Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:28]=[CH:27][C:12]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([C:24](O)=[O:25])[O:23][C:17]=3[CH2:16]2)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][CH2:30][CH2:31][OH:32].C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C(#N)C>[OH:32][CH2:31][CH2:30][NH:29][C:24]([C:22]1[O:23][C:17]2[CH2:16][N:15]([C:13](=[O:14])[C:12]3[CH:27]=[CH:28][C:9]([C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][CH:11]=3)[CH2:20][CH2:19][C:18]=2[CH:21]=1)=[O:25]
Reactant: NCCO
Reactant: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3cc(C(=O)O)oc3C2)cc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3cc(C(=O)NCCO)oc3C2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.545 g (1.452 mmol) of 6-(4-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-2-carboxylic acid, 98 mg (1.6 mmol) of 2-aminoethanol, 0.61 ml (4.4 mmol) of triethylamine and 1.40 ml (14.5 mmol) of carbon tetrachloride in 20 ml of acetonitrile, 1.14 g (4.36 mmol) of triphenylphosphine was added under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=9/1); the resulting solid was washed with diethyl ether to yield the desired product.
Reaction SMILES: CN(C=O)C.Br[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1.[F:17][C:18]1[C:23]([F:24])=[CH:22][C:21]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:20]([O:32][CH3:33])[CH:19]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)(=O)C>[F:17][C:18]1[C:23]([F:24])=[CH:22][C:21]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)=[CH:29][CH:30]=2)=[C:20]([O:32][CH3:33])[CH:19]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a mixture of DMF (5 ml), 1-bromomethyl-3-nitro-benzene (0.92 g, 4.2 mmol), and 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (1 g, 4.2 mmol) was added lithium bis(trimethylsilyl)amide (1M in THF, 4.4 ml). The reaction was stirred at room temperature overnight and was then diluted with ethyl acetate (200 mL), washed with water (200 mL), aqueous ammonium chloride (10%, 200 mL) and brine, dried over magnesium sulfate and concentrated to yield 4,5-difluoro-2-methoxy-4′-(3-nitro-benzyloxy)-biphenyl as yellow solid (1.5 g, 95%). LC-MS (ES) calculated for C20H15F2NO4, 371.1; found m/z 370 [M−H]−.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[N:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[N:19][C:18]=1[O:25][CH2:26][C:27]([F:30])([F:29])[F:28]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:24]([CH2:23][C:21]3[CH:20]=[N:19][C:18]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:17]([CH3:16])[N:22]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1nc(CN)cnc1OCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1nc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Yield: 84 %

Procedure:
The title compound is prepared in 84% yield (560 mg, colorless solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and (6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanamine hydrochloride (460 mg, 1.8 mmol, Amine-67) in a similar manner to Intermediate-2.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH3:18]>CC(C)=O>[CH2:17]([C:3]1([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH3:18]
Reactant: COC(=O)C1CCCC1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1(C(=O)OC)CCCC1=O
Yield: 101.6 %

Procedure:
Under vigorously agitation, 14.8 g of methyl 2-oxocyclopentane carboxylate was added to 41.9 g of fine powdery anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml of acetone. The reaction mixture was further stirred for 15 to 30 minutes at room temperature, then thereto was dropwise added 31.2 g of ethyl iodide. Upon the completion of the addition, the reaction mixture was heated for reflux for 2 hours. The solvent was removed under reduced pressure, and solid residue was washed with diethyl ether. The washing liquor was collected and washed with water. After removing the solvent, 18.0 g of pale yellow liquid was obtained, The liquid was distilled under reduced pressure, and 15.9 g of colorless liquid as a distillate cut of 122-124° C./25 mmHg was collected. Yield: 93.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:17])[N:10]2[CH2:13][CH:14]2[CH2:16][O:15]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1>CN(C=O)C>[OH:15][CH:14]([CH2:13][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:12]=2)[CH2:7][CH2:8][C:9]1=[O:17])[CH2:16][N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2c(n1)N(CC1CO1)C(=O)CC2
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)N(CC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CC2
Yield: 37.9 %

Procedure:
A solution of 7-(methyloxy)-1-(2-oxiranylmethyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (428 mg, 1.829 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (366 mg, 1.829 mmol) in DMF (2 ml) under argon was heated at 120° C. for 1 h. The mixture was then evaporated and chromatographed (0-10% methanol/DCM) to give the product as a yellow oil (301 mg, 38%).
Reaction SMILES: [OH-].[Na+].[C:3]([OH:16])(=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N+]([O-])([O-])=O.[Ag+:21]>O.C1(C)C=CC=CC=1>[C:3]([O-:16])(=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Ag+:21]
Reactant: CCCCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)[O-]

Procedure:
1.9 g of sodium hydroxide was dissolved in 100 ml of water, with which 12 g of lauric acid in 100 ml of toluene was mixed to emulsify (at 25° C.). An aqueous solution of 8.5 g of silver nitrate dissolved in 50 ml of water was then added to the above emulsion, which resulted in separation into a silver laurate-containing toluene phase and an aqueous phase. After removal of the aqueous phase, the toluene phase was dispersed into 200 ml of ethanol, and then, silver laurate was collected by centrifuging. 12 g of spindle-like silver laurate crystals of a longer diameter of about 3 μ was obtained.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])=[N:4]1.[O:19]([C:26]([NH:28][C:29]1[N:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[N:30]=1)=O)C1C=CC=CC=1>C(#N)C>[CH3:36][O:35][C:33]1[CH:32]=[C:31]([O:37][CH3:38])[N:30]=[C:29]([NH:28][C:26]([NH:18][S:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:5]2[O:6][CH2:7][CH2:8][O:3][N:4]=2)(=[O:16])=[O:17])=[O:19])[N:34]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: NS(=O)(=O)c1ccccc1C1=NOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C2=NOCCO2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
0.79 g (0.033 mol) of sodium hydride are added under argon to a mixture of 4.0 g (0.017 mol) of 2-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)benzenesulphonamide and 4.6 g (0.017 mol) of 2-phenoxycarbonylamino-4,6-dimethoxypyrimidine in 20 ml of absolute acetonitrile, and the mixture is stirred at room temperature for 18 hours. The precipitate is filtered off with suction and stirred up with a 20% solution of sodium dihydrogen phosphate. The precipitate is filtered off with suction and dried under high vacuum. 3.9 g (56% of theory) of N-(4,6-dimethoxypyrimidin-2-yl)-N'-(2-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)benzenesulphonyl)urea are obtained with a melting point of 189° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH2:7][CH2:8][C:9](=[O:10])[C@@H:4]2[O:3]1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH2:7][CH2:8][C@H:9]([OH:10])[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@@H]2CCC(=O)[C@@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)O[C@H]2[C@@H](O)CC[C@H]2O1

Procedure:
(3 aR,6aR)-2,2-dimethyldihydro-3 aH-cyclopenta[d][1,3]dioxol-4(5H)-one (1-2) (2.75 g, 17.6 mmol, 1 equiv) was dissolved in methanol (166 mL) and sodium borohydride (1.0 g, 26.4 mmol, 1.5 equiv) was added portion wise at 0° C. Upon disappearance of the starting material as monitored by LC-MS analysis, water was added and the mixture was concentrated. The aqueous phase was extracted with DCM (3×100 mL), the combined organics were dried (Na2SO4), and the solvent was removed to afford (3AS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (1-3) as a colorless oil that did not require further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7](Br)[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(NCC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1c(N)c(Br)cc2cn[nH]c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COC(=O)c1c(N)c(C#C[Si](C)(C)C)cc2cn[nH]c12
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 60.3 %

Procedure:
To a solution of 1.5 g (5.6 mmol) of 6-amino-5-bromo-1H-indazole-7-carboxylic acid methyl ester, prepared as in step a in example 16, in 3 mL of N,N-dimethylformamide under an atmosphere of argon is added 785 μL (5.6 mmol) of trimethylsilylacetylene, 8.65 mL of diethylamine (83.2 mmol), 194 mg (0.28 mmol) of dichlorobis(triphenylphosphine)palladium II and 53 mg (0.28 mmol) of copper iodide. The reaction mixture is stirred in a microwave oven at 150° C. for 5 minutes, filtrated over Celite (washing with ethyl actetate) and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, hexane/ethyl acetate 2:1) to afford 970 mg of the product (61%) as a yellowish solid; LC/MS:288/289 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][CH:12]([CH3:24])[CH2:13][CH:14]([C:17]1[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[CH2:15][NH2:16]>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:16][CH2:15][CH:14]([C:17]1[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[CH2:13][CH:12]([CH3:24])[CH3:11])=[O:6]
Reactant: Cc1ccc(C(CN)CC(C)C)cn1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccc(C(CNC(=O)c2ccccc2C)CC(C)C)cn1

Procedure:
From 2-methylbenzoic acid and 4-methyl-2-(6-methylpyridin-3-yl)-pentylamine. LCMS (MH30 ): m/z=311.0, tR (minutes, Method A)=1.31
Reaction SMILES: [C:1]([O-:14])(=O)[CH2:2][CH2:3][CH2:4]CCCCCCCC.[C:15]([O-:28])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[C:38](OCC)(=[O:40])C>>[CH2:38]([C:2]([CH2:1][OH:14])([CH2:15][OH:28])[CH2:3][CH3:4])[OH:40]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: CCOC(C)=O
Agent: CCCC[Sn+2]CCCC
Product: CCC(CO)(CO)CO

Procedure:
About 18.5 g of activated carbon is suspended in 450 g of ethyl acetate. The suspension is mixed first with 1 g of di-n-butyltin dilaurate, then with 1000.5 g of a 75 percent solution of a product obtained from the reaction of tolylenediisocyanates and 1,1,1-trimethylolpropane in ethyl acetate, then with 88.5 g of di-n-butylether and finally with 30 g of a dimethylpolysiloxane having an Si-bonded hydroxyl group in each of its terminal units and having an average of about 13 silicon atoms per molecule. The resultant mixture is refluxed for 1 hour, then cooled to 50° C., and filtered under anhydrous conditions. The filtrate thus obtained has the same properties as the filtrate obtained in Example 2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:18])([CH3:17])[CH2:11][C:12](=[O:16])[C:13]([OH:15])=O)[C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[C:32](=[O:33])[O:31][N:30]=[C:29]([CH2:34]C)[C:28]=2[CH:36]=1.O>CC(N(C)C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:18])([CH3:17])[CH2:11][C:12](=[O:16])[C:13]([NH:23][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[O:33])[O:31][N:30]=[C:29]([CH3:34])[C:28]=4[CH:36]=3)=[O:15])[C:4]=2[O:3][CH2:2]1
Reactant: CCc1noc(=O)c2ccc(N)cc12
Reactant: CC(C)(CC(=O)C(=O)O)c1cccc2c1OCO2
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1noc(=O)c2ccc(NC(=O)C(=O)CC(C)(C)c3cccc4c3OCO4)cc12
Reaction time: 0.33 h
Yield: 40.2 %

Procedure:
10 g of 4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxo-pentanoic acid is dissolved in 125 ml of dimethylacetamide and mixed with 3.5 ml of thionyl chloride under argon at −0° C. After 20 minutes of stirring at −3 to +3° C., 7.6 g of 6-amino-4-ethyl-2,3-benzoxazin-1-one (WO00/32584) is added. It is stirred for 96 hours at room temperature, then mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried (Na2SO4), and after the solvent is concentrated by evaporation and after chromatography of the crude product on silica gel with hexane/ethyl acetate (100:0→60:40), 6.56 g of 6-[4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxo-valeroyl-amino]-4-methyl-2,3-benzoxazin-1-one is obtained as a beige solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[F:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:63][CH2:62]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Fc1ccc(NC2CCNCC2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Nc2ccc(F)cc2F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 16.5 %

Procedure:
DIPEA (232 mg, 1.8 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (148 mg, 0.6 mmol) in DMF (2 mL) followed by HOBt (95 mg, 0.7 mmol) and EDCI.HCl (137 mg, 0.7 mmol. After 2 minutes (2,4-difluoro-phenyl)-piperidin-4-yl-amine dihydrochloride (prepared by the method used for the synthesis of Intermediate 3) (150 mg, 0.6 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer thus collected was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) to afford 43 mg (16.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2,4-difluoro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 440.18, 94.52%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.1 (m, 1H), 7.8 (m, 2H), 7.4 (m, 4H), 7.0 (m, 1H), 6.9 (m, 2H), 5.0 (m, 1H), 4.4 (m, 1H), 4.2 (m, 2H), 3.5 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.0 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[C:7]2[C:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[C:20](=[O:22])[O:21][C:6]=2[CH:5]=1.C(N(CC)CC)C.Cl.[Cl:31][CH2:32][CH2:33][N:34]1[CH2:40][CH:39]2[CH2:41][CH2:42][CH:36]([CH2:37][CH2:38]2)[CH2:35]1>>[ClH:31].[CH:39]12[CH2:41][CH2:42][CH:36]([CH2:37][CH2:38]1)[CH2:35][N:34]([CH2:33][CH2:32][N:17]1[CH2:18][CH2:19][C:14]3[C:7]4[C:8]([O:12][CH3:13])=[C:9]([O:10][CH3:11])[C:4]([O:3][CH3:2])=[CH:5][C:6]=4[O:21][C:20](=[O:22])[C:15]=3[CH2:16]1)[CH2:40]2
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: COc1cc2oc(=O)c3c(c2c(OC)c1OC)CCNC3
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc2oc(=O)c3c(c2c(OC)c1OC)CCN(CCN1CC2CCC(CC2)C1)C3
Yield: 37 %

Procedure:
Prepared by the method described in Example 13 from 1,2,3,4-tetrahydro-8,9,10-trimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one hydrochloride (10.0 g, 0.031 moles), triethylamine (6.8 g, 0.067 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (7.5 g, 0.034 moles). The crude product began to precipitate as the monohydrochloride shortly after reflux of the reaction mixture began. The product is filtered and recrystallized several times from 2-methoxyethanol/water to yield the final product (5.5 g) as the monohydrochloride, mp 241°-243° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-:28])=[O:27].CO.[ClH:31]>O1CCOCC1.C(OCC)C>[ClH:31].[N+:26]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[CH:25]=2)[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: Nc1ccc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 72 %

Procedure:
1,1-dimethylethyl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (example 8, step 1) (6.0 g, 15.6 mmol) was taken into warm methanol (50 mL) followed by addition of 4M hydrogen chloride in dioxane (50 mL) in portions and the warm solution was allowed to slowly cool to room temperature over 1 h. The mixture was diluted with ethyl ether (100 mL) and the yellow solid was collected by filtration and dried to give 2-nitro-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)aniline hydrochloride salt (3.61 g, 72% yield) as a yellow solid. 1H NMR (400 MHz, D2O): 7.79 (s, 1H), 7.44 (d, 1H), 7.29 (s, 1H), 7.26 (d, 1H), 7.02 (d, 1H), 6.82 (d, 1H), 4.34 (s, 2H), 4.32 (br m, 2H), 3.67 (br m, 2H).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][S:10][CH:11]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:13][CH2:12][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][S:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-c1csnn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: BrCc1ccccc1-c1csnn1

Procedure:
A solution of 4-o-tolyl-[1,2,3]thiadiazole (100 mg, 0.57 mmol), N-bromosuccinimide (100 mg, 0.57 mmol) and 2,2′-azobisisobutyronitrile (9.4 mg, 0.057 mmol) in chloroform (10 ml) was heated at reflux temperature for ˜18 h. Additional chloroform was added and the mixture was washed with water, 5% sodium thiosulfate solution and brine. Drying and solvent evaporation gave 4-(2-bromomethyl-phenyl)-[1,2,3]thiadiazole; 1H NMR (CDCl3, 300 MHz) δ8.87 (s, 1H), 7.67-7.39 (m, 4H), 4.71 (s, 2H). cls Step D: 4-(2-Azidomethyl-phenyl)-[1,2,3]thiadiazole (I-13-4)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:54]=[CH:53][CH:52]=[CH:51][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH:18]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([O:43]C)=[O:42])=[C:37]([O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:36]=2)=[CH:13][CH:12]=1.O.Cl>CO.[OH-].[Na+]>[C:41]([C:38]1[CH:39]=[CH:40][C:35]([CH2:34][O:33][CH:18]2[CH:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]4[CH:51]=[CH:52][CH:53]=[CH:54][C:3]=4[O:2][CH3:1])=[CH:16][CH:15]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:19]2)=[CH:36][C:37]=1[O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])([OH:43])=[O:42]
Reactant: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)O

Procedure:
The mixture of 1.90 g of benzyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[4-methoxycarbonyl-3-(3-methoxypropoxy)benzyloxy]piperidine-1-carboxylate (Example 29a) in 15 ml of methanol and 5.0 ml of 1N NaOH is stirred at reflux over 2 hours. The reaction mixture is cooled, admixed with water (100 ml) and 2N HCl (3.0 ml), and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are dried with sodium sulphate, filtered, concentrated by evaporation. This gives the crude title compound as a yellowish oil. Rt=5.72.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)Cl)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) dissolved in DCM (10 ml), cooled to 0° C. and added oxalyl chloride (1.2 ml, 13.8 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 2-fluoro-4-(methylsulfonyl)benzoyl chloride quantitatively. 4-Bromo-2-fluoroaniline (1.4 g, 7.37 mmol) dissolved in DCM and added Pyridine (0.7 g, 8.84 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 2-fluoro-4-(methylsulfonyl)benzoyl chloride (2.08 g, 8.84 mmol). After continuing stifling at rt for 15 mins, reaction mixture diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (1 g) as a brown solid.
Reaction SMILES: COC[N:4]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20](COC)[C:19]([C:25]1[N:29]([CH3:30])[N:28]=[CH:27][N:26]=1)=[CH:18]2)[S:5]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=[O:7])=[O:6].Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:30][N:29]1[C:25]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:4][S:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)(=[O:6])=[O:7])=[N:26][CH:27]=[N:28]1
Reactant: COCN(c1cccc2cc(-c3ncnn3C)n(COC)c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cn1ncnc1-c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Yield: 20.8 %

Procedure:
N-(Methoxymethyl)-N-[1-(methoxymethyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (0.42 g), concentrated hydrochloride (1 mL) and methanol (6 mL) were heated under reflux for 6 hr. The reaction mixture was neutralized with aqueous sodium bicarbonate, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.07 g, yield 20%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point>271° C. (decomposition).