Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:5][C:4]=1[NH:15][CH:16]=O.CS(C1[N:23]=[CH:24][C:25]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]=2[N:27]=1)(=O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:23]=[CH:24][C:25]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]=2[N:27]=1
Reactant: COc1cc(-c2cncn2C)ccc1NC=O
Reactant: CC(C)(C)CNc1nccc2cnc(S(C)(=O)=O)nc12
Product: COc1cc(-c2cncn2C)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
Yield: 38 %

Procedure:
The title compound was prepared according to Example 40 using N-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)formamide (Preparation 74) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47). The residue was purified by silica gel column chromatography eluting with 0-20% MeOH in EtOAc followed by a second chromatography eluting with 0-10% MeOH in EtOAc to give the title compound (7.5 mg, 38%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:16]([C:20]1[N:21]=[CH:22][N:23]2[CH:27]=[CH:26][S:25][C:24]=12)(=[O:19])(=[O:18])[NH2:17].C(OCC)(=O)C>CN(C=O)C>[Si:1]([NH:17][S:16]([C:20]1[N:21]=[CH:22][N:23]2[CH:27]=[CH:26][S:25][C:24]=12)(=[O:19])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)c1ncn2ccsc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butyldimethylsilyl chloride (0.30 g) and 0.33 ml of triethylamine were added to a solution of 0.20 g of 7-sulfamoylimidazo[5,1-b]thiazole in 5 ml of DMF. The mixture was stirred at room temperature for one hr. Ethyl acetate was added to the reaction mixture, followed by washing with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 0.34 of 7-(t-butyldimethylsilylsulfamoyl)imidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][C:4]#[C:5][CH2:6][S:7][CH2:8][CH2:9][NH2:10].CO[C:14]1[C:18](OC)=[N:17][S:16](=[O:22])(=[O:21])[N:15]=1.[NH3:23]>>[NH2:23][C:14]1[C:18]([NH:10][CH2:9][CH2:8][S:7][CH2:6][C:5]#[C:4][CH2:3][N:2]([CH3:1])[CH3:11])=[N:17][S:16](=[O:22])(=[O:21])[N:15]=1
Reactant: N
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)CC#CCSCCN
Product: CN(C)CC#CCSCCNC1=NS(=O)(=O)N=C1N

Procedure:
In a manner similar to Example 1, reaction of 2-(4-dimethylamino-but-2-ynylthio)ethylamine and 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide followed by reaction with ammonia gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9](Cl)[N:8]=[C:7]([Cl:14])[N:6]=1)=[O:4].[NH3:15]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:15])[N:8]=[C:7]([Cl:14])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1OC
Reactant: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(Cl)nc(N)c1OC
Reaction time: 0.5 h
Yield: 29 %

Procedure:
2,6-Dichloro-5-methoxypyrimidine-4-carboxylic acid methyl ester (750 mg, 3.16 mmol; see J. Med. Chem. 49(5), 1693-1705; 2006 for preparation) was dissolved in chloroform and 2N ammonia in methanol (2 eq) was added dropwise while in a cooling bath. The reaction mixture was stirred for 30 min, after which an additional 2 eq of 2N ammonia in methanol was added. The reaction was stirred at ambient temperature for 16 h. Additional 2N ammonia in methanol (2 eq) was added. The reaction was stirred for 2 h during which time a solid precipitated. The solid was filtered off and water was added to the filtrate. The crude material was extracted from the filtrate with dichloromethane three times and the combined organic phases were washed with brine, dried and concentrated under vacuum. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to provide the title compound (202 mg, 29% yield): mp 162-167° C.; 1HNMR (CDCl3): δ 5.75 (br s, 2H), 3.97 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH:12]1([O:17][C:18](=[O:24])[C@@H:19]([NH2:23])[CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15][CH2:14][CH2:13]1.[P:25](Cl)(Cl)(=[O:37])[O:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.[Cl:47]CCl>>[Cl:47][C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[O:26][P:25](=[N:23][C@@H:19]([CH:20]([CH3:22])[CH3:21])[C:18]([O:17][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:24])=[O:37]
Reactant: ClCCl
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: CC(C)[C@H](N)C(=O)OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)OC1CCCC1
Yield: 72 %

Procedure:
Using the general procedure for synthesizing naphthyl (amino acid ester) phosphorochloridates and tosylate salt of (S)-cyclopentyl-2-amino-3-methylbutanoate (2.58 g, 7.2 mmol), naphthalene-1-yl phosphorodichloridate (1.88 g, 7.2 mmol), triethyl amine (2.014 mL, 14.4 mmol) and dichloromethane (20 mL) were combined to give 2.12 g of desired (2S)-cyclopentyl 2-(chloro(naphthalen-1-yloxy)-phosphorylamino)-3-methylbutanoate as a pale yellow viscous oil in 72% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](O)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:12][C:13]1[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=1.C(OP(C#N)(OCC)=O)C.C(N(CC)CC)C>COCCOC.CCOC(C)=O>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[NH:20][C:15]3[CH:14]=[C:13]([CH3:12])[CH:18]=[CH:17][C:16]=3[N:19]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: Cc1ccc(N)c(N)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Yield: 45.9 %

Procedure:
A mixture of 3-amino-6-bromo-pyrazine-2-carboxylic acid (2.5 g, 11.47 mmol), 4-methylbenzene-1,2-diamine (1.401 g, 11.47 mmol), diethoxyphosphoryl-formonitrile (2.058 g, 1.871 mL, 12.62 mmol) and triethylamine (2.321 g, 3.197 mL, 22.94 mmol) was heated in DME (75.00 mL) at 170° C. in the microwave for 1 hour. The reaction mixture was diluted with EtOAc, filtered and washed with water and brine, dried over MgSO4 and concentrated to a brown solid. The mixture was slurried in DCM and treated with diethyl ether/petroleum ether. The resultant solid was washed with ether and dried to afford the product as an orange/brown solid (1.6 g, 46% Yield). MS (ES+) 305.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:16][CH2:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C([BH3-])#N.[Na+]>CO>[N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH:13][CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][CH3:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCCCC(=O)CC
Reactant: NCCOc1ccc(-n2ccnc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCC(CC)NCCOc1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 8, react 2-[4-(1H-imidazol-1-yl)phenoxy]ethanamine with 3-octanone and sodium cyanoborohydride in methanol to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)CCCc1ccc(Br)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1
Yield: 85.1 %

Procedure:
In a manner similar to that described in Example 3, 4-(4-bromo-phenyl)-butyryl chloride (0.086 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.089 g of 4-{4-[4-(4-bromo-phenyl)-butyrylamino]-phenyl}-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+419.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH:4]=[C:5]([CH3:8])[CH2:6]Cl.[OH2:16]>O1CCCC1>[CH2:10]([NH:13][C:6](=[O:16])[C:5]([CH3:8])=[CH:4][C:3]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:2]=1[Cl:1])[CH:9]=[CH2:3]
Reactant: O
Reactant: CC(=Cc1cc([N+](=O)[O-])ccc1Cl)CCl
Solvent: C1CCOC1
Product: C=CCNC(=O)C(C)=Cc1cc([N+](=O)[O-])ccc1Cl
Reaction time: 2 h
Yield: 81 %

Procedure:
At 5° to 10° C., 10.4 g (0.04 mol) of 2-chloro-5-nitro-α-methylcinnamyl chloride in 100 ml of tetrahydrofuran was added to 4.6 g (0.08 mol) of alkylamine in 50 ml of tetrahydrofuran. After 2 hours the solvent was stripped off, and the remaining mixture was stirred into water. The solid which formed was isolated. Drying of the solid gave 8.1 g (81% of theory) of 2-chloro-5-nitro-α-methylcinnamic acid-N-allylamide of m.p. 111°-112° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([Br:12])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>C(Cl)(Cl)Cl>[Br:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]([NH:1][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[N:11][CH:10]=1
Reactant: COC(=O)c1cc(N)ncc1Br
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1cc(C(=O)OC)c(Br)cn1
Temperature: 40 °C
Yield: 99.9 %

Procedure:
Methyl 2-amino-5-bromoisonicotinate (200 g, 865 mmol) was dissolved in chloroform (1.2 L) and placed into a 2 L Parr apparatus. Ethyl isocyanate (204 mL, 2.59 mol) was added, and the Parr apparatus was heated at 40° C. for 36 h at which time the reaction was determined to be complete. The mixture was then cooled to room temperature, concentrated, and the solid was dissolved in 2:1 ethyl acetate: tetrahydrofuran (3 L). This solution was extracted with water (1 L), and the water was back extracted with ethyl acetate (300 mL). The organic layers were combined then dried over sodium sulfate, filtered, and concentrated yielding 261 g (quant) of methyl 5-bromo-2-(3-ethylureido)isonicotinate as a dark yellow solid.
Reaction SMILES: [CH2:1](N)[CH2:2][CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]([CH3:27])[CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:15]1[CH:14]=[C:13]([C:28](=[S:30])[NH2:29])[CH:12]=[CH:11][C:10]=1[S:9]2.Cl>C(O)C.C(OCC)(=O)C.C(OCC)C>[Cl:5][C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]([CH3:27])[CH2:21][N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[C:15]1[CH:14]=[C:13]([C:28](=[S:30])[NH:29][CH2:1][CH2:2][CH3:3])[CH:12]=[CH:11][C:10]=1[S:9]2
Reactant: CCN(CC)CC(C)N1c2ccc(Cl)cc2Sc2ccc(C(N)=S)cc21
Reactant: CCCN
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccc(Cl)cc1S2
Reaction time: 4 h

Procedure:
Propylamine (0.75 cc) is added to a solution of 7-chloro-10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (0.6 g) in absolute ethanol (5 cc). The mixture is brought to 200° C. for 4 hours and then diluted with ethyl acetate (50 cc), washed with distilled water (2×100 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual solid is purified by chromatography on a column (height: 8.5 cm; diameter: 2 cm) of silica gel (0.6-0.02 mm), eluting with a 20:80 (by volume) mixture (1.5 liters) of ethyl acetate and cyclohexane, collecting 30-cc fractions. Fractions 25 to 36 are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) to give a brown oil, which is dissolved in ethyl ether (10 cc). 2.2N ethereal hydrochloric acid (2 cc) is added to this solution. The suspension obtained is filtered to give 7-chloro-10-[(2RS)-1-diethylamino-2-propyl]-N-propyl-2-phenothiazinecarbothioamide (0.06 g), m.p. 130° C.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23]>O>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH:23][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CN(C)CCCN
Solvent: O
Product: CN(C)CCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (22.4 g) in water (24 ml), 3-dimethylaminopropylamine (120 ml) was added, while cooling. Then the reaction mixture was heated to 100° C and kept at this temperature for 2 hours. After cooling and evaporating in vacuo to dryness, the residue was dissolved in water (80 ml) and adjusted to a pH of 7.5 by addition of 4N hydrochloric acid. The precipitated 4-(3-dimethylaminopropylamino)-3-nitro-5-sulphamyl-benzoic acid was collected by suction and recrystallized from water. The melting point was 262° C (decomp.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+].I[CH2:26][CH:27]([OH:30])[CH2:28][OH:29].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:19])=[CH:21][CH:22]=1
Reactant: OCC(O)CI
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: O
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCO)cc1

Procedure:
A solution of 7.34 g. of 4-(11-hydroxyundecylamino)benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-(11-hydroxyundecylamino)benzoate.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH2:6]([O:13][C:14](=[O:28])[CH:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][C:14](=[O:28])[CH:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:17]([N:3]([O:4][CH3:5])[CH3:2])=[O:19])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)C(=O)OCc1ccccc1
Agent: Cl
Product: CON(C)C(=O)CC(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
This compound was prepared by a method analogous to that of Example 3-part (d) from N,O-Dimethylhydroxylamine hydrochloride and 2-tert-Butoxycarbonylamino-succinic acid 1-benzyl ester.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:14])[CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.N1C=CC=CC=1.[CH3:25][CH:26](O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CCOCC>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH:26]([CH3:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:10])=[C:7]([F:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCC(C)O
Reactant: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCC(C)OC(=O)c1ccc(OC(C)=O)cc1F

Procedure:
To 10.8 g (0.06 mol) of 4-acetoxy-2-fluorobenzoic acid was added 60 ml of thionyl chloride, and the mixture was allowed to react under reflux for 7 hours. Then, excess thionyl chloride was distilled off, and 10 ml of pyridine and 5.3 g (0.0402 mol) of 2-octanol were added dropwise. The resultant mixture was stirred at room temperature for a whole day, and then diluted with 200 ml of ether. An organic layer was washed with dilute hydrochloric acid, with a 1N sodium hydroxide aqueous solution and with water in this order, and dried over magnesium sulfate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=C(Br)[CH:7]=[N:6][CH:5]=1.C([SiH]([CH2:17][CH3:18])CC)C.C(N(CC)CC)C.[C]=[O:27]>C(#N)C.C1(P([Pd-4](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)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:18]([CH:17]=[O:27])[CH:7]=[N:6][CH:5]=1
Reactant: CC[SiH](CC)CC
Reactant: [C]=O
Reactant: COC(=O)c1cncc(Br)c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cncc(C=O)c1
Temperature: 60 °C
Yield: 15 %

Procedure:
Subject a mixture of methyl-5-bromonicotinate (1.0 g, 4.63 mmol), triethylsilane (0.807 g, 6.94 mmol), tetrakis(triphenylphosphino)palladium (0) (0.531 g, 0.460 mmol), and triethylamine (1.03 g, 10.18 mmol) in acetonitrile (10 mL) to an atmosphere of carbon monoxide gas (20 psi) heated at 60° C. for 5 h. Cool the reaction to room temperature and then absorb directly onto silica gel. Purify the residue by chromatography over silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as an oil (0.114 g, 15%). 1H NMR (CDCl3, 300 MHz) δ 3.90 (s, 3H), 7.35-7.50 (m, 1H), 8.32-8.42 (m, 1H), 8.77-8.90 (m, 1H), 9.23 (s, 1H); TLC Rf=0.37 (4:1 Hexanes/Ethyl Acetate).
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[C:3]([NH2:5])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1.C1COCC1.Br[CH2:39][C:40](=O)[C:41]([O:43][CH2:44][CH3:45])=[O:42]>O>[F:1][C:2]([F:10])([C:3]1[S:20][CH:39]=[C:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[N:5]=1)[C:6]([F:9])([F:8])[F:7]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1csc(C(F)(F)C(F)(F)F)n1
Yield: 44.9 %

Procedure:
A mixture of 2,2,3,3,3-pentafluoropropanamide (2 g), Lawesson's reagent (2.98 g) and THF (30 ml) was heated under reflux overnight. Then ethyl 3-bromo-2-oxopropanoate (2.99 g) was added, and the mixture was heated at the same temperature overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (0.91 g) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[OH:9].[N-:14]=[N+:15]=[N-:16].[Na+]>O>[N:14]([CH2:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[OH:9])=[N+:15]=[N-:16]
Reactant: O=C(O)Cc1ccc(O)c(CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCc1cc(CC(=O)O)ccc1O

Procedure:
A solution of 3-chloromethyl-4-hydroxybenzeneacetic acid (0.1 mole) and sodium azide (0.1 mole) in 250 ml of water is stirred at room temperature for about 16 hours. Removal of the solvent gives the title compound combined with sodium chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[H-].[Na+].O([CH2:21][P:22]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:23])S(C(F)(F)F)(=O)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][O:7][CH2:21][P:22](=[O:23])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Reactant: COc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCc1cccc(OC)c1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methoxybenzyl alcohol (1 mmol) and sodium hydride (1.5 mmol) in 5 mL DMF was stirred at rt for 1 h and then added via cannula to a solution of diethylphosphonomethyl triflate (1 mmol) in 5 mL of DMF and the resulting mixture stirred at rt for 16 h. Extraction and chromatography provided diethyl 3-methoxyphenylmethoxymethylphosphonate as an oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([Br:16])=[CH:9][N:8]=1)C>C(O)(=O)C.[Fe]>[Br:16][C:10]1[CH:11]=[C:12]2[C:7]([O:6][CH2:5][C:4](=[O:3])[NH:13]2)=[N:8][CH:9]=1
Reactant: CCOC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1COc2ncc(Br)cc2N1
Temperature: 60 °C
Yield: 85.3 %

Procedure:
Iron powder (22.8 g, 408 mmol) was added to a solution of (5-bromo-3-nitro-pyridin-2-yloxy)-acetic acid ethyl ester (2.28 g, 7.47 mmol) in acetic acid (230 mL), and the reaction mixture was heated at 60° C. over 150 min, cooled to room temperature, and filtered. The filtrate was evaporated, taken up in dichloromethane/methanol 1:1 and neutralized with 1 M aq. sodium carbonate solution. The organic layer was washed with water and the aqueous layer re-extracted with dichloromethane. The combined organic layers were washed again with 1 M aq. sodium carbonate solution, dried (Na2SO4), and evaporated to produce 7-bromo-1H-4-oxa-1,5-diaza-naphthalen-2-one (1.46 g, 85%). Off-white solid, MS (ISP)=226.9 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.CN1CCOCC1>CO>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:23][CH:22]=1
Reactant: NCc1ccncc1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccncc3)cc2s1
Yield: 10.8 %

Procedure:
the title compound (13 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), C-pyridin-4-ylmethylamine (62 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 401.3 (M+1, 100%). Yield=11%.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[O:18][C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[O:18][C:17]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCNCC4)o3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCN(CCCCO)CC4)o3)ccc21

Procedure:
The preparation was carried out as already described starting from 75 mg (0.15 mmol) of 4-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-oxadiazol-2-yl]piperidine and 33 μl (0.23 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC. The product is in the form of the TFA salt.