([N:13]([C:28](=[O:29])[NH:27][C:24]1[S:25][CH:26]=[C:22]([CH3:21])[CH:23]=1)[C:9](=[N:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[S:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Reactant: Cc1csc(N=C=O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCN=C(SCC)N(CCCCCCC)C(=O)Nc1cc(C)cs1

Procedure:
The equipment was the same as in Example 26 above. 3.0 g (0.01 mole) 1,3-di-n-heptyl-2-S-ethyl isothiourea was mixed with 25 ml of methylene chloride. Two drops of triethylamine and 1 drop of dibutyltindilaurate were added and then 1.65 g (0.01 mole) 4-methyl thiophenyl isocyanate was added. The temperature rose from 23° to 33°. The reaction mixture was then vacuum evaporated to remove the methylene chloride to produce 4.65 g (100 percent of theory yield) of a yellow liquid having a nD30 of 1.5340. The liquid solidified on standing into a semi-solid. The product was identified as the title product by IR and NMR spectra analyses. Compound No. in Table 47 in Table I.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[CH2:29]([O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)[CH3:30].O>C1(C)C=CC=CC=1.C(O)C.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>[CH2:29]([O:31][C:32]1[CH:37]=[C:36]([C:3]2[CH:2]=[C:18]([O:19][CH3:20])[C:17]([O:21][CH3:22])=[CH:16][C:4]=2[CH:5]=[C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH:35]=[CH:34][CH:33]=1)[CH3:30]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: COc1cc(C=C2C(=O)Nc3ccccc32)cc(Br)c1OC
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOc1cccc(-c2cc(OC)c(OC)cc2C=C2C(=O)Nc3ccccc32)c1
Reaction time: 12 h
Yield: 62.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added to a solution of 3-(3-bromo-4,5-dimethoxybenzylidene)-1,3-dihydroindol-2-one (0.2 g, 0.56 mmol) in toluene (1 ml) and ethanol (1 ml), followed by addition of 2M aqueous sodium carbonate (1 ml, 2 mmol). To this mixture was added 3-ethoxyphenylboronic acid (0.1 g, 0.62 mmol) and the mixture was held at 100° C. in a sealed tube for 12 hours. The reaction mixture was then added to water (40 ml) and extracted with ethyl acetate (2×75 ml) The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml), dried over magnesium sulfate and concentrated. The resulting solid was triturated with methylene chloride/hexanes to afford 0.14 g (64%) of 3-(3′-ethoxy-4,5-dimethoxybiphenyl-2-ylmethylene)-1,3-dihydroindol-2-one as a yellow/orange solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][N:13]3[C:16](=[O:33])[C@@H:17]([NH:25]C(=O)OC(C)(C)C)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O.[ClH:41]>ClCCl.CCOCC>[ClH:41].[NH2:25][C@@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:15]=2)[CH2:11][CH2:12]1)=[O:33]
Reactant: Cn1cc(-c2ccc3c(c2)N(C(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)CC3)cn1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cn1cc(-c2ccc3c(c2)N(C(=O)[C@@H](N)Cc2ccccc2)CC3)cn1
Reaction time: 3 h

Procedure:
Tert-butyl (S)-1-(6-(1-methyl-1H-pyrazol-4-yl)indolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate (60.0 mg, 134 μmol) was dissolved in dichloromethane (1.5 mL) and TFA (1.50 mL, 19 mmol) was added and the solution was stirred for three hours. The reaction mixture was then concentrated to dryness and then taken up in ethyl acetate and extracted and basified with saturated sodium bicarbonate solution. The organic layer was then concentrated and the residue was dissolved in ethyl acetate and 3.0 equivalents of 1M HCl in ether solution was added forming an off-white precipitate that was filtered and washed with hexanes to give (2S)-2-amino-1-(6-(1-methyl-1H-pyrazol-4-yl)indolin-1-yl)-3-phenylpropan-1-one hydrochloride 82. MS ESI (pos.) m/e: 347.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:19][CH3:20])=[C:6]([F:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(=O)OC)cc1F
Yield: 100.7 %

Procedure:
A solution of 3-fluoro-4-hydroxy-benzoic acid methyl ester (1.5 g, 8.82 mmol), K2CO3 (2.43 g, 17.6 mmol) and ethyliodide (2.75 g, 17.6 mmol) in DMF (15 ml) was heated to 80° C. for 2 hrs. Addition of excess Na2CO3 and extraction with EtOAc followed by washing with satd. NaCl, then drying with Na2SO4 and evaporation afforded the title compound (1.76 g, 101% yield) as an orange oil. MS: m/e=170 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: O=C(Cc1ccc(F)cc1)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)C(Br)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At room temperature, to 20 g (0.093 mol) of α-(p-fluorophenyl)-acetophenone in 200 ml of chloroform, are added a few drops of a charge of 4.8 ml of bromine (0.93 mol) (a deep orange-color results). The resultant solution is heated to initiate reaction (the solution turns yellow), and then cooled to 0° C., and the balance of the 4.8 ml of bromine is added dropwise. The reaction mixture is stirred at room temperature for about 16 hours.
Reaction SMILES: [Br:1][C:2]1C=CC(C=C)=CC=1.[CH:10]([CH:12]=[CH2:13])=O.[C:14]([O-:19])(=[O:18])[C:15]([CH3:17])=[CH2:16].CC(N=NC(C#N)(C)C)(C#N)C.[CH3:32][CH:33](OC(C)=O)[CH2:34][O:35]C>>[Br:1][CH:2]=[CH:14][C:15]1[CH:17]=[CH:13][CH:12]=[CH:10][CH:16]=1.[CH:34]([CH:33]=[CH2:32])=[O:35].[C:14]([O-:19])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: COCC(C)OC(C)=O
Reactant: C=Cc1ccc(Br)cc1
Agent: C=C(C)C(=O)[O-]
Agent: C=CC=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: BrC=Cc1ccccc1
Temperature: 67 °C

Procedure:
3 g of 4-bromostyrene, 4 g of acrolein, 3 g of methacrylate and 0.2 g of AIBN were sufficiently mixed with 50 g of PGMEA. The mixture was polymerized by heating the mixture at 67° C. for 8 hours. After completion of the polymerization, the polymerization product was precipitated in n-hexane, filtered, and dried in vacuo to give a poly(bromostyrene-acrolein-methacrylate) copolymer.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH:24]1[CH2:30][C:29](=[O:31])[O:28][C:26](=[O:27])[CH2:25]1.Cl>[OH-].[Na+]>[C:14]([C:12]1[CH:13]=[C:8]([N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:29]([CH2:30][CH:24]([CH3:23])[CH2:25][C:26]([OH:28])=[O:27])=[O:31])[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CC(C)(C)c1cc(Nc2ccccc2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(CC(=O)O)CC(=O)N(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 140 °C
Yield: 54 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2.97 g (0.01 mole) of 4-anilino-2,6-di-t-butylphenol and 6.40 g (0.05 mole) of 3-methylglutaric anhydride was heated at 140° C. for 2 hours. After cooling, the reaction mixture was suspended in 10% sodium hydroxide, and acidified with 10% hydrochloric acid. The resulting precipitate was collected, rinsed with water, air dried, and recrystallized twice from a mixture of ethyl acetate and hexane to give a beige solid. This material was purified by silica gel chromatography, eluting with ethyl acetate, followed by trituration with a mixture of ethyl acetate and hexane. The resulting solid was recrystallized from a mixture of ethyl acetate and hexane to give 2.3 g of white solid 4-[N-(3,5-di-t-butyl-4-hydroxyphenyl)-N-phenylcarbamoyl]-3-methylbutyric acid, m.p. 153°-155° C. Analysis: Calculated for C26H35NO4 :% C, 73.4; % H, 8.3; % N, 3.3 Found: % C, 73.4; % H, 8.6; % N, 3.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=O)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C1(S(O)(=O)=O)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[F:25][C:26]1[CH:32]=[CH:31][C:29]([N:30]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[CH:28][CH:27]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Reactant: Nc1ccc(F)cc1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=S(=O)(c1ccccc1)N1CCC(C(=Nc2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 69 %

Procedure:
A mixture of 13.0 g (0.037 mol) of (4-fluorophenyl)[1-(phenylsulfonyl)-4-piperidinyl]methanone, 24.4 g (0.22 mol) of 4-fluoroaniline, and 0.7 g (0.004 mol) of benzenesulfonic acid in 500 mL of xylene was heated at reflux for 7 days. Water was removed with a Dean-Stark trap. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 phase was dried (Na2SO4), and the solvent was removed in vacuo. The residue was recrystallized from CH2Cl2 /hexane to give 11.24 g (69%) of a light grey solid, mp 123°-124° C.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=2[Br:19])=[CH:7][CH:6]=1.[BH4-].[Na+]>CO>[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][NH:2][CH3:1])=[CH:13][C:12]=2[Br:19])=[CH:7][CH:6]=1
Reactant: CN
Reactant: COc1ccc(COc2ccc(C=O)cc2Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(OCc2ccc(OC)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 2M methylamine in MeOH (30 mL) was added intermediate 32 (2.91 g, 9.1 mmol, 1 eq). After stirring this mixture at room temperature for 30 min, the solvent was removed and the residue was partitioned between saturated NaHCO3 and DCM (2×100 mL). The organic layer was dried (Na2SO4) and concentrated. The resultant residue was dissolved in MeOH (25 mL) and, after addition of sodium borohydride (1.0 g, 27.6 mmol, 3 eq), the mixture was stirred at room temperature for 1 h. Solvent was removed and the residue was partitioned between a Na2CO3 solution and CHCl3. The resultant organic layer was dried (Na2SO4) and concentrated in vacuo to give 2.7 g, (88%) of (4-(4-methoxybenzyloxy)-3-bromophenyl)-N-methylmethanamine (33).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N:13]([O-])=O.[Na+].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.C(O)(=O)C(O)=O>O>[ClH:1].[ClH:1].[NH:2]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)[NH2:13]
Reactant: Nc1cccc2ncccc12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: O
Product: NNc1cccc2ncccc12
Temperature: -1 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a 250 ml flask under a nitrogen atmosphere, water (20 ml) and concentrated HCl (60 ml, 0.61 moles) were charged and cooled down to −2 to 0° C. 5-Aminoquinoline (10 g, 0.069 moles) was added in one portion as a solid. An increase in temperature of 10° C. was observed. The orange-yellow suspension was re-cooled to −2 to 0° C. and sodium nitrite (5.8 g, 0.084 moles) dissolved in water (10 ml) was added dropwise to the acidic solution through an addition funnel over a period of 20 minutes at −2 to 0° C. The resulting mixture (dark-brown solution) was stirred for 1 hour at −2 to 0° C. L-Ascorbic acid (14.3 g, 0.081 moles) was then added in portions as a solid over a period of 20 minutes at −2 to 0° C. The reaction was allowed to come to room temperature (18-20° C.) over a period of 30 minutes, then heated at 50° C. and stirred for 30 hours at this temperature. The resultant slurry was cooled to room temperature (18-20° C.), stirred for 1 hour at this temperature, filtered and washed with propan-2-ol (40 ml). The product was dried to constant weight in an air tray drier at 40° C. to afford 11.75 g of 5-hydrazinoquinoline dihydrochloride as a green solid (HPLC purity calculated as area percent: 98%, with 1.6% of oxalic acid intermediate; 71.5% molar yield).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=O)[O:3]1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26]>>[F:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[CH3:20])[CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[O:3]
Reactant: CON(Cc1ccc(C)c(F)c1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CS(N)(=O)=O
Product: CON(Cc1ccc(C)c(F)c1)C(=O)C=C(O)C(=O)NS(C)(=O)=O
Yield: 67.7 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-fluoro-4-methyl-benzyl)-N-methoxy-acetamide (0.135 g, 0.418 mmol) with methanesulfonamide (0.042 g, 0.44 mmol) as described in the preparation of compound 22 gave 0.102 g (68% yield) of the title amide as a white solid. 1H NMR (400 MHz, DMSO) δ: mixture of rotamers: 2.2 (3H, s, CH3), 2.87 and 2.88 (3H, 2 S, SO2CH3), 3.63 and 3.67 (3H, 2 s, OCH3), 4.73 and 4.78 (2H, 2 s, NCH2), 6.14 and 6.16 (1H, 2 s, CH), 7.04-7.27 (3H, m, aromatics). HRMS (ESI/neg) calculated for C14H16FN2O6S: [M−H]−: 359.071312; found: 359.071347.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]([O:8]C)=O.[S:19]1[C:23]([C:24]2[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][CH:25]=2)=[CH:22][C:21]2[CH:38]=[CH:39][CH:40]=[CH:41][C:20]1=2>>[N:31]1([CH2:30][CH2:29][O:28][C:27]2[CH:36]=[CH:37][C:24]([C:23]3[S:19][C:20]4[CH:41]=[CH:40][CH:39]=[CH:38][C:21]=4[C:22]=3[C:6]([C:5]3[CH:10]=[CH:11][C:12]([CH2:13][N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:8])=[CH:25][CH:26]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1ccc(CN2CCCC2)c(OC)c1
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)ccc1CN1CCCC1
Yield: 51 %

Procedure:
By essentially following the procedure used to prepare Example 137, Part C, the title compound was prepared from methyl 3-methoxy-4-[(1-pyrrolidinyl)methyl]benzoate (Part B) and 1-[2-[4-(benzo[b]thiophen-2-yl)phenoxy]ethyl]pyrrolidine (Example 4, Part A) in 51% yield as a yellow foam. The flash chromatography was carried out by eluting with a gradient of EtOAc(100-90%)/Et3N(0-5%)/MeOH(0-5%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C@H:9]1[O:13][C:12](=[O:14])[CH:11]=[CH:10]1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])C.C(Cl)(Cl)Cl>O1CCOC1>[O:31]1[CH2:34][CH2:33][O:32][CH:29]1[C@@H:10]1[C@@H:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[O:13][C:12](=[O:14])[CH2:11]1
Reactant: O=C1C=C[C@@H](COC2CCCCO2)O1
Reactant: CCOC(C)=O
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: C1COCO1
Solvent: ClC(Cl)Cl
Product: O=C1C[C@H](C2OCCO2)[C@@H](COC2CCCCO2)O1

Procedure:
A solution containing 136 mg (0.686 mmol) compound (2f) and 18.7 mg (0.103 mmol) benzophenone in 100 mL [1,3]-dioxolane was irradiated at 20° C. for 5.75 hours according to the general procedure. Column chromatography (silica gel 40 g, ethyl acetate in hexanes 60%) gave compound (3f) as two diastereomers (170 mg, 91%) as a colorless oil, Rf=0.25, [α]25D −129°, c 0.8, CHCl3. 1H-NMR (300 MHz, CDCl3) δ: 1.38-1.82 (m, 6H), 2.40-2.46 (m, 1H), 2.60-2.75 (m, 2H), 3.39-3.48 (m, 1H), 3.61-3.70 (m, 1H), 3.75-3.81 (m, 2H), 3.84-3.87 (m, 2H), 3.93-3.98 (m, 2H), 4.53-4.63 (m, 2H), 4.86-4.89 (m, 1H). 13C-NMR (75.4 MHz, CDCl3, Dept) diastereomer A: δ: 18.72 (−), 25.20 (−), 29.98 (−), 30.02 (−), 40.08 (+), 61.52 (−), 64.68 (−), 65.33 (−), 68.33 (−), 78.98 (+), 98.21 (+), 103.64 (+), 176.51 (quat); B: δ: 19.23 (−), 25.20 (−), 30.21 (−), 30.24 (−), 40.08 (+), 62.20 (−), 65.05 (−), 65.45 (−), 68.81 (−), 79.08 (+), 99.09 (+), 103.71 (+), 176.72 (quat). C13H20O6; Exact Mass: 272.13; Mol. Wt.: 272.29; C, 57.34; H, 7.40; O, 35.25.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][CH3:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]=[C:22]=[O:23]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([CH2:18][CH3:19])[C:22]([NH:21][CH3:20])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: CCNC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: CCN(C(=O)NC)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
A solution of 1-benzyloxycarbonyl-4-(N-ethylamino)-piperidine (4.0 g) and methyl isocyanate (11 mL) was stirred for 30 hours at ambient temperature. The reaction mixture was diluted with chloroform and evaporated to give the urea as an oil; MS: m/z=320(M+1). The material was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3C[CH2:12]3)[CH:10]=[C:6]2[CH:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[N:3]=1.[C:27]([N:30]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>CN1C(=O)CCC1>[C:27]([N:30]1[CH2:36][CH2:35][CH2:34][N:33]([C:6]2[N:7]3[N:8]=[C:9]([CH2:11][CH3:12])[CH:10]=[C:2]3[N:3]=[C:4]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc3cc(C4CC4)nn3c(Cl)n2)cc1
Reactant: CC(=O)N1CCCNCC1
Solvent: CN1CCCC1=O
Product: CCc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCCN(C(C)=O)CC3)n2n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-c]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2H, 75 mg, 0.21 mmol) and N-acetylhomopiperazine (59 mg, 0.42 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted once more with EtOAc, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by recrystallization from ether and EtOAc to give the titled compound (50 mg, 51% yield) as an off-white solid. ESI-MS: m/z 465 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[OH-].[K+].I[CH3:12]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: Nc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CNc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2 g (11.6 mmol) 3-Bromoaniline is dissolved in 15 mL DMF and treated with 716 mg (1.1 eq.) KOH and 0.722 mL (1 eq.) iodomethane under continuous stirring at room temperature for 20 hours. The reaction mixture is extracted with ethyl acetate and water, the combined organic phases are washed with brine and dried with sodium sulfate and evaporated to dryness. The residue is column chromatographed (ethyl acetate/petroleum ether 2:5) to yield after evaporation the desired product as a yellow oil.