Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:16]3[O:17][C:18]4([C:28]([CH3:30])([CH3:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]4[CH3:31])[CH:19]=[N:20][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6])[CH3:2].C(N(CC)CC)C.[C:45](Cl)(=[O:48])[CH2:46][CH3:47]>C(Cl)Cl>[C:45]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:16]3[O:17][C:18]4([C:28]([CH3:29])([CH3:30])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]4[CH3:31])[CH:19]=[N:20][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1)(=[O:48])[CH2:46][CH3:47]
Reactant: CCC(=O)Cl
Reactant: CCN(CCO)c1ccc(-c2cc3c(c4ccccc24)OC2(C=N3)N(C)c3ccccc3C2(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCCN(CC)c1ccc(-c2cc3c(c4ccccc24)OC2(C=N3)N(C)c3ccccc3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(ethyl(4-(1,3,3-trimethylspiro[indoline-2,2′-naphtho[1,2-b][1,4]oxazine]-6′-yl)phenyl)amino)ethanol (Example 8, Step 3) (0.085 g, 0.17 mmol) in DCM (5 ml) was treated with triethylamine (0.026 g, 0.26 mmol) in one portion followed by propionyl chloride (0.019 g, 0.21 mmol) and stirred at RT for 18 hrs. The solvent was then evaporated in vacuo and the crude residue purified by column chromatography (silica gel) eluting with 0-10% EtOAc/Petroleum ether, which gave the pure product, 2-(ethyl(4-(1,3,3-trimethylspiro[indoline-2,2′-naphtho[1,2-b][1,4]oxazine]-6′-yl)phenyl)amino)ethyl propionate, as a pale green foam upon evaporation of the solvent in vacuo (0.08 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.[CH:35](=O)[CH3:36].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:35][CH3:36])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNCc2ccc(Cl)c(Cl)c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(Cl)c(Cl)c1

Procedure:
4-Amino-5-chloro-N-((1-(4-(3,4-dichlorobenzylamino)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide (1.9 g) as starting compound, acetaldehyde (0.26 ml) and sodium cyanoborohydride (0.3 g) were reacted and treated in the same manner as in Example 136 to give 1.1 g of 4-amino-5-chloro-N-((1-(4-(N-(3,4-dichlorobenzyl)-N-ethylamino)butyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1)=O.[N:20]1([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1.[BH4-].[Na+]>CO.C(O)C>[N:20]1([CH2:25][CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][CH2:1][C:3]3[CH:8]=[CH:7][C:6]([O:9][S:10]([C:13]4[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=4)(=[O:12])=[O:11])=[CH:5][CH:4]=3)=[CH:32][CH:33]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Oc2ccc(CNc3ccc(OCCN4CCCC4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A solution of toluene-4-sulfonic acid 4-formyl-phenyl ester (3.28 g, 11.88 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (2.45 g, 11.88 mol) in 40 mL of methanol was stirred at room temperature overnight. The reaction mixture was concentrated to dryness. A portion of the crude residue (1.36 g, ˜2.92 mmol) was dissolved in 35 mL of ethanol and was treated with sodium borohydride (0.687 g, 18.16 mmol), which was added in portions over a period of about 3 hr. The reaction was stirred at room temperature overnight at which time it was concentrated to one-half of its original volume. To this mixture was added 25 mL of water and 25 mL of saturated sodium bicarbonate. The mixture was extracted three times with methylene chloride and the combined organic layers were dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (2% methanol/methylene chloride to 10% methanol/methylene chloride) afforded 1.06 g (80%) of the title compound. MS 467.1 (M+1)+
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[N:25]=1>>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:29])[N:25]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Nc1nc(-c2ccccc2C(=O)O)cs1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1-c1csc(N)n1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-(2-Amino-thiazol-4-yl)-benzoic acid. LC-MS (basic): tR=1.15 min; [M+H]+=479.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]([C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[C:17]#[N:18])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.[NH2:29][OH:30]>CCO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:13]([C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[C:17]([NH:29][OH:30])=[NH:18])=[N:14][C:10]=3[CH:9]=2)=[CH:6][N:7]=1
Reactant: NO
Reactant: CC(C)(C)n1c(-c2ccccc2C#N)nc2cc(-c3cnc(N)nc3)ccc21
Solvent: CCO
Product: CC(C)(C)n1c(-c2ccccc2C(=N)NO)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a suspension of 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-benzonitrile (1.1 mg, 2.99 mmol) in EtOH (20 mL) is added hydroxylamine 50% aqueous solution (3.94 mL 59.71 mmol) at room temperature. The solution is stirred at 80° C. for 2 hours. The reaction mixture is cooled to room temperature and the ethanol removed in vacuo. EtOAc (50 mL) is added and the organics washed with H2O then dried (Na2SO4), filtered and concentrated to afford 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-N-hydroxy-benzamidine (1.1 g, 92%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH2:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH:56][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Agent: Cl
Product: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (130 mg) was prepared from (3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (153 mg) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride following general procedure A. LC-MS (m/z) 736.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:9](=[CH2:10])[NH:8][CH:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)=[O:4].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[CH3:10][C:9]1[NH:8][C:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:6][C:5]=1[C:3](=[O:4])[CH2:2][N:26]1[CH2:27][CH2:28][N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C=C1NC(c2cccnc2)N=C1C(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1[nH]c(-c2cccnc2)nc1C(=O)CN1CCN(c2ccccc2)CC1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a stirred suspension of 4 g of 2-bromo-1-[5-methyyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone in 50 ml of dry tetrahydrofuran was added rapidly a mixture of 2.3 g of 1-phenylpiperazine and 1.4 g of triethylamine in 5 ml of dry tetrahydrofuran. This mixture was stirred for one hour and then filtered. Evaporation of the filtrate left a gummy foam which became amorphous upon trituration with 200 ml of ether. This solid was collected, washed with ether, suspended in 6 ml of acetone and stirred for 15 minutes. The solid was collected, washed repeatedly with acetone and then dried, giving 2.6 g of the desired intermediate, mp 141°-152° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=3)[CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH:7]=[C:8]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=1)[CH:9]=[C:10]2[N:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1
Reactant: CNc1nccc(-c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c3cc(OC)ccc3c2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1nccc(-c2cc(N3CCNCC3)c3cc(OC)ccc3c2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Tert-butyl 4-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)piperazine-1-carboxylate was dissolved in dichloromethane (25 ml) and 4.0 M HCl in dioxane (10 ml) was added to the reaction. The reaction was allowed to stir at room temperature for 15 hours and 4-(6-methoxy-4-(piperazin-1-yl)naphthalen-2-yl)-N-methylpyrimidin-2-amine hydrochloride 112 was isolated by filtration as a yellow solid (1.27 g). LC/MS (m/z): 350 [M+H].
Reaction SMILES: [C-:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH2:13][C:12](=O)[CH2:11][CH2:10]2.Cl>[I-].[Zn+2].[I-].C(#N)C>[C:1]([C:12]1[CH2:11][CH2:10][C:9]2[C:14](=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][CH:8]=2)[CH:13]=1)#[N:2]
Reactant: [C-]#N
Reactant: COc1cccc2c1CC(=O)CC2
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: CC#N
Product: COc1cccc2c1C=C(C#N)CC2
Temperature: 120 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
Trimethylsylyl cyanide (6.9 g, 9.3 ml, 0.07 mol) is added dropwise in 10 minutes to a mixture of 8-methoxy-3,4-di-hydronaphthalen-2(1H)-one (10.9 g, 0.06 mol) prepared as described in the literature (J. Chem. Soc., 1958, 409), anhydrous acetonitrile (60 ml) and a catalytic amount of zinc iodide under nitrogen atmosphere and the obtained mixture is heated to 80° C. ext. for 3 hours. The reaction mixture is cooled, 1N HCl (20 ml) is slowly added thereto and stirring is continued for 2 hours at room temperature. The solvent is then evaporated off under vacuum, the residue is taken up in ethyl acetate, and the organic solution is washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The obtained product is triturated with petroleum ether, filtered and dissolved in pyridine (100 ml). POCl3 (20 ml) is added dropwise in 10 minutes and the obtained mixture is heated to 120° C. ext. for 3 hours. The reaction mixture is then poured into ice, made acidic by the addition of concentrated hydrochloric acid and extracted with ethyl ether. The organic phase is washed with water, dried and evaporated to dryness and the obtained residue is crystallised from isopropyl ether yielding 2-cyano-8-methoxy-3,4-dihydronaphthalene (7.2 g); m.p. 66°-68° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=2)=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])(=[O:13])=[O:12])=[C:6]([CH3:42])[C:5]=1[CH3:43].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[C@@H:69]1(N)[O:77][C@H:76]([CH2:78][OH:79])[C@H:74]([OH:75])[C@H:72]([OH:73])[C@H:70]1[OH:71]>CN(C=O)C.ClCCl>[ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31](=[NH:32])[NH2:33])=[CH:29][CH:30]=2)=[O:21])[CH2:16][C:17](=[O:19])[NH:18][C@@H:69]2[O:77][C@H:76]([CH2:78][OH:79])[C@H:74]([OH:75])[C@H:72]([OH:73])[C@H:70]2[OH:71])(=[O:13])=[O:12])=[C:6]([CH3:42])[C:5]=1[CH3:43]
Reactant: N[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](Cc2ccc(C(=N)N)cc2)C(=O)N2CCCCC2)c(C)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C(=O)N[C@H](Cc2ccc(C(=N)N)cc2)C(=O)N2CCCCC2)c(C)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-N-(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-L-asparaginyl-4-amidino-D-phenylalanine-piperidide hydrochloride (1.0 g), HOBt (0.23 g) and DCCI (0.37 g) were dissolved in DMF and dichloromethane 1:1 (50 mL) and, after 0.5 h of stirring, β-D-galactopyranosyl-amine (1.0 g) was added. The reaction mixture was stirred for 48 h at room temperature and then filtered and concentrated by evaporation in vacuo. The residue was dissolved in ethyl acetate and washed with water. The crude product was purified by column chromatography on silica gel with chloroform/methanol 5:1. Yield: 1.2 g. TLC analysis: Rf=0.73 (chloroform/methanol 3:1). Barium oxide (0.25 g) was added to a solution of the intermediate compound (1.2 g) in chloroform/methanol 2:1 (100 mL), and the mixture was stirred for 2 h and then filtered. The flitrate was neutralized with methanolic HCl and concentrated by evaporation in vacuo. The residue was purified by column chromatography (Sephadex LH 20). Yield: 1.0 g. TLC analysis: Rf=0.042 (chloroform/methanol 3:1). [α]D +19.3° (c=1 in methanol). M.p. 186°-190° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[C:5]([C:4]1[C:3]([CH3:11])=[C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)[CH:10]=[CH:9][CH:8]=1)(=[O:6])[NH2:7]
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: Cc1c(Br)cccc1C(N)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C(N)=O)cccc1-c1ccc2cc(NC(=O)c3ccsc3)ccc2c1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
3-bromo-2-methylbenzamide (12.5 mg, 0.0584 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (45.8 mg, 0.121 mmol), Fibercat palladium catalyst (Johnson-Matthey, 31.9 mg), and K2CO3 (2 M in water, 0.15 ml, 0.30 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (0.7 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 10 minutes and then cooled to room temperature. The reaction was diluted with water (5 ml) and extracted with dichloromethane (3×10 ml) and EtOAc (10 ml). The organic extracts were combined, dried over magnesium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (6.6 mg, 29%). MS (ESI pos. ion) m/z: 387 (M+H). Calc'd Exact Mass for C23H18N2O2S: 386.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Cl[S:27]([C:30]1[CH:31]=[C:32]([C:40]([O:42][CH3:43])=[O:41])[CH:33]=[C:34]([CH:39]=1)[C:35]([O:37][CH3:38])=[O:36])(=[O:29])=[O:28]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:27]([C:30]4[CH:39]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[CH:33]=[C:32]([CH:31]=4)[C:40]([O:42][CH3:43])=[O:41])(=[O:29])=[O:28])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Cl)c1
Agent: Cl
Product: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and dimethyl 5-(chlorosulfonyl)isophthalate as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[N:8][N:9]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCOCC1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCOCC1

Procedure:
A solution of 4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (150 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (167 mg), tetrakis(triphenylphosphine)palladium(0) (45.5 mg) and 2M aqueous sodium carbonate solution (1.0 mL) in DME (15 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (119 m).
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[CH:4]([CH2:21][CH3:22])[CH:5]([C:11]1[CH:20]=[CH:19][C:14]2[N:15]=[C:16]([NH2:18])[S:17][C:13]=2[CH:12]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[CH2:1]([N:3]([CH3:23])[CH:4]([CH2:21][CH3:22])[CH:5]([C:11]1[CH:20]=[CH:19][C:14]2[N:15]=[C:16]([NH:18][C:24](=[O:26])[CH3:25])[S:17][C:13]=2[CH:12]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH3:2]
Reactant: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)CC
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCC(C(c1ccc2nc(NC(C)=O)sc2c1)n1ccnc1)N(C)CC
Temperature: 40 °C
Reaction time: 72 h

Procedure:
A mixture of 6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (50 mg, 0.151 mmol) and acetic anhydride (37 mg, 0.37 mmol) in THF (4 mL) was stirred at 40° C. over 3 days. The reaction was quenched with saturated sodium carbonate, extracted with 5% methanol in DCM. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC to afford N-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)acetamide. MS ESI: m/z 372.28 [M+1+].
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:26]([O:28][C@H:29]([C@H:32]([CH2:34][OH:35])[OH:33])[C:30]=1[OH:31])=[O:27])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C@@H:6]1([O:24][C:25]2[C:26]([O:28][C@H:29]([C@H:32]([CH2:34][OH:35])[OH:33])[C:30]=2[OH:31])=[O:27])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC2=C(O)[C@@H]([C@@H](O)CO)OC2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.5 h
Yield: 100 %

Procedure:
After dissolving 2-O-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)ascorbic acid (300 mg, 0.6 mmol) in methanol (10 ml), a solution of potassium carbonate (600 mg) in water (9 ml) was added and the mixture was stirred for 30 minutes. The reaction solution was neutralized with IR-120(H+), the resin was filtered off, and washing was performed with methanol and a 50% methanol aqueous solution. The filtrate and washing solution were combined and concentrated, and then water was added and the mixture was lyophilized to obtain 2-O-(β-D-glucopyranosyl)ascorbic acid as amorphous crystals (190 mg; 100% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[C:14]([F:17])([F:16])[CH2:15][CH:9]1[CH2:10][CH:11](CC([O-])=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:23].[K+].[K+]>CO>[CH2:1]([N:8]1[CH:13]2[C:14]([F:17])([F:16])[CH2:15][CH:9]1[CH2:10][CH:11]([OH:23])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C([O-])CC1CC2CC(F)(F)C(C1)N2Cc1ccccc1
Agent: [K+]
Solvent: CO
Product: OC1CC2CC(F)(F)C(C1)N2Cc1ccccc1

Procedure:
A solution of compound 116f (1.48 g, 4 mmol, 1.0 eq) and K2CO3 (1.1 g, 8 mmol, 2.0 eq) in MeOH (20 mL) was stirred at room temperature for 16 h. The mixture was quenched with water (100 mL), extracted with EA (100 mL) two times, the organic layer was combined, dried over Na2SO4 and concentrated to give 8-benzyl-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-ol 116g as a colorless oil, 1.02 g, crude yield: 100° A. MS: calc'd (MH+) 254, measured (MH+) 254.
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=1O>C(Cl)Cl>[C:1]([O:15][C:18]1[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:17]=1[Cl:16])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC(=O)O
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Yield: 95.9 %

Procedure:
A solution of n-tridecanoic acid (Sigma Chemical Co.) (12.5 g.), 2,4,5-trichlorophenol (11.5 g.), and N,N-dicyclohexylcarbodiimide (12.0 g.) in methylene chloride (650 ml.) is stirred at room temperature for 16 hours. The reaction mixture is then filtered and dried in vacuo to give 2,4,5-trichlorophenyl n-tridecanoate (22 g.). The material is purified by column chromatography over silica gel (Woelm) using toluene as the eluent. Fractions are monitored by TLC using a shortwave UV light for detection. Fractions containing the purified product are pooled and concentrated in vacuo to dryness.