Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[P:28](Cl)(=[O:43])([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][P:28]([O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([O:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:43])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](CO)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](COP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 80.3 %

Procedure:
In 30 ml of dried methylene chloride was dissolved 3.75 g of benzyl N-t-butoxycarbonyl-D-serine, and 1.23 ml of pyridine, 1.86 g of 4-dimethylaminopyridine, and 4.09 g of diphenyl phosphorochloridate were successively added thereto at room temperature, followed by stirring at that temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 2% acetone-containing chloroform) to obtain 5.38 g of benzyl N-t-butoxycarbonyl-O-diphenylphosphono-D-serine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]([NH:25][CH2:26][CH3:27])[CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:29](Cl)(=[O:31])[CH3:30]>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH:23]([N:25]([C:29](=[O:31])[CH3:30])[CH2:26][CH3:27])[CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: CCNC(C)c1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(C(C)=O)C(C)c1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-(1-ethylamino-ethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [CH3:1][CH:2]([CH:21]([N+:29]([O-])=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:4][C:5](=[O:13])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)(=O)C.[Pd]>[CH3:1][CH:2]([CH:21]([NH2:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:3]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[NH:4][C:5](=[O:13])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C(C(=O)OC(C)(C)C)[N+](=O)[O-])[C@H](NC(=O)Nc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C(N)C(=O)OC(C)(C)C)[C@H](NC(=O)Nc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A solution of di t-butyl 3-methyl-4-nitrophenylcarbamoyl-L-glutamate (4.7 g) in ethyl acetate (125 ml) yes hydrogenated over 30% Pd/C (0.5 g). The mixture obtained was then filtered through Celite (a purified and calcined diatomaceous earth-particle size 20-45 um obtainable inter alia from Fluka Chemicals Ltd) and evaporated to a dark solid. This solid was chromatographed on silica eluted using ethyl acetate:hexane (1:1) to give di t-butyl 3-methyl-4-aminophenylcarbamoyl-L-glutamate as in oil yield=3.71 g 83%. NMR: 7.98(s)1H; 6.9(m)2H; 6.52(d)1H; 6.15(d)1H; 4.53(s)2H; 4.15(m)1H; 2.25(m)2H; 2.04(s)3H; 1.8(m)2H; 1.45(d)18H.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:14]2[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=3)[CH2:12][CH2:13]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)cc3)CC2)CC1

Procedure:
From (4-chlorophenyl)(4-piperidyl)methanone hydrochloride (100 mg) and [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (intermediate C, 102 mg) by procedure A.1. Yield: 128 mg (74%). Light yellow solid. MS (m/z): 449.3 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:35]([CH:37](Br)[CH3:38])[CH3:36]>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:38][CH2:37][CH2:35][CH2:36]3)=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(N)cc2)CC1
Reactant: CC(Br)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(N3CCCC3)cc2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To 1-tert-butyloxycarbonyl-4-[(4-aminophenyloxy)methyl]piperidine (0.75 g) obtained in Example 13 were added dimethylformamide (10 ml), potassium carbonate (1.4 g) and dibromobutane (0.54 g) and the mixture was heated to 70° C. and stirred overnight. To the reaction solution was added water which was extracted with ethyl acetate (50 ml×3). The combined extract was dried over sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1 (v/v)) to obtain 1-tert-butyloxycarbonyl-4-[(4-pyrrolidinophenyloxy)methyl]piperidine (0.55 g) as colorless crystals, m.p. 141°-145° C.
Reaction SMILES: [C:1](CCSCCC#N)#[N:2].[C:10]([NH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[N:32]=[N:33][C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][C:37]([N+:43]([O-:45])=[O:44])=[CH:36][C:35]=1Br)[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C-]#N.[Na+]>O>[C:10]([NH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[N:32]=[N:33][C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][C:37]([N+:43]([O-:45])=[O:44])=[CH:36][C:35]=1[C:1]#[N:2])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(=O)C=Cc2ccccc2)c1
Reactant: N#CCCSCCC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(=O)C=Cc2ccccc2)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 85.5 %

Procedure:
Into a solution composed of 6.8 parts of cuprous bromide in 300 parts by volume of bis-(β-cyanoethyl) sulfide, there are introduced 26 parts of 3-cinnamoylamino-4-(2'-bromo-4', 6'-dinitrophenylazo)-N,N-diethylaniline. The mixture is heated to 100° C. and, during several minutes, a solution of 2.6 parts of sodium cyanide in 16 parts of water is allowed to flow in. Stirring is continued for 1 to 2 hours more, at 115° C. After cooling to 30° C., the 3-cinnamoylamino-4-(2'-cyano-4',6'-dinitrophenylazo)-N,N-diethylaniline formed is separated, under the same conditions as in example 1. The yield is 85.5%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Cl>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: ClCc1ccccn1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccccn3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 2-picolyl choride, whereby the product was isolated as free base, 2-methyl-7-(pyridin-2-ylmethoxy)-4-pyrrolidin-1-yl-quinoline as a light brown solid. ISP mass spectrum, m/e: 320.4 (M+1 calculated for C20H21N3O: 320).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:33])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)[CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:40][CH2:41][C:42](Cl)=[O:43]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:33])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:42](=[O:43])[CH2:41][Cl:40])=[CH:29][CH:30]=3)[CH2:19][CH2:18]4)(=[O:13])=[O:14])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(C(=O)N2CCc3cc(S(=O)(=O)n4cc(-c5ccccc5)[nH]c4=O)ccc32)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc(C(=O)N2CCc3cc(S(=O)(=O)n4cc(-c5ccccc5)[nH]c4=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
4-Phenyl-1-[N-(4-aminobenzoyl)indoline-5-sulfonyl]-2-imidazolone (150 mg, 0.3 mmol) prepared in Example 10 was dissolved in 10 ml of dichloromethane. Pyridine (73 μl, 0.9 mmol) and chloroacetylchloride (36 μl, 0.45 mmol) were added thereto one after another, and then the reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. After stirring, the reaction mixture was diluted with 30 ml of dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1, v/v) to afford 130 mg of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH2:26]([O:28][CH2:29][CH2:30][C:31](=[N:33]O)[NH2:32])[CH3:27]>>[CH2:26]([O:28][CH2:29][CH2:30][C:31]1[N:33]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:32]=1)[CH3:27]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Reactant: CCOCCC(N)=NO
Product: CCOCCc1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.655 mmol) of the compound from Example 7A and 355 mg (approx. 2.152 mmol) of 3-Ethoxy-N′-hydroxypropanimidamide were reacted Yield: 389 mg (49% of theory)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21]C)=O)[CH:17]=3)[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH:11]=2)[N:5]=1)([CH3:3])[CH3:2].[NH2:33][NH2:34]>O1CCOCC1>[CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:33][NH2:34])=[O:21])[CH:17]=3)[NH:12][CH:11]=2)[N:5]=1)([CH3:2])[CH3:3]
Reactant: NN
Reactant: COC(=O)c1ccc2c(c1)c(-c1nccc(C(C)C)n1)cn2S(=O)(=O)c1ccc(C)cc1
Solvent: C1COCCO1
Product: CC(C)c1ccnc(-c2c[nH]c3ccc(C(=O)NN)cc23)n1
Temperature: 90 °C
Yield: 44.4 %

Procedure:
A light-yellow mixture of methyl 3-(4-isopropylpyrimidin-2-yl)-1-tosyl-1H-indole-5-carboxylate (1.37 g, 3.05 mmol) in anhydrous hydrazine (2.39 mL, 76 mmol) and dioxane (1 mL) was heated in an oil bath at 90° C. for 3 h. The mixture was cooled to RT, treated with 20 mL of ice cold H2O. The precipitated pink solid was filtered, rinsed with 2×5 mL of water and 2×20 mL of EtOAc. The filtrate was transferred to a separatory funnel. The aqueous layer was discarded. The EtOAc layer was concentrated to half of its volume. The precipitated brown solid was filtered, rinsed with 2×2 mL of Et2O. The above obtained pink solid and brown solid were combined and dried in a vacuum oven at 40° C. for 18 h to afford 3-(4-isopropylpyrimidin-2-yl)-1H-indole-5-carbohydrazide (400 mg). This material was used in next step without further purification. MS (ESI, pos. ion) m/z: 296.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[Br:12]Br>C(#N)C>[NH2:1][C:2]1[C:7]([Br:12])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: BrBr
Solvent: CC#N
Product: Nc1c(O)cc([N+](=O)[O-])cc1Br
Yield: 85.2 %

Procedure:
To a solution of 2-amino-5-nitro-phenol (500 g, 3.24 mol) in ACN (12 L) was added bromine (290 mL, 5.63 mol) drop wise over a period of 30 min under stirring. The resulting mixture was stirred at 30-35° C. for 1 h. After the completion of the reaction (by TLC), solvent was evaporated till dryness. Hexane was added (2 L) and the mixture evaporated to remove solvent traces. Hexane (5 L) was added again to the residue and the mixture stirred for 1 h then filtered. The resulting solid (1102 g) was washed with hexane (2 L). The residue was added to ice-cold water (2.5 L) followed by addition of a saturated solution of sodium thiosulfate (2.5 L) and extraction with EtOAc (2×10 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated at 40-45° C. under reduced pressure to obtain the desired product (643 g crude yield 85%).
Reaction SMILES: [NH:1]1[C:8]2=[CH:9][CH:10]=[CH:11][CH2:12][CH:7]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:13].P(Cl)(Cl)(Cl)(Cl)Cl.[Br:20]Br>C(Cl)(Cl)Cl.II>[Br:20][CH:3]1[CH2:4][CH2:5][CH2:6][CH:7]2[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]2[NH:1][C:2]1=[O:13]
Reactant: BrBr
Reactant: O=C1CCCCC2CC=CC=C2N1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)Cl
Product: O=C1NC2=CC=CCC2CCCC1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 15 gm (0.084 mol) of hexahydrobenzoazocin-2-one (Chemica Scandinavia, 18, 191 (1964)) in 150 ml of chloroform at 0° C. was added 8.8 gm of PCl5 in small increments over a period of an hour. To this reaction mixture was added 70 mg of iodine, followed by the slow dropwise addition of 84 ml of a 1M solution of bromine in chloroform and this reaction mixture was warmed to room temperature and stirred for 1 hour, at which time it was concentrated at reduced pressure. A mixture of ice and water was added to the crude product and the mixture was extracted three times with methylene chloride. The combined organic fractions were filtered through MgSO4 and concentrated at reduced pressure. The solid bromide was recrystallized with a mixture of chloroform and hexanes to give 12 gm of pure 3-bromohexahydrobenzoazocin-2-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:43])([CH3:42])[CH2:6][N:7]([S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32])[CH2:8][C@@H:9]([OH:30])[C@@H:10]([NH:18][C:19](=[O:29])[O:20][C@@H:21]1[C@H:28]2[C@H:24]([O:25][CH2:26][CH2:27]2)[O:23][CH2:22]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.[CH3:53][N:54]([CH3:58])[C:55](Cl)=[O:56]>C1COCC1>[CH2:11]([C@H:10]([NH:18][C:19](=[O:29])[O:20][C@@H:21]1[C@H:28]2[C@H:24]([O:25][CH2:26][CH2:27]2)[O:23][CH2:22]1)[C@H:9]([OH:30])[CH2:8][N:7]([CH2:6][C:5]([CH3:43])([CH3:42])[CH2:4][CH2:3][CH2:2][NH:1][C:55]([N:54]([CH3:58])[CH3:53])=[O:56])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCN)c1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCNC(=O)N(C)C)c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of 50 mg (0.081 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-((5-amino-2,2-dimethylpentyl) [3-(methylamino)phenyl]sulfonylamino)-1-benzyl-2-hydroxypropyl]carbamate and 17 μL (0.097 mmol) of N,N-diisopropylethylamine in 5 mL of anhydrous THF at 0° C. was treated with 8.2 μL (0.089 mmol) of N,N-dimethylcarbamyl chloride. The solution was allowed to warm to RT with stirring. After 18 hours the solution was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 44 mg (79%) of the desired compound as a white foam. H1-NMR (CDCl3): 7.31-7.11 (m, 6H), 7.03 (d, 1H), 6.95 (s, 1H), 6.73 (d, 1H), 5.92 (d, 1H), 5.60 (d, 1H), 4.94 (q, 1H), 4.63 (t, 1H), 4.19 (m, 2H), 3.94-3.73 (m, 4H), 3.63 (m, 2H), 3.30-3.00 (m, 6H), 2.91-2.78 (m, 11H), 2.69 (dd, 1H), 1.59-1.19 (m, 6H), 0.94 (s, 3H), 0.86 (s, 3H). MS(ESI): 690(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[OH-].[K+].Br[CH:13]([CH3:19])[C:14]([O:16]CC)=[O:15]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH:13]([CH3:19])[C:14]([OH:16])=[O:15]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(Sc1ccc(Cl)cc1Cl)C(=O)O
Temperature: 25 °C
Yield: 25 %

Procedure:
A mixture of 11.78 g of 2,4-dichlorothiophenol and 12.0 g of potassium hydroxide in 50 ml of acetone was stirred and heated to reflux. 11.77 g of ethyl 2-bromopropionate were added gradually and the mixture was heated under reflux for 22 hours. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in 400 ml of diethyl ether and the solution was washed with 400 ml of water and 400 ml of 10% sodium carbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness. A solution of the residue in a mixture of 30 ml of ethanol and 17 ml of 10% potassium hydroxide solution was heated under reflux for 21 hours. The solution was evaporated to dryness and the residue was dissolved in 50 ml of water. The resulting solution was washed twice with 50 ml of diethyl ether each time and then acidified with concentrated hydrochloric acid and extracted twice with 150 ml of ethyl acetate each time. The combined organic extracts were washed twice with 200 ml of water each time, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from diethyl ether to give 4.08 g of 2(RS)-(2,4-dichlorophenyl-thio)propionic acid in the form of a yellow solid of melting point 95°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[CH2:33]([NH:40][C:12]([C:10]1[S:11][C:7]2[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A suspension of 29.4 mg (0.10 mmol) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 18.4 mg (0.11 mmol) 1.1′-carbonyl-diimidazole in 3 ml dimethylformamide was stirred at room temperature for one hour. 12.1 μl (0.11 mmol) benzylamine were added, stirring was continued and after 20 hours 15 ml water were added. Extraction with ethyl acetate and chromatography on silicagel with dichloromethane/ethyl acetate 95/5 yielded 31.2 mg (41%) of yellow 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid benzylamide with mp.: 156-158° C., MS m/e (%): 384 (M+H+, 100).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[CH3:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1>C(#N)C>[Cl:1][CH2:2][C:3]1[N:14]=[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:7])[N:13]2[CH:5]=1
Reactant: Cc1cccc(N)n1
Reactant: O=C(CCl)CCl
Solvent: CC#N
Product: Cc1cccc2nc(CCl)cn12
Yield: 41.9 %

Procedure:
1,3-Dichloroacetone (17.6 g, 138.3 mmol) was added to a solution of 6-methylpyridin-2-amine (10 g, 92.5 mmol) in acetonitrile (200 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). The mixture was concentrated under reduced pressure, the residue was diluted with water, and the pH was adjusted to 7.5 with sodium bicarbonate solution. The mixture was extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (7.0 g, 70.7%) as a pale yellow solid. 1H NMR: 200 MHz, CDCl3: δ 8.15 (s, 1H), 7.6 (dd, 2H), 7.1 (t, 1H), 6.8 (t, 1H), 4.95 (s, 2H), 2.6 (s, 3H). MS: [M+H]+: m/z=181.5.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[NH:12])[NH2:11])=[CH:5][CH:4]=1.Cl.[CH2:14]([N:21]1[CH2:27][CH2:26][C:25](=O)[CH:24]([C:29](OCC)=[O:30])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-]CC.[Na+]>>[CH2:14]([N:21]1[CH2:22][CH2:23][C:24]2[C:29](=[O:30])[NH:12][C:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][CH:7]=3)=[N:11][C:25]=2[CH2:26][CH2:27]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CCC1=O
Reactant: Cc1ccc(CC(=N)N)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(Cc2nc3c(c(=O)[nH]2)CCN(Cc2ccccc2)CC3)cc1
Yield: 43 %

Procedure:
Under nitrogen, 2-(4-methylphenyl)ethanimidamide hydrochloride (360 mg, 1.95 mmol) and ethyl 1-benzyl-5-oxoazepane-4-carboxylate hydrochloride (500 mg, 1.61 mmol) were added to a freshly-prepared solution of sodium ethoxide (from sodium (120 mg, 5.22 mmol) dissolved in ethanol (15 ml)) and the mixture refluxed overnight. The reaction mixture was concentrated in vacuo and the residue treated with water. The mixture was acidified with 2M HCl solution, then rebasified using saturated aqueous NaHCO3 solution and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by purified by column chromatography on silica gel, eluting with DCM:MeOH, 98:2 to 94:6, to afford the title compound as a solid in 43% yield, 250 mg.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:42](O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30]([O:32][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:31])[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccccc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)OCc1ccccc1

Procedure:
The procedure described in Example 22 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid and benzyl alcohol, to thereby obtain the title compound as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19](=[S:21])[NH2:20]>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:20]=[C:19]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]=2[CH3:12])[S:21][CH:2]=1
Reactant: Cc1ccncc1C(=O)CBr
Reactant: Cc1ccncc1C(N)=S
Product: Cc1ccncc1-c1csc(-c2cnccc2C)n1
Yield: 42 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (392 mg) and 4-methylpyridine-3-thiocarboxamide (152 mg), the title compound (112 mg) was obtained as colorless powder crystals.