Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH2:11])[CH2:8][CH2:7][C:5]=2[N:6]=1.[CH:12](=O)[CH2:13][CH2:14][CH3:15].[BH4-].[Na+].[ClH:19]>CN(C)C=O.O>[ClH:19].[ClH:19].[NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: CCCC=O
Reactant: Nc1nc2c(s1)CC(N)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNC1CCc2nc(N)sc2C1
Temperature: 50 °C

Procedure:
To a solution of 3.4 g (0.02 Mol) of 2,6-diamino- 4,5,6,7-tetrahydro-benzthiazole in 34 ml of dimethylformamide are added 1.8 g (0.022 Mol) of n- butanal and the mixture is heated to 50° C. for 1 hour. After cooling, the reaction solution is mixed with 0.8 g (0.02 Mol) of sodium borohydride and heated to 50° C. for 30 minutes. The solvent is largely eliminated in vacuo. Whilst cooling with ice, the residue is mixed with 20 ml of water and 2N hydrochloric acid until a pH of 1 is obtained. The aqueous solution is extracted with ethylacetate and the organic phase discarded. The aqueous phase is mixed with potassium carbonate until an alkaline reaction is obtained and then extracted with ethyl acetate. The organic phase is dried and concentrated. The compound crystallizes out when ethereal hydrochloric acid is added.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]=[CH2:16])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]([CH2:27][C:28]2[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:35])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:14]([N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:12][N:11]([CH2:18][C:19]2[N:20]([CH2:27][C:28]3[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=3[Cl:34])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=2)[C:10]1=[O:13])[CH:15]=[CH2:16]
Reactant: O=[N+]([O-])c1cn(Cc2c(Cl)cccc2Cl)c(CCl)n1
Reactant: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(Cc2nc([N+](=O)[O-])cn2Cc2c(Cl)cccc2Cl)c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
110 mg (0.47 mmol) of the compound from Example 12A were dissolved in 10 ml of DMF, and 150 mg (0.47 mmol) of the compound from Example 41A and 229 mg (0.70 mmol) of cesium carbonate were added. The mixture was stirred at 80° C. for 16 h. After cooling to RT, the reaction mixture was added to about 25 ml of ice-water and stirred for 10 min. This resulted in the formation of a precipitate which was filtered off with suction and washed with water. The solid was dried under high vacuum. This gave 120 mg (44% of theory) of the target compound of a purity of 90%.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.CCN(CC)CC>C(Cl)Cl>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([C:23]2[C:18]3[N:17]=[N:16][NH:15][C:19]=3[CH:20]=[CH:21][CH:22]=2)=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2[nH]nnc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)c1cccc2[nH]nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
p-Nitrobenzyl chloroformate (0.5 mmol) was dissolved in 5 mL of CH2Cl2 and treated with benzotriazole (0.5 mmol) using Et3N (2 mmol) as base. The mixture was stirred overnight at room temperature, diluted with CH2Cl2 (20 mL) and washed with 3×5 mL of 1N HCl, 2×5 mL of 1N NaOH and 1×5 mL of brine. The organic phase was dried and filtered. The volatiles were removed and the product was triturated with diethyl ether to provide a pale yellow solid (59% yield). mp 160-162° C. 1H NMR (CDCl3) δ 8.27 (d, 1H, J=8.9 Hz), 8.17 (m, 3H), 7.72 (d, 1H, J=8.9 Hz), 7.65 (td, 1H, J=8.3 Hz, 1.1 Hz), 7.53 (m, 2H), 5.26 (s, 2H). 13C NMR (CDCl3) δ 154.84, 146.17, 142.27, 141.30, 132.01, 130.82, 128.78, 126.37, 124.16, 120.86, 113.58, 68.66. HRMS (FAB) calcd for C14H11N4O4 ([M+H]+): 299.0775. found 297.0775.
Reaction SMILES: [CH3:1][C:2]1[C:7](Br)=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[CH3:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][CH:5]=[C:6]([CH3:9])[C:7]=1[B:17]([OH:20])[OH:18]
Reactant: COB(OC)OC
Reactant: COc1ccc(C)c(Br)c1C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C)c(B(O)O)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dimethyl-3-bromoanisole (3.3 g, 15 mmol) in THF (15 mL) is added dropwise at −78° C. to a solution of n-butyllithium (11 mL of 1.6M in hexane, 17 mmol) in THF (35 mL). After 30 minutes, trimethyl borate (2.3 mL, 20 mmol) is added and the mixture is allowed to warm to room temperature overnight. The mixture is poured onto 10% HCl and extracted with ethyl acetate. The organic fraction is washed with saturated brine, dried (Na2SO4), and concentrated to give the desired product as a brownish oil. 1H NMR (CDCl3) 6.98 (d, 1H), 6.75 (d, 1H), 4.64 (br s), 3.80 (s, 3 H), 2.27 (s, 3H), 2.22 (s, 3H)
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)=[O:19])[CH2:3]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine (0.63 g, 5 mmol) and 4-chlorophenyl isocyanate (0.768 g, 5 mmol). The product was purified as the 1:1 maleate (1.23 g), mp 182°-183° C. (dec).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([CH:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[CH:7]=1.O>ClCCl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH:14]([CH3:19])[C:15]([F:16])([F:17])[F:18])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)C(F)(F)F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(c1cc(F)ccc1O)C(F)(F)F
Temperature: 25 °C

Procedure:
Boron tribromide (19.1 mL, 198 mmol) was added to a −78° C. solution of 4-fluoro-1-methoxy-2-(1,1,1-trifluoropropan-2-yl)benzene (C43) (20.0 g, 90.0 mmol) in dichloromethane (400 mL). The cooling bath was removed and the reaction mixture was allowed to warm to room temperature over 66 hours. It was then cooled in an ice bath and treated drop-wise with water (50 mL) while venting into an aqueous potassium carbonate trap. When the vigorous reaction had subsided, additional water (300 mL) was added, and the mixture was stirred until all the solids had dissolved. The aqueous layer was extracted with dichloromethane (200 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure, while keeping the water bath between 23° C. and 35° C. The product was obtained as an oil, which contained some impurities by 1H NMR assessment; this was used without additional purification. Yield: 20.6 g, assumed quantitative. 1H NMR (400 MHz, CDCl3), product peaks only: δ 1.45 (d, J=7.4 Hz, 3H), 3.98-4.12 (m, 1H), 6.74 (dd, J=8.8, 4.5 Hz, 1H), 6.85-6.91 (m, 1H), 7.04-7.09 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:31]/[O:32][C:33]2([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:35][CH2:34]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH:29]=O)[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:52][CH2:53][CH:54]1[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:55]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CN(C=O)C>ClCCCl>[CH:39]([O:38][C:36]([C:33]1([O:32]/[N:31]=[C:14](/[C:12]2[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:10][CH:11]=2)\[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH2:29][NH:52][CH2:53][CH:54]3[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:55]3)[CH:26]=[N:25]2)=[O:16])[CH2:35][CH2:34]1)=[O:37])([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(C=O)n2)cs1
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CNCC3CN(C(=O)OC(C)(C)C)C3)n2)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-formyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (150 mg, 0.21 mmol) in DCE (4 ml) at 0° C. was added tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (78 mg, 0.420 mmol), sodium triacetoxyborohydride (66.7 mg, 0.315 mmol), and DMF (0.4 mL). After stirring at rt for 3 h, the reaction mixture was quenched with saturated NaHCO3 (aq) and diluted with 10% EtOH/DCM (40 mL). The organic layer was separated, dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was used as such in the following step. LCMS: Rt=0.55 min, m/z=885.5 (M+1). Method 2m_acidic.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCSc1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCS(=O)c1ccncc1
Yield: 79 %

Procedure:
To a solution of 4.03 g (15.0 mmol) of 4-[3-(t-butoxycarbonylamino)propylthio]pyridine in 100 ml of methylene chloride, 3.05 g (15.0 mmol) of m-chloroperbenzoic acid was added with stirring under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed two times with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent:ethyl acetate/ethanol=10:1) to give 3.37 g of the desired compound (78.9% yield, colorless crystals).
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:6][NH:7][CH2:8][CH:9]([NH:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CN1CCOCC1>CO.CN(C)C=O>[CH:3]1([CH2:6][N:7]2[C:19](=[O:21])[CH2:18][CH2:17][NH:16][CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8]2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)CCNC(CNCC1CC1)c1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1CCNC(c2ccccc2)CN1CC1CC1
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Sodium hydroxide (1M; 6.53 mL, 6.53 mmol) was added to a solution of ethyl N-{2-[(cyclopropylmethyl)amino]-1-phenylethyl}-beta-alaninate (1.81 g, 6.22 mmol) in methanol (10 mL). After 1 h, the mixture was concentrated and azeotroped with toluene (3×) to give the crude acid. Diphenylphosphoryl azide (2.68 ml, 12.43 mmol) was added to a solution of the crude acid (1.77 g, 6.22 mmol) and 4-methylmorpholine (1.37 mL, 12.4 mmol) in N,N-dimethylformamide (124 mL). After 18 h, the reaction was concentrated and diluted with water. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→90% dichloromethane/10% (10% ammonium hydroxide/methanol)] gave the title compound (1.38 g). MS 245 (M+1). 1H NMR (500 MHz, CDCl3) □ 7.47-7.30 (m, 5H), 3.89-3.88 (m, 2H), 3.65 (dd, J=13.9, 6.6 Hz, 1H), 3.31-3.26 (m, 1H), 3.24-3.21 (m, 1H), 3.02-2.93 (m, 3H), 2.70-2.65 (m, 1H), 1.02-0.97 (m, 1H), 0.58-0.49 (m, 2H), 0.28-0.21 (m, 2H).
Reaction SMILES: [Sn](Cl)Cl.[N:4]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[C@H:6]([NH:12][C:13]([C:15]1[O:16][C:17]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:18]=3[CH:19]=1)=[O:14])[CH2:5]2>CN(C=O)C.CO>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11]1)[C@H:6]([NH:12][C:13]([C:15]1[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:18]=3[CH:19]=1)=[O:14])[CH2:5]2
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc2oc(C(=O)N[C@@H]3CN4CCC3CC4)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.0 ml (4 mmol) of a 2 M tin(II) chloride solution in DMF are added to N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzofuran-2-carboxamide (135 mg, 0.32 mmol), and the mixture is stirred at RT for 18 h. The crude product is taken up in methanol and shaken together with acidic ion exchange resin (Dowex WX2-200) for about 20 min. The loaded ion exchanger is washed three times with in each case 30 ml of methanol, then with water/methanol 8:2, again with methanol, with dichloromethane and finally again with methanol. The product is eluted using methanol/triethylamine 95:5. The solvent is removed under reduced pressure using a rotary evaporator, and 20 ml of 1N aqueous sodium hydroxide solution are added to the crude mixture. The aqueous phase is extracted six times with in each case 20 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure using a rotary evaporator. 100.7 mg (82% of theory) of the title compound are isolated. The analytical data correspond to those of the enantiomeric compound from example 32.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:28]3[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Methylphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.17 (t, 1H), 6.97 (br, 2H), 6.77 (d, 1H), 5.39 (s, 2H), 3.68 (m, 4H), 3.31 (m, 2H), 3.22 (m, 2H), 2.27 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=401.1, found=401.1.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH:7]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1.N1C=CC=CC=1>C(Cl)Cl>[S:1]([O:6][CH:7]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1)([CH3:4])(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C1CCC(O)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Mesyl chloride (0.15 ml) was added dropwise to tert-butyl 3-hydroxycyclopentanoate (373 mg) dissolved in methylene chloride (2 ml) and pyridine (0.32 ml) at a temperature of 0° C. The mixture was stirred at a room temperature for 4 hours. The reaction mixture was poured into ice-water (10 ml). The mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then evaporated to obtained the title compound having the following physical data.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([OH:14])(=O)=[O:12])[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([Cl:16])(=[O:14])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccc2cccnc12
Product: O=S(=O)(Cl)c1cccc2cccnc12
Temperature: 140 °C

Procedure:
Equal quantities by weight of 8-quinolinesulfonic acid and phosphorous pentachloride were ground together in a mortar. This mixture was then refluxed at approximately 140° C. for 3 hours after which work-up of the reaction mixture gave 8-quinolinesulfonyl chloride.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([N:14]4[C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:17][N:16]=[N:15]4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1>CO.[Pd]>[C:19]([C:18]1[N:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[CH:2][CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)[N:15]=[N:16][CH:17]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cnnn1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cnnn1-c1nc2c(s1)CCOc1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A suspension of 8-bromo-2-(5-tert-butyl-[1,2,3]triazol-1-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (101 mg, 0.25 mmol) and 10% Pd/C (250 mg) in MeOH (5 mL) was stirred at RT under a hydrogen atmosphere for 16 h. The reaction mixture was flushed with nitrogen, filtered through Celite, washed with ethyl acetate and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to give 434 as a white solid (54 mg, 66%). LCMS (Method C): RT=13.19 min, [M+H]+=327. 1H NMR (CDCl3): 8.30 (1H, dd, J=7.9, 1.8 Hz), 7.55 (1H, s), 7.29 (1H, m), 7.17-7.12 (1H, m), 7.08 (1H, dd, J=8.0, 1.4 Hz), 4.43 (2H, t, J=5.1 Hz), 3.39 (2H, t, J=5.1 Hz), 1.55 (9H, s).
Reaction SMILES: [C:1]1([C:15](O)=[O:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C1COCC1.CO.Cl>O>[C:1]1([CH2:15][OH:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2cc3ccccc3cc12
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc2cc3ccccc3cc12
Yield: 66.6 %

Procedure:
To a 500 mL 2-neck flask equipped with condenser, addition funnel with N2 inlet, and stirring bar was added 1-anthracenecarboxylic acid (6.88 g, 31 mmol) and dry THF (250 mL). To the addition funnel, was added a 1M solution of BH3 in THF (Aldrich, 50 mL, 50 mmol) via cannula. The BH3 solution was added over 1 h and the solution stirred overnight at RT. CH3OH was then added until H2 evolution ceased. H2O (5 mL) and then 1N HCl (5 mL) was added to the flask. The solvents were removed and then PhCH3 (100 mL) added to the flask. The PhCH3 was then also removed. The resulting solid was recrystallized from EtOAc/hexane to give 4.3 g (67%) of (1-anthryl)methanol mp 124°-125°, (C,H), (lit. 124°-125°, S. Akiyama et. al., Bull. Chem. Soc. Jap. 35 1826 (1962)).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc(OC)c1OC

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3,4,5-trimethoxybenzoyl chloride (12 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:18])[C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)=[CH:2]1.[CH3:19][N:20]([CH3:34])[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:18][CH:24]2[CH2:23][CH2:22][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([N:20]([CH3:34])[CH3:19])[CH2:26][CH2:25]2)[C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)=[CH:2]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Cc1csc([C@@H](N)Cc2c[nH]c3ccccc23)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1csc([C@H](Cc2c[nH]c3ccccc23)NC2CCC(c3ccccc3)(N(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-2-(1H-indol-3-yl)-1-(4-methylthiazol-2-yl)ethylamine (500 mg, 1.94 mmol) and 4-dimethylamino-4-phenylcyclohexanone (421 mg, 1.94 mmol) in anhydrous tetrahydrofuran (40 mL) was mixed with sodium sulphate (1.00 g) and stirred for 3 h at room temperature. After adding acetic acid (291 mg, 287 μL, 4.85 mmol), sodium triacetoxyboron hydride (574 mg, 2.71 mmol) was added and the mixture stirred overnight at room temperature. The mixture was then filtered, the filtrate concentrated to low volume in a vacuum, the residue mixed with 1M potassium carbonate solution (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (750 mg) was purified by flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/methanol [97:3→9:1 and 1% NH3 in each case (33% in water)].
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18].[OH-].[K+].O>CS(C)=O>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: Cc1nc[nH]n1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Temperature: 80 °C
Yield: 26.2 %

Procedure:
Step F (1): A mixture of 3-methyl-1H-1,2,4-triazole (5.0 g, 60.2 mmol), 1-chloro-2-methoxy-4-nitrobenzene (11.3 g, 60.2 mmol), and KOH flakes (3.4 g, 48.1 mmol) in anhydrous DMSO (50 mL) was heated at 80° C. for 6 h. The reaction mixture was allowed to cool to rt and was poured into 800 mL of water with vigorous stirring. The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified using silica gel chromatography (0-2% MeOH/chloroform, linear gradient) to afford 1-(2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (3.7 g, 26% yield). LC-MS (M+H)+=235.2.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH2:13][NH2:14])[CH:3]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18].CCCCCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Cl:15][CH2:16][C:17]([NH:14][CH2:13][C:4]1[CH:3]=[C:2]([CH3:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1)=[O:18]
Reactant: Cc1cc(CN)nn1-c1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cc(CNC(=O)CCl)nn1-c1ccccc1
Temperature: 25 °C

Procedure:
5-Methyl-3-aminomethyl-1-phenylpyrazole (2.434 g, 15 mmol) was dissolved in 20 mL of purified methylene chloride, dropwisely added with chloroacetyl chloride (1.194 mL, 15 mmol) at 0° C. and then stirred at room temperature. Completion of the reaction was confirmed by TLC (hexane:ethyl acetate=1:1). Upon completion of reaction, the reaction mixture was adjusted to pH 7 using saturated aq. NaHCO3 and then extracted with methylene chloride. The resulting organic layer was dried with anhydrous magnesium sulfate and filtered, and the filtrate was concentrated and dried in vacuo to obtain the title compound, 3-(2-chloroacetamido)methyl-1-phenyl-5-methylpyrazole.