Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([CH2:10]Cl)[N:9]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[N+:42]([C:45]1[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=1)([O-:44])=[O:43]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8](/[CH:10]=[CH:49]/[C:48]2[CH:51]=[CH:52][C:45]([N+:42]([O-:44])=[O:43])=[CH:46][CH:47]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1sc(NC(C)=O)nc1CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(NC(C)=O)nc1/C=C/c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a stirring solution of ethyl 2-(acetylamino)-4-(chloromethyl)-1,3-thiazole-5-carboxylate (1.0 g, 3.81 mmol) in N,N-dimethylformamide (20 mL) was added triphenylphosphine (1.2 g, 4.57 mmol) at room temperature. The resultant mixture was stirred at 65° C. for 5 hours. To the mixture was added potassium tert-butoxide (555 mg, 4.95 mmol) at 5° C., and the resultant mixture was stirred at 5° C. for 30 minutes p-Nitrobenzaldehyde (805 mg, 5.33 mmol) was added at 5° C. After stirring for 1 hour at room temperature, the reaction was quenched with water, and the mixture was filtered to give the title compound (1.0 g, 72.7%) as a yellow solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[Sn:17](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:26]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:27][CH2:28][CH3:29]
Reactant: Brc1ccc2ccccc2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc2ccccc2c1

Procedure:
2.5 M of n-BuLi (1.9 mL/hexane, 4.83 mmol) was added to 2-bromonaphthalene (1 g, 4.83 mmol/THF (20 mL)) and reacted at −78° C. for 40 minutes under a dry and anaerobic operation condition to form a solution. SnBu3Cl (1.5 mL, 5.31 mmol) was then added to the solution and reacted at −78° C. for 1 hour. After returning to room temperature, the solution was continuously reacted for 8 hours. After the reaction was completed, the solution was extracted by ether (30 mL) and deionized water (50 mL). An organic phase was collected. After removal of ether by a rotary concentrator, the organic phase was purified by reduced-pressure distillation to form a transparent pale yellow oily product (22, 1.68 g, 83%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C.[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[OH:13][CH:14]([CH2:23][OH:24])[CH2:15][N+]1C=CC=CC=1C.[OH:25][CH:26]([CH2:35][OH:36])[CH2:27][N+]1C=CC=CC=1C.N1C=CC(C)=CC=1.S([O-])([O-])(=O)=O.OC(CO)C[N+]1C=CC(C)=CC=1.OC(CO)C[N+]1C=CC(C)=CC=1>>[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[OH:13][CH:14]([CH2:23][OH:24])[CH2:15][N+:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH:25][CH:26]([CH2:35][OH:36])[CH2:27][N+:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccn1
Reactant: Cc1cccc[n+]1CC(O)CO
Agent: Cc1cc[n+](CC(O)CO)cc1
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccncc1
Product: OCC(O)C[n+]1ccccc1

Procedure:
In analogy to the above-described procedure, α-picoline was used as a starting material to prepare bis-N-(2,3-dihydroxypropyl)-α-picolinium sulfate, which has the formula ##STR5## This compound was found to have a refractive index of nD20 =1.5268. Similarly, γ-picoline was used as a starting material to prepare bis-N-(2,3-dihydroxypropyl)-γ-picolinium sulfate, which has the formula ##STR6## and which had a refractive index of nD20 =1.5272.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](O)[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31]Cl>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:31][CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)CCCCl
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 9 h
Yield: 7.7 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (200 mg, 1.44 mmol) and 3-dimethylaminopropyl chloride hydrochloride (114 mg, 0.72 mmol) in order. The mixture was stirred at room temperature for 9 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (14% methanol/chloroform) to give the subject compound (13 mg, yield 7%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])=[O:4].[Na+].[I-:21]>CC(C)=O>[I:21][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])=[O:4]
Reactant: [I-]
Reactant: COc1cc(COC(=O)CBr)c([N+](=O)[O-])cc1OC
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(COC(=O)CI)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4.5-dimethoxy-2-nitrobenzyl 2-bromoacetate (100 mg, 0.3 mmol) was dissolved in acetone (2 ml) and NaI (50 mg, 0.33 mmol) was added. After stirring for two hours at room temperature, mixture was filtered, evaporated and purified by chromatography (Si-gel, CH2Cl2) to yield 4.5-dimethoxy-2-nitrobenzyl 2-iodoacetate (compound E (see FIG. 12c): P6—C1[X═I]) (97 mg, 85%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.[C:13]1([P:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:20]C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClC1C=CC=CC=1Cl>[C:13]1([P:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([P:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:20])=[N:4][N:3]=2)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: COP(c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1nnc(P(=O)(c2ccccc2)c2ccccc2)c2ccccc12
Reaction time: 312 h
Yield: 48.1 %

Procedure:
To a stirred, refluxing mixture of 5.00 g of 1,4-dichlorophthalazine in 50 ml of o-dichlorobenzene under nitrogen was added dropwise 15.00 g of methyl diphenylphosphinite. After the addition was completed, the mixture was refluxed for 6 hours and then allowed to stand at room temperature for 13 days. The resulting solid was separated by filtration, washed with benzene and with hexane, recrystallized from 125 ml of toluene with decolorizing charcoal treatment, and dried at 100° C./0.1 mm (13 Pa) to give 6.41 g of 1,4-bis(diphenylphosphinyl)phthalazine (shown by formula in claim 6) as a light-yellow solid, mp 225°-228.5° C. Anal. Calcd for C32H24N2O2P2 : C, 72.45; H, 4.56; N, 5.28; P, 11.68. Found: C, 72.49; H, 4.62; N, 5.36; P, 11.95.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.Cl.[OH:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:17][CH2:18][CH2:19][CH:14]([OH:13])[CH2:15]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: OC1CCCNC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(N2CCCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 3-hydroxypiperidine hydrochloride (3.0 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (10 mL) was stirred at 120° C. for 18 h. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 50:50 CHCl3/EtOAc) to yield the product as an orange solid (0.89 g, 54%).
Reaction SMILES: [N-]=[N+:2]=[N-:3].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:16]([CH2:24][C:25]([CH3:27])=[O:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O.C(O)C>[N+:2](=[C:24]([C:25](=[O:26])[CH3:27])[C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:23])=[N-:3]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC(=O)C(=[N+]=[N-])C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
A mixture of sodium azide (683 mg, 10.5 mmol), p-toluenesulfonyl chloride (2.0 grams, 10.5 mmol), and 70% aqueous ethanol (30 mL) was stirred at room temperature for 1 hour. 1-Benzoylacetone (1.62 grains, 10.0 mmol) and triethylamine (1.46 mL, 10.5 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours and then poured into deionized water (200 mL). The mixture was extracted with petroleum ether (2×200 mL). The extracts were combined and then washed with a saturated aqueous sodium chloride solution. The organic solution was dried using anhydrous magnesium sulfate, filtered, and concentrated to give 0.980 grams of 2-diazo-1-phenyl-1,3-butanedione as a yellow oil. Decomposition temperature: 128° C. (by DSC).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]([F:24])[C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:23]=[C:22]([F:24])[C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cc(F)c43)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cc(F)c43)cc2s1
Temperature: 110 °C
Yield: 63.8 %

Procedure:
A stirred mixture of 6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.33 g, 3.14 mmol), (1R,2R)-2-aminocyclohexanol (1.09 g, 9.43 mmol), DIEA (1.62 g, 12.58 mmol) and DMA (40 mL) was heated in a sealed vial at 110° C. for 15 h. The mixture was cooled to rt and then partitioned between water and EtOAc. The organic layer was separated and washed sequentially with water and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residual solid was purified by trituration with a 6:1 mixture of diethyl ether and DCM to afford (1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (952 mg, 64%) as a tan solid. A 90 mg portion was further purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (15 mg) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.98 (d, J=10.0 Hz, 1H), 7.74 (d, J=5.0 Hz, 1H), 7.54 (m, 1H), 7.33 (m, 1H), 7.29 (d, J=10.0 Hz, 1H), 7.08 (m, 1H), 5.52 (s, 2H), 4.75 (d, J=5.0 Hz, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.59-1.64 (m, 2H), 1.16-1.30 (m, 4H); LCMS (ESI) m/z 475 and 477 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:9][NH:8]/[C:7](=[N:10]\[C:11]([C:13]2[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=2)=[O:12])/[NH:6]1.[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[C:22]1([CH2:28][C:29]([NH:1][CH2:2][CH2:3][CH2:4][C@H:5]2[CH2:9][NH:8]/[C:7](=[N:10]\[C:11]([C:13]3[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=3)=[O:12])/[NH:6]2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC[C@H]1CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCNC(=O)Cc3ccccc3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [(S)-4-(3-amino-propyl)-imidazolidin-(2E)-ylidene]-amide (Ex. 31) (0.030 g, 0.96 mmol) in DMF (2 ml), phenylacetyl chloride (0.013 ml, 0.096 mmol) is added. The yellow solution is stirred at room temperature for 10 minutes. Purification by catch and release resin (SCX-2) eluting with MeOH and 7M NH3 in MeOH affords the title compound; [M+H]+ 430.98
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[CH3:21][CH2:22][O:23]C(C(F)F)=O>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:22](=[O:23])[CH3:21])[CH:15]=1
Reactant: CCOC(=O)C(F)F
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)c1cc(Br)ccc1F
Temperature: -70 °C
Reaction time: 2.5 h

Procedure:
A solution of 17.78 ml (126 mmol) diisopropyl amine in 375 ml THF was cooled to −78° C. A 1.6 M solution of BuLi in hexanes (79 ml, 126 mmol) was added drop wise. After 15 minutes 20 g of 4-bromo-1-fluoro benzene (114 mmol) was added dropwise while keeping the temperature below −60° C. After stirring for 2.5 h at −70° C. 13.22 ml ethyl difluoro acetate were added. The mixture was warmed to −40° C. and then quenched by pouring the mixture onto 1M HCl. The mixture was extracted with ligroine, dried with MgSO4.H2O, concentrated and purified by column chromatography (silica gel; hexane/5-15% TBME) to give the desired product as a yellow liquid. 1H-NMR (CDCl3, 360 MHz): 8.09 (dd, 1H), 7.82-7.77 (m, 1H), 7.17 (t, 1H), 6.45 (t, 1H, CHF2)
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8](Cl)[N:9]=1)[CH2:2][CH2:3][CH3:4].[H][H].C([O-])(=O)C.[K+].CCCCCC.C(OCC)(=O)C>CO.[Pd].[C]>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(=O)OC)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1

Procedure:
A solution of 1.00 g (0.003 mole) of 2-butyl-1-(4-carbomethoxybenzyl)-4-chloro-5-formylimidazole in 75 mL of methanol is reduced at low pressure with hydrogen and 0.30 g of 5% Pd/carbon in the presence of 0.30 g of potassium acetate to give product; mp 62°-64° C.; tlc (1:1 hexane-ethyl acetate) 1 spot, Rf 0.2; MS (CI) 301 (M+ +1).
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:39]=[CH:38][C:9]2[S:10][C:11]([CH2:13][C:14]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C@H:28]4[CH2:32][CH2:31][CH2:30][NH:29]4)=[CH:22][CH:21]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:8]=2[CH:7]=1)(=[NH:5])[NH2:4].Cl.[C:41](=[NH:46])(OCC)[CH3:42].C(N(CC)CC)C>C(O)C>[ClH:1].[ClH:1].[C:41]([N:29]1[CH2:30][CH2:31][CH2:32][C@@H:28]1[CH2:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:14]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH2:13][C:11]2[S:10][C:9]3[CH:38]=[CH:39][C:6]([C:3](=[NH:4])[NH2:5])=[CH:7][C:8]=3[CH:12]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:25][CH:24]=1)(=[NH:46])[CH3:42]
Reactant: CCOC(=O)C(Cc1cc2cc(C(=N)N)ccc2s1)(C(=O)OCC)c1ccc(OC[C@H]2CCCN2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1cc2cc(C(=N)N)ccc2s1)(C(=O)OCC)c1ccc(OC[C@H]2CCCN2C(C)=N)cc1
Temperature: 25 °C

Procedure:
1.0 g of ethyl 3-(5-amidinobenzo[b]thien-2-yl)-2-ethoxycarbonyl-2-[4-[((2R)-2-pyrrolidinyl)methoxy]phenyl]propionate dihydrochloride was dissolved in 20 ml of ethanol, followed by the addition of 0.42 g of ethyl acetimidate hydrochloride. 0.51 g of triethylamine was added to the thus prepared solution during stirring under ice cooling, and the resulting mixture was warmed up to room temperature and stirred for 18 hours. Thereafter, the solvent was distilled off to obtain ethyl 2-[4-[((2R)-1-acetimidoyl-2-pyrrolidinyl)methoxy]phenyl]-2-ethoxycarbonyl-3-(5-amidinobenzo[b]thien-2-yl)propionate dihydrochloride. The thus obtained ester compound was dissolved in 50 ml of 5 N hydrochloric acid and refluxed under heating for 60 minutes. After distilling off the solvent, the resulting residue was subjected to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent. Fractions of interest were pooled and concentrated, and the resulting residue was subjected to reversed phase high performance liquid chromatography using a column packed with octadecyl-bonded silica gel and using a water/acetonitrile mixture as an elution solvent. Thereafter, the thus eluted fractions of interest were pooled, mixed with dilute hydrochloric acid, and then concentrated to dryness. In this way, 360 mg of the title compound was obtained in the form of a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[N:5]1([CH2:4][CH2:3][CH2:2][NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=2)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCCCn1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCn1ccnc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(3-amino-propyl)imidazole (2.1 g, 16.8 mmol), diisopropyl-ethylamine (3.5 mL, 20.0 mmol) and 4-N,N-dimethyl-aminopyridine (200 mg, 1.7 mmol) in methylene chloride (15 mL) at 0C was added dropwise 4-chlorobenzoyl-chloride (2.1 mL, 16.8 mmol). The reaction was then allowed to warm to room temperature. After 5 hours, the reaction was diluted with methylene chloride, washed with 1N sodium hydroxide, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide a white solid. This material was washed with diethyl ether to provide N-(3-imidazol-1-yl-propyl)-4-chlorobenzamide. To a slurry of the above amide (1.58 g, 6.0 mmol) in tetrahydrofuran (30 mL) was slowly added lithium aluminum hydride (456 mg, 12.0 mmol) upon which the reaction became exothermic. The mixture was heated to 80° C., stirred for 1 hr, cooled to 0° C. and quenched by addition of water (0.5 mL), 15% sodium hydroxide (0.5 mL) and an additional 1.5 mL of water. The reaction was diluted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide compound 20.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(CC)CC.C(O[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:41]3[C:36](=[CH:37][C:38](F)=[CH:39][CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1)=[O:25])(C)(C)C.[N+](C1C=CC(OC(=O)[NH:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH:62]([CH3:64])[CH3:63])=[CH:57][CH:56]=2)=CC=1)([O-])=O>CN(C=O)C.O>[CH:62]([O:61][C:58]1[CH:59]=[CH:60][C:55]([NH:54][C:24]([N:26]2[CH2:27][CH2:28][CH:29]([C:32]3[C:41]4[C:36](=[CH:37][C:38]([NH:1][CH2:2][CH2:3][CH2:4][N:5]5[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]5)=[CH:39][CH:40]=4)[N:35]=[CH:34][N:33]=3)[CH2:30][CH2:31]2)=[O:25])=[CH:56][CH:57]=1)([CH3:64])[CH3:63]
Reactant: CN1CCN(CCCN)CC1
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4cc(NCCCN5CCN(C)CC5)ccc34)CC2)cc1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(3-aminopropyl)-1-methylpiperazine (0.1 mmol), Et3N (0.1 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 65b, in DMF (1 mL) was stirred at 130° C. for 3 h. It was then diluted with water and extracted with EtOAc. The combined extracts were washed with water, brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo. The crude product was then treated with 3M HCl/MeOH (2 mL) and stirred at rt for 2 h, then concentrated in vacuo. The crude residue was dissolved in a mixture of DCM:MeOH (1:1; 2 mL) and neutralized with excess Et3N and treated with (4-isopropoxy-phenyl)-carbamic acid 4-nitrophenyl ester (0.11 mmol), which was prepared as described in Example 1a, at rt for 1 h. It was then concentrated in vacuo and the crude product was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was then purified by Preparative TLC (silica gel; DCM:MeOH, 9:1) to obtain 3.2 mg (6% overall yield over the three steps) of the title compound. 1H-NMR (300 MHz, CDCl3): 8.97 (s, 1H), 7.88 (d, 1H), 7.28-7.22 (m, 3H), 6.97-6.81 (m, 4H), 6.33 (s, 1H), 4.53-4.43 (m, 1H), 4.30-4.20 (d, 2H), 3.66-3.32 (m, 2H), 3.11 (t, 2H), 2.85-2.55 (m, 8H), 2.43 (s, 4H), 2.20-1.85 (m, 8H), 1.31 (d, 6H). LC/MS (ESI): 546.2 (MH)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][O:14][CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH:27][S:28]([C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:23][CH:24]=2)[CH:19]=[N:18]1>>[Cl:8][C:7]1[C:2]([N:27]([CH2:26][C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:17]([CH2:16][CH2:15][O:14][CH3:13])[N:18]=[CH:19]3)[S:28]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)(=[O:30])=[O:29])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COCCn1ncc2cc(CNS(=O)(=O)c3ccc(C(=O)OC)cc3)ccc21
Product: COCCn1ncc2cc(CN(c3ncc(C(F)(F)F)cc3Cl)S(=O)(=O)c3ccc(C(=O)OC)cc3)ccc21

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-(2-methoxyethyl)-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-3 of Example 20).