Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[C:19](Cl)(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>N1C=CC=CC=1.C(Cl)Cl>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: CCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
Analogously to Example 1, 400 mg (1.53 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) in 8 ml of pyridine/methylene chloride 1:1 are reacted at 0° C. with 288 μl (1.68 mmol) of octanoic acid chloride to form 4-(3-chlorophenylamino)-3-octanoylamino-1H-pyrazolo[3,4-d]pyrimidine (18 hours RT): HPLC: tRet(grad20-100)=14.5; FAB-MS: (M+H)+=387.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:21]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)N(C)c4ccccc4)cc23)CC1

Procedure:
Beginning with 13.0 mg (0.056 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 10.1 mg (0.059 mMol) N-methyl-N-phenyl carbamoyl chloride, 17.4 (86%) of the title compound were recovered.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[C:14]([O-])(O)=O.[Na+].IC>CN(C=O)C.[Na+].[Cl-]>[CH3:14][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CCC(=O)c1ccc(C(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCC(=O)c1ccc(C(=O)OC)cc1
Yield: 77.4 %

Procedure:
4-propionylbenzoic acid (890 mg, 5 mmol), NaHCO3 (1.26 g, 15 mmol), and iodomethane (935 μL, 15 mmol) in DMF (10 mL) were stirred at RT overnight. The mixture was diluted with saturated aqueous NaCl (50 mL) and extracted with ether (3×50 mL). The organic phase was washed with water (50 mL), dried, and evaporated. Flash chromatography (90 g silica, 2/1 petroleum ether—EtOAc) gave white solids of 4-Propionyl-benzoic acid methyl ester (744 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:13])=[O:12])[C:8]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][C:3]=1[C:4](Cl)=[O:5].CC1C=C(Cl)C(S(C)(=O)=O)=CC=1C(O)=O.OO.O=S(Cl)Cl.[NH2:39][C:40]([NH2:42])=[NH:41]>>[NH2:41][C:40]([NH2:42])=[N:39][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([S:14]([CH3:17])(=[O:16])=[O:15])[C:9]([S:11]([CH3:13])=[O:12])=[CH:10][C:2]=1[CH3:1]
Reactant: N=C(N)N
Reactant: Cc1cc(S(C)=O)c(S(C)(=O)=O)cc1C(=O)Cl
Agent: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Agent: OO
Solvent: O=S(Cl)Cl
Product: Cc1cc(S(C)=O)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
Analogously to Example 1, by reaction of 1.3 g of 2-methyl-4-methylsulfinyl-5-methylsulfonylbenzoyl chloride [obtainable by reaction of 2-methyl-4-chloro-5-methylsulfonylbenzoic acid with Na methanethiolate, subsequent partial oxidation with hydrogen peroxide and conversion into the acid chloride, e.g. with SOCl2 ] with guanidine, N-diaminomethylene-2-methyl-4-methylsulfinyl-5-methylsulfonylbenzamide is obtained after customary working up and recrystallization from diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:12])=[C:6]([NH:8]C(=O)C)[CH:7]=1>O.CC(O)C>[NH2:8][C:6]1[C:5]([OH:12])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(=O)Nc1cc(Cl)cc([N+](=O)[O-])c1O
Solvent: CC(C)O
Solvent: O
Product: Nc1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 30 °C
Yield: 91 %

Procedure:
230.6 g (1 mole) of N-(5-chloro-2-hydroxy-3-nitrophenyl)acetamide prepared according to Example 1 b was suspended in a mixture of 950 ml of water and 100 ml of 2-propanol under a mild nitrogen purge. 345 ml of 36% w/w hydrochloric acid was added followed by 25 ml of water. The mixture was heated to reflux in about 30° C., while vigorously stirring and refluxed for 2 hours. The mixture was cooled to 0-5° C. in about one hour and stirred for an additional hour at 0-5° C. The solid was filtered off, washed twice with 250 ml of water, and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 91%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18]1([C:24]2[S:25][CH:26]=[C:27]([C:29](O)=[O:30])[N:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:9]([NH:8][C:6]1[CH:7]=[C:2]([NH:1][C:29]([C:27]2[N:28]=[C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:25][CH:26]=2)=[O:30])[CH:3]=[CH:4][C:5]=1[Cl:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Product: O=C(Nc1cc(NC(=O)c2csc(-c3ccccc3)n2)ccc1Cl)c1ccccc1

Procedure:
N-(5-amino-2-chlorophenyl)benzamide (0.20 mmol) was used in general procedure 2 with 2-phenylthiazole-4-carboxylic acid (0.25 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-2-phenylthiazole-4-carboxamide. MS (Q1) 434.0 (M)+
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[C:16]1([Mg]Br)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.O.Cl>CC1C=CC=CC=1C.O1CCCC1>[OH:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[P:2]([C:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1)[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Br[Mg]c1cccc2ccccc12
Reactant: ClP1Oc2ccccc2-c2ccccc21
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccccc1-c1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Temperature: 25 °C
Yield: 69.7 %

Procedure:
14.1 g (60 mmol) of 6-chloro-6H-dibenz[c,e][1,2]-oxaphosphorine in 50 ml of anhydrous o-xylene are introduced, in an argon atmosphere with stirring, and a solution of 150 mmol of 1-naphthylmagnesium bromide in tetrahydrofuran is added dropwise. The temperature increases in the course of this from 25° to 45° C. The mixture is then stirred for 3 hours at 80° C. and 5 hours at 120° C. The mixture is cooled to room temperature and 100 ml of water are added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. 19.0 g of colorless oil are obtained. By crystallization with methanol/water, 10:1, 22.8 g (89%) of colorless crystals having melting point 255° to 256° C. are obtained.
Reaction SMILES: C([N:3](C([O-])=O)[N:4]=[C:5]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)C.O=[S:29](Cl)Cl>>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([C:5]2[N:4]=[N:3][S:29][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CCN(N=C(Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1)C(=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2nnsc2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Yield: 60.3 %

Procedure:
Acylhydrazone 35 (21 g, 58.7 mmol) was added to SOCl2 (80 ml) at 0° C. The temperature was increased to 50° C., and the reaction was complete (by TLC) after 4 hours. SOCl2 was removed under reduced pressure. The crude solid was recrystallized from ETOAc/MeOH to afford 36 (11.6 g, 60.3%) m.p. 185°-186.5° C.
Reaction SMILES: C[CH2:2][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([O:6][CH3:7])=[O:5].[O-][CH2:14]C.[Na+].[Na].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19]>CCO>[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][C:3]([CH3:2])([C:4]([O:6][CH2:7][CH3:14])=[O:5])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)C(CC)C(=O)OC
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
Diethyl methyl malonate (1.60 ml, 9.25 mmol) was added to a freshly prepared solution of sodium ethoxide solution [(sodium (212 mg, 9.25 mmol) in EtOH (20 ml)] and stirred for 1 h. 4-Nitrobenzyl bromide (2.00 g, 9.25 mmol) was added dropwise to the reaction mixture and stirred for 6 h at reflux. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between water and CHCl3. The separated organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. This was purified by column chromatography over silica gel (100-200 mesh) using 5% ethyl acetate in petroleum ether as eluent to afford 850 mg (29.7%) of diethyl 2-(4-nitrobenzyl)-2-methylmalonate as oily liquid.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.Cl[C:13]1[N:14]=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.C1OCCOCCOCCOCCOCCOC1>[F:11][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([O:10][C:13]2[N:14]=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=2)[CH:7]=[CH:6][N:5]=1
Reactant: COc1cnnc(Cl)c1
Reactant: Oc1ccnc(OC(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: COc1cnnc(Oc2ccnc(OC(F)F)c2)c1
Temperature: 25 °C
Yield: 45 %

Procedure:
2-Difluoromethoxy-4-hydroxypyridine (123 g, 0.764 mol), 3-chloro-5-methoxypyridazine (110.47 g, 0.764 mol), potassium carbonate (211.18 g, 1.53 mol), CuBr (54.80 g, 0.382 mol) and 18-crown-6 (1 g) were mechanically stirred under nitrogen in diglyme (1.28 L) at 100° C. for 30 h. The mixture was cooled to RT and partitioned between ethyl acetate and 2 L of 3% HCl. The layers were separated. The aqueous layer was then adjusted to pH--1 with conc. HCl and extracted twice with additional ethyl acetate. The combined organics were filtered through silica gel and then extracted twice with 1.5 N NaOH. Solids were formed which were removed by filtering the organic layer through silica gel and celite. The organic layer was dried (MgSO4), filtered through silica gel and evaporated in-vacuo. The residue was triturated with ethyl acetate and filtered to give pure 3-[[2-(difluoromethoxy)-4-pyridinyl]oxy]-5-methoxypyridazine (92.5 g, 45% yield) as a light brown solid, mp=119° C. -120.5° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:17])[C@H:6]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:7])[CH3:3].[C:18]([NH:25][C:26]([CH3:31])([C:28](O)=[O:29])[CH3:27])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:17])[C@H:6]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:7][C:28](=[O:29])[C:26]([NH:25][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:31])[CH3:27])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CSCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CSCc1ccccc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of S-benzyl-L-cysteine ethyl ester hydrochloride (7.98 g, 29 mmol), BOC-α-methylalanine (5.89 g, 29 mmol), triethylamine (2.93 g, 29 mmol), 1-hydroxybenzotriazole (HOBT, 3.92 g, 29 mmol) and EDCI (5.57 g, 29 mmol) in methylene chloride (200 mL) is stirred under an argon atmosphere at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is dissolved in ethyl acetate (200 mL). The solution is washed with water (50 mL), 1 N HCl (50 mL), water (50 mL), 5% sodium bicarbonate (50 mL), water (50 mL) and finally brine (25 mL). The solution is then dried over sodium sulfate, filtered and evaporated to dryness to give N-[2-(BOC-amino)-2-methylpropionyl]-S -benzyl-L-cysteine ethyl ester.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)#[N:2].O1CCCC1.C(O[K])(C)(C)C.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH2:33]Br)[CH:27]=1>O.CN(C)C=O>[Br:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][CH:3]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[C:1]#[N:2])[CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(CC#N)cc1
Reactant: BrCCc1cccc(Br)c1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C#N)CCc2cccc(Br)c2)cc1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a mixed solution of methyl 4-(cyanomethyl)benzoate (3.50 g, 20.0 mmol), tetrahydrofuran (25 mL) and N,N-dimethylformamide (10 ml) was added tert-butoxy potassium (2.69 g, 24.0 mmol) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added 1-bromo-3-(2-bromoethyl)benzene (3.37 mL, 22.0 mmol) at the same temperature, and the mixture was stirred under ice-cooling for 4 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (3.94 g, 55%) as a colorless oil.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[N:20][C:21]#[N:22])OC2C=CC=CC=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[N+:2]=[N-:3].[C:23]([NH2:28])([CH2:26][CH3:27])([CH3:25])[CH3:24]>C(O)(C)C>[N:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12]([NH:20][C:21]#[N:22])=[N:28][C:23]([CH3:25])([CH3:24])[CH2:26][CH3:27])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: CCC(C)(C)N
Reactant: N#CN=C(Nc1cc(Cl)cc(N=[N+]=[N-])c1)Oc1ccccc1
Solvent: CC(C)O
Product: CCC(C)(C)N=C(NC#N)Nc1cc(Cl)cc(N=[N+]=[N-])c1
Yield: 65.4 %

Procedure:
Step B-2. To a stirred suspension of N-(3-azido-5-chlorophenyl)-N'-cyanocarbamimidic acid, phenyl ester (B-1, 0.705 g, 2.25 mmol) in 10 mL of isopropanol is added tert-amylamine (1.0 mL, 9.02 mmol). The reaction mixture is heated at reflux for 4 hours, cooled and concentrated. The organic residue is purified by flash chromatography using 30% ethyl acetate in hexane as the eluent to afford 0.45 g of N-(3-azido-5-chlorophenyl)-N'-cyano-N"-(1,1-dimethylpropyl)guanidine. (B-2) Mp 147°-149° C.; IR (mull) 3325, 3234, 2925, 2159, 2121, 2108, 1611, 1595, 1578, 1558, 1495, 1414, 1228, 853 cm-1 ; 1H NMR (DMSO) δ7.10 (bs, 1 H), 6.80 (m, 1 H), 6.74 (m, 1 H), 6.65 (m, 1 H), 1.55 (q, 2 H, J=7 Hz), 1.14 (s, 6 H), 0.68(t, 3 H, J=7 Hz).; 13 C NMR (DMSO) δ156.3, 141.8, 141.7, 134.5, 116.5, 116.2, 113.4, 109.2, 54.7, 32.3, 26.1, 8.4; Melt Solvate: 0.63% Chloroform; Analysis calculated for C13H16ClN7 plus 0.63% CHCl3 :C, 50.81; H, 5.23; N, 31.86; Cl, 12.08. Found: C, 50.73; H, 5.15; N, 31.57; Cl, 12.35.
Reaction SMILES: [NH2:1][NH2:2].C([O-])([O-])=O.[Na+].[Na+].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(=O)=O.Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>C(#N)C>[CH3:9][S:10]([NH:1][NH:2][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])(=[O:12])=[O:11]
Reactant: NN
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)OC(=O)NNS(C)(=O)=O
Temperature: 10 °C

Procedure:
In a 1-liter 3-neck flask is placed 17 g. (0.5 mole) anhydrous hydrazine, 27 g. (1/4 mole) Na2CO3 and 100 cc. acetonitrile. The mixture is stirred as 57.3 g. (1/2 mole) of methanesulfonyl chloride is added slowly. The temperature of the mixture increases and CO2 is evolved. Then another 27 g. of Na2CO3 is added and the mixture is stirred as 61.5 g. (0.5 mole) of isopropyl chloroformate is added, keeping the temperature under 40° C. Finally the mixture is stirred 2 hours and then cooled to 10° C. and filtered, washed with cold water and dried. This product melts at 129°-131° C.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:8]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]1=O.[C:20]1([CH2:26][C:27]([NH2:29])=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.CN(C)C=O.O>[CH2:26]([C:27]1[S:28][C:2]2[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=2[N:29]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=S)Cc1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCC(Br)C2=O
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCc1sc(Cc3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 14 h
Yield: 21.5 %

Procedure:
A solution of ethyl [(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate (2.16 g, 6.61 mmol) and phenylthioacetamide (1.00 g, 6.61 mmol) in a mixture of ethanol (25 mL) and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 14 hours and, then, refluxed for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate=1:5) to provide ethyl [(2-benzyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (540 mg). To a solution of this compound (0.54 g, 1.42 mmol) in a mixture of tetrahydrofuran (16 mL) and methanol (4 mL) was added 1N-hydrochloric acid followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to provide 320 mg of the title compound Yield 14%.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:11]([C:12](=[O:23])[CH:13]([NH:15]C(=O)OC(C)(C)C)[CH3:14])[N:10]=[C:9]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[S:8]1)=[N+:2]=[N-:3].Cl>CCO>[NH2:15][CH:13]([CH3:14])[C:12]([N:11]1[N:10]=[C:9]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[S:8][C:7]1([CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:23]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(N)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
tert-Butyl 1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1-oxopropan-2-ylcarbamate (70 mg, 0.131 mmol) was dissolved in 7.0 mL of EtOH. HCl (0.65 mL, 0.659 mmol) was then added and the reaction stirred at 23° C. for 4 hours. The reaction was then concentrated and purified by chromatography (2-10% MeOH/DCM), yielding the product (54 mg, 95%) as a yellow oil. MS ESI (+) m/z 431 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ7.69 (m, 1H), 7.53 (d, 2H, J=8 Hz), 7.42 (t, 2H, J=7 Hz), 7.34 (m, 3H), 4.91 (m, 3H), 3.21 (m, 1H), 3.17 (m, 2H), 2.68 (m, 1H), 2.19 (m, 1H), 1.99 (m, 1H), 1.73 (d, 1.5 H, J=8 Hz), 1.64 (d, 1.5H, J=8 Hz).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[CH:7]=[C:6]([Sn:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=1)(O)=[O:2].Cl.C[N:23](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.N>C(#N)C.C1COCC1>[C:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[CH:7]=[C:6]([Sn:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=1)(=[O:2])[NH2:23]
Reactant: CCN=C=NCCCN(C)C
Reactant: C[Sn](C)(C)c1cc(C(=O)O)c2c(c1)oc1ccccc12
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc(C(N)=O)c2c(c1)oc1ccccc12
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a stirred solution of the stannane 306 (1.1 g, 2.96 mmol) in anhydrous acetonitrile (5 mL) and THF (15 mL) under a nitrogen atmosphere was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.13 g, 5.9 mmol) and 1-hydroxybenzotriazole hydrate (1.2 g, 8.9 mmol). The solution was stirred 30 min., then 11 mL of a 2.6 M ethanolic ammonia solution was added. The resulting milky white solution was stirred an additional 30 min. before being quenched with saturated aqueous ammonium chloride. The solvents were removed under vacuum and the residue taken up in ether (75 mL) and EtOAc (75 mL). The solution was washed with water (3 times) and brine (2 times), then dried with magnesium sulfate and filtered. The solution was concentrated under vacuum and the residue was purified by flash chromatography (silica gel, 35% EtOAc in hexanes) to provide 979 mg (88% yield) of stannane 307 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[C:20]3[C:21]([CH3:27])=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[C:20]3[C:21]([CH3:27])=[C:22]([NH:23][C:40](=[O:41])[C:39]4[CH:43]=[CH:44][CH:45]=[C:37]([C:36]([F:35])([F:46])[F:47])[CH:38]=4)[CH:24]=[CH:25][CH:26]=3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(-c2cc3nccc(-c4cccc(N)c4C)c3o2)cc1OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2cc3nccc(-c4cccc(NC(=O)c5cccc(C(F)(F)F)c5)c4C)c3o2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
To a 20-mL glass vial was added 3-[2-(3,4-dimethoxyphenyl)furo[3,2-b]pyridin-7-yl]-2-methylaniline (19.20 mg; 0.05 mmol), triethylamine (0.01 ml; 0.11 mmol) suspended in DCM (2.00 ml). 3-(trifluoromethyl)benzoyl chloride (16.67 mg; 0.08 mmol) was then added. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture which was then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude mixture was purified using Biotage column chromatography (20-100% EtOAc/Hexanes). Fractions containing the desired product were combined and concentrated. The mixture was then purified using preparative HPLC to afford the title compound as a yellow solid (3.80 mg, 13%). HPLC (method F): 100%, RT=4.531 min. 1H NMR (CDCl3) δ [ppm] 8.58 (d, 1H), 8.19 (s, 1H), 8.12 (d, 1H), 7.96 (d, 1H), 7.88-7.84 (m, 2H), 7.71-7.68 (m, 2H), 7.60-7.47 (m, 3H), 7.39-7.38 (m, 2H), 7.00-6.97 (m, 1H), 4.01 (s, 3H), 3.96 (s, 3H), 2.27 (s, 3H). MS: m/z=533 [M+H]+, RT=3.91 min.