Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:15](Cl)[CH:16]([CH3:18])C)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[C-:20]#[N:21].[K+].C1OCCOCCOCCOCCOCCOC1.O>C(#N)C>[CH3:1][N:2]([CH:15]([CH2:16][CH3:18])[C:20]#[N:21])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: [C-]#N
Reactant: COc1ccc(CCN(C)C(Cl)C(C)C)cc1OC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCC(C#N)N(C)CCc1ccc(OC)c(OC)c1
Yield: 87 %

Procedure:
4.67 g of 3-((N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-amino)- 2-methylpropyl chloride was dissolved in 40 ml of acetonitrile, followed by the addition of 2.13 g of potassium cyanide and 0.1 g of 18-crown-6. The obtained mixture was heated under reflux for 40 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (1:1)] to obtain 3.93 g of the title compound as a pale yellow oil (yield: 87%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C.[BH4-].[Na+]>ClCCCl>[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(NC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 15 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
A solution of 4-fluoroaniline (32.7 g), N-benzylpiperidinone (106.0 g) and acetic acid (106.0 g) in 1,2-dichlorethane (1200 ml) is brought to a temperature below 15° C. To the stirred solution is added slowly a suspension of acetic acid (495.0 g) and sodium borohydride (31.2 g). After 2 h stirring at 15° C. and another 2 h at r.t., the solvent is removed in vacuo. Ethyl acetate (500 ml) and water (700 ml) are added under stirring and the resulting mixture is neutralised with sodium carbonate (ca. 250 g). The organic phase is separated, washed with a 2 M NaHCO3 solution (100 ml) and water (100 ml) and dried with sodium sulphate. 53.8 g product is obtained as orange crystals after removal of the solvent and recrystallisation from ether/petroleum ether. Mp. 90-92° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCNCCC
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (13.28 g, 0.04 mole) and 1,1'-carbonyldiimidazole (7.14 g, 0.044 mole) in 300 ml of tetrahydrofuran was stirred at room temperature for 6 hrs. Then, under nitrogen atmosphere, dipropylamine (12.12 g, 0.12 mole) was added and the reaction mixture was heated at reflux for 3 hrs. The reaction mixture was filtered and the filtrate was evaporated to dryness. The solid was dried under high vacuum overnight and was recrystallized from isopropyl alcohol-water. The crystalline solid was collected by filtration, washed with water, and dried under high vacuum over the weekend to give 9.0 g (54%), mp 153°-55° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
tert-Butyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (500 mg; 2.3 mmol) in pyridine (20 mL) was cooled to 0° C. To this cooled solution was added a solution of p-toluenesulfonyl chloride (483 mg, 2.53 mmol) in pyridine (5 mL) over a period of 1 hour. The reaction mixture was allowed to slowly warm to ambient temperature and stirring was continued at ambient for 48 hours. The volatiles were removed in vacuo, and the residue was redissolved in toluene and concentrated again in vacuo. The crude material was triturated with ethyl acetate. This was further purified by chromatography on a 12 g silica gel column eluted with 5% ethyl acetate/hexanes for 3 minutes and then eluted with a gradient to 100% ethyl acetate over 20 minutes. The title compound was isolated as an oil (397 mg; 64% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82-7.69 (m, 2H), 7.48 (d, J=7.9 Hz, 2H), 4.92 (d, J=2.8 Hz, 1H), 4.23-3.82 (m, 4H), 3.12 (dd, J=25.5, 13.9 Hz, 2H), 2.42 (d, J=3.6 Hz, 3H), 1.87 (d, J=20.3 Hz, 2H), 1.35 (dd, J=23.0, 13.0 Hz, 9H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][C:5]1[N:6]=[C:7]([NH:17][C:18](=[NH:22])SCC)[S:8][C:9]=1[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1>C(O)C>[CH2:1]([NH:3][C:18]([NH:17][C:7]1[S:8][C:9]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)=[C:5]([CH3:4])[N:6]=1)=[NH:22])[CH3:2]
Reactant: CCN
Reactant: CCSC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Solvent: CCO
Product: CCNC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1

Procedure:
To a solution of ethylamine in ethanol (20% w/w, 10 ml) was added N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-S-ethylisothiourea (292 mg), and the mixture was heated in a steel autoclave at 110° C. for 17 hours. The mixture was evaporated under reduced pressure and crystallized from ethanol. The precipitate was collected by filtration to give N-ethyl-N′-(4-methyl-5-(4-methylpyridin-2-yl)-thiazol-2-yl)guanidine (124 mg).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[C:8]([OH:10])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1.O.O1CCOCC1.Cl[CH:22]([F:24])[F:23]>[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH:22]([F:24])[F:23])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(O)cc(OC(F)F)n1
Reactant: FC(F)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(OC(F)F)cc(OC(F)F)n1
Temperature: 40 °C
Yield: 86.7 %

Procedure:
14.0 g (0.067 mole) of 4-difluoromethoxy-6-hydroxy-2-methylthiopyrimidine are suspended in 18 ml of 50% potassium hydroxide solution, 10 ml of water and 160 ml of dioxane. After the addition of 0.5 g of 18-crown-6, the reaction mixture is heated to 40° C., and 20 g of chlorodifluoromethane are subsequently introduced over 5 hours. The aqueous phase is then separated and the organic phase is distilled under a high vacuum, affording 15.0 g (86.4% of theory) of 4,6-bis-difluoromethoxy-2-methylthiopyrimidine with a boiling point of 63° C./0.06 mbar. The substance melts at 46°-48° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH:33]2[CH2:38][CH2:37][CH:36]([P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:35][CH2:34]2)=[C:26]2[C:30]=1[C:29](=[O:31])[N:28]([CH3:32])[CH2:27]2>>[CH2:41]([O:40][P:39]([CH:36]1[CH2:37][CH2:38][CH:33]([C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:2]3[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[O:19][CH3:20])[N:3]=3)=[C:30]3[C:26]=2[CH2:27][N:28]([CH3:32])[C:29]3=[O:31])[CH2:34][CH2:35]1)(=[O:46])[O:43][CH2:44][CH3:45])[CH3:42]
Reactant: COc1ccccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: CCOP(=O)(OCC)C1CCC(c2ccc(N)c3c2CN(C)C3=O)CC1
Product: CCOP(=O)(OCC)C1CCC(c2ccc(Nc3nc(Nc4ccccc4OC)ncc3C(F)(F)F)c3c2CN(C)C3=O)CC1

Procedure:
The title compound was prepared according to the procedure for Example 102 using 4-chloro-N-(2-methoxyphenyl)-5-(trifluoromethyl)pyrimidin-2-amine (7.2 mg, 0.024 mmol) and diethyl [4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexyl]phosphonate (Compound 193A, 9.0 mg, 0.024 mmol). The reaction mixture was purified by MDP (basic buffer) to give a white solid. The material was further purified by silica gel chromatography (ISCO Combi-flash system, eluting with 0-8% MeOH/DCM), affording the title compound as a white solid, 5 mg. (4:1 mixture, cis and trans unassigned). 1H NMR (CDCl3): 1.40 (t, J=7.1 Hz, 6H), 1.11 (t, J=7.6 Hz, 3H), 1.70-1.84 (m, 4H), 2.09-2.28 (m, 5H), 2.58 (m, 1H), 3.23 (s, 3H), 3.94, 3.95 (2xs, 3H), 4.14-4.23 (m, 4H), 4.39, 4.43 (2xs, 2H), 6.95-7.02 (m, 2H), 7.10 (m, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.93 (m, 1H), 8.26 (m, 1H), 8.38 (s, 1H), 8.58 (d, J=8.3 Hz, 1H), 10.64 (s, 1H). MS (ES+): m/z=648.33 [MH+]. HPLC: tR=4.53 min (ZQ3, polar—5 min).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[O:7][C:8]([F:11])([F:10])[O:9][C:5]=2[CH:4]=1.[C-]#N.[Na+].CS(C)=[O:19]>>[F:10][C:8]1([F:11])[O:7][C:6]2[CH:12]=[CH:13][C:3]([CH2:2][OH:19])=[CH:4][C:5]=2[O:9]1
Reactant: FC1(F)Oc2ccc(CCl)cc2O1
Reactant: CS(C)=O
Agent: [C-]#N
Agent: [Na+]
Product: OCc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of 5-(chloromethyl)-2,2-difluorobenzo[d][1,3]dioxole (117.6 g, crude from last step) and NaCN (84 g, 1.7 mmol) in DMSO (800 mL) was stirred for 2 h at 25° C. The reaction, mixture was poured into ice and extracted with EtOAc (500 mL×3). The combined organic layers were dried with anhydrous Na2SO4 and concentrated in vacuo to give crude product which was purified by column chromatography (P.E./EtOAc 10:1) to give (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol (77.8 g, 66%), 1H NMR (300 MHz , CDCl3) δ 7.06-7.07 (m, 3H), 3.75 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[N:10][C:4]=2[CH:3]=1.[CH2:17]([O:19][C:20]1[C:21](=O)[C:22](=[O:27])[C:23]=1[O:24]CC)[CH3:18].C1(OC2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]([C:21]3[C:22](=[O:27])[C:23](=[O:24])[C:20]=3[O:19][CH2:17][CH3:18])[C:4]=2[CH:3]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1O2
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOc1c(N2Cc3ccccc3Oc3ccc(Cl)cc32)c(=O)c1=O
Reaction time: 2 h

Procedure:
A mixture of 8-chloro-dibenz[b,f][1,4]oxazepine (2 g), 3,4-diethoxy-3-cyclobutene-1,2-dione (5 g), diphenylether (2 g) and dioxane (10 mL) was heated to reflux. After 2 hours, most of the dioxane was removed in vacuo and the precipitated title compound (0.75 g) was collected by filtration as yellow solid. The filtrate was treated with cold methanol when more of the title compound (1.2 g) precipitated. This material was used in Example 6 without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([OH:16])[OH:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:30][C:31](=[CH2:36])[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([CH2:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH2:30])(=[O:15])[OH:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CBr)C(=O)OC
Reactant: CC(NC(=O)OCc1ccccc1)P(O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(CP(=O)(O)C(C)NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.8 %

Procedure:
To a stirred solution of 2.25 g (9.3 mmol) of 1-(benzyloxycarbonylamino)ethylphosphonous acid in 70 ml of methylene chloride, were added triethylamine (2.87 ml, 20 mmol), trimethylsilyl chloride (2.60 ml, 20 mmol), and methyl 2-bromomethylacrylate (1.66 g, 9.3 mmol) at 0° C. After stirring at room temperature for 20 hours, the reaction mixture was washed with H2O, 2N HCl, and then saturated NaCl solution and dried over anhydrous magnesium sulfate. The mixture obtained by filtration and evaporation was purified by silica gel chromatography (eluted with chloroform followed by 10% methanol-chloroform) to give 2.50 g (yield 79%) of the product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH2:9][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(CN2CCCC2)c(Cl)c1
Yield: 56.1 %

Procedure:
Pyrrolidine (22.0 mL, 0.255 mol) was added to a suspension of intermediate 14, 2-chloro-4-hydroxybenzaldehyde (30.8 g, 0.196 mol) in dichloromethane (620 mL). The reaction mixture was cooled with an ice bath. Sodium triacetoxyborohydride (65.8 g, 0.295 mol) was added in portions under stirring. The reaction mixture was stirred for 12 h at room temperature. Water (600 mL) and dichloromethane (600 mL) were added. The reaction mixture was acidified with concentrated HCl to pH˜2. The organic layer was separated. The aqueous one was subjected to extraction with EtOAc (2×500 mL), and the extracts were discarded. The aqueous fraction was alkalized with a saturated solution of potassium carbonate to pH 9-10. The product was extracted with CHCl3 (3×500 mL). The organic layer was dried with anhydrous Na2SO4 (50 g). The solvent was evaporated in vacuo. The obtained oil was refluxed in Et2O (400 mL) for 1 h. Then hexane (200 mL) was added, and the mixture was cooled. The formed residue was separated by filtration and dried. 1H NMR spectrum showed the presence of acetic acid (2.3% w/w). The residue was dissolved in a mixture of Et2O (100 mL) and CH2Cl2 (100 mL), and a solution of NaOH (0.4 g) in water (4 mL) was added. The product was extracted form the organic layer. The extract was dried with anhydrous Na2SO4 (50 g), evaporated, and coevaporated with dioxane. The title compound (23.5 g, 0.11 mol, 56%) was obtained as a pale-yellow powder. LC/MS data: 212.0 and 214.0 (M+H)+ (calculated for C22H14ClNO 211.7). 1H NMR data (DMSO-d6): 9.73 (br.s., 1H, OH); 7.24 (d, 1H, J=8.3 Hz, Ar—H); 6.78 (d, 1H, J=2.4 Hz, Ar—H); 6.70 (d.d., 1H, J1=8.3 Hz, J2=2.4 Hz, Ar—H); 3.54 (s, 2H, CH2Ar); 2.40-2.47 (m, 4H); 1.63-1.70 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.1 g, 9.8 mmol) was dissolved in 100 mL dry diethyl ether under an argon atmosphere, added dry pyridine (3.3 mL, 32.5 mmol), cooled to 0° C. then added oxalyl chloride (1.4 mL, 16.3 mmol) dropwise. A precipitate forms immediately upon addition of oxalyl chloride and therefore reaction requires vigorous stirring. Stirred at 0° C. for one hour than at ambient temperature for 2 hours. Dry diethyl ether (100 mL) was added and the solids were filtered off, washing with more diethyl ether. The filtrates were concentrated, then redissolved in dry DCM under argon, cooled to 0° C., added 1 mL dry pyridine then added 4-amino-benzonitrile (0.96 g, 8.1 mmol) in one portion. Stirred at ambient temperature for 2 hours, concentrated, redissolved in ethyl acetate (250 mL), washed with 10% citric acid (3×100 mL), water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white foam. (2.4 g, 93%) APCI (AP−): 314.1 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][S:17](=[O:20])(=[O:19])[NH2:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>CO.O1CCOCC1>[ClH:21].[ClH:21].[N:11]1([CH2:14][CH2:15][CH2:16][S:17]([NH2:18])(=[O:19])=[O:20])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCS(N)(=O)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NS(=O)(=O)CCCN1CCNCC1

Procedure:
4-(3-Sulfamoyl-propyl)-piperazine-1-carboxylic acid tert-butyl ester (310 mg) in methanol (5 mL) was deprotected with 4 N hydrochloric acid in dioxane (3 mL) to give 3-piperazin-1-yl-propane-1-sulfonic acid amide dihydrochloride (229 mg, white solids)
Reaction SMILES: C(S[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH:14]=2)[NH:9][C:8]([CH3:25])([CH3:24])[CH:7]=1)C=C.BrCC1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](C3C=CC=CC=3OC)[CH:36]=2)[NH:31]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].C(S)C=C>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:24])([CH3:25])[CH:7]=[C:6]2[CH2:5][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C=CCSCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: C=CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-Allylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 50 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 15 μL of allyl mercaptan reacted to give 5 mg of the title compound as a foam.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH2:14]1[O:17][CH:15]1[CH3:16]>C(O)C>[CH3:1][N:2]([CH2:14][CH:15]([OH:17])[CH3:16])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC1CO1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CC(O)CN(C)CCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of N-methyl-4-nitrophenethylamine (1.8 g) and propylene oxide (0.66 g) in ethanol (50 ml) was stirred at reflux for 5 hours. After evaporation to dryness the residual orange oil was chromatographed on silica (37 Kieselgel 60" - Trade Mark) eluting with ethyl acetate followed by collection and evaporation of suitable fractions to give the title compound as a yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:21]=[C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[Cl:22][C:23]1[C:32]([CH:33]=O)=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:35])[CH:29]=2)[N:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:22][C:23]1[C:32]([CH2:33][N:18]2[CH2:17][CH2:16][N:15]([C:11]3[N:12]=[C:13]([NH2:14])[N:8]4[N:7]=[C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)[CH:21]=[C:9]4[N:10]=3)[CH2:20][CH2:19]2)=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:35])[CH:29]=2)[N:24]=1
Reactant: Cc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: Nc1nc(N2CCNCC2)nc2cc(-c3ccco3)nn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc2nc(Cl)c(CN3CCN(c4nc(N)n5nc(-c6ccco6)cc5n4)CC3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7-Furan-2-yl-2-piperazin-1-yl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of 2-chloro-6-methyl-quinoline-3-carbaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 7.4-8.0 (m, 4H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.2 (s, 1H) 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 2.35 (br s, 3 H). MS: m/z: 476 [M+H]+.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Br:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([NH2:19])=[C:14]([NH2:20])[CH:13]=1>>[Br:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][C:17]=1[F:18])[NH:19][C:1](=[O:8])[C:2](=[O:4])[NH:20]2
Reactant: Nc1cc(F)c(Br)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(F)c(Br)cc2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (1.97 mL, 13.5 mmol) and 4-bromo-5-fluoro-1,2-diaminobenzene (277 mg, 1.35 mmol) was heated to reflux under N2 for 12 h. The reaction was allowed to cool to room temperature and the dark-brown solid collected by vacuum filtration and rinsed with ethanol (20 mL) and air dried to give 233 mg (67%) of a powdery brown solid. A portion of this solid (100 mg) was taken and dissolved in 5 mL 1N NaOH. The solution was treated with activated charcoal and filtered through a pad of Celite. The Celite was rinsed with 10 mL additional NaOH solution. The resulting solution was carefully acidified with 1N HCl (pH=5). Bright yellow needles slowly formed in the solution and were collected by vacuum filtration, rinsed with 15 mL of H2O and dried under vacuum (0.1 torr, 78° C.) to yield 40.0 mg of yellow crystals. 1H NMR (d6 -DMSO) δ6.99 (d,1H, J=9.3, H-8), 7.29 (d, 1H, J=6.3, H-6), 11.95 (br s, 2H, 2(NH)). EIMS m/z 260 (M+2, 96), 258 (M+(bp)), 232 (51), 230 (52), 123 (83). EIHRMS calc. for C8H4BrFN2O2 256.9941, found 257.9441.