Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[N:4]1)[CH3:2].[CH2:17]([C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][N:20]1C(OC(C)(C)C)=O)[CH3:18]>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:22]2[N:23]=[CH:24][C:6]3[CH:5]=[N:4][N:3]([C:1]4[CH:2]=[CH:18][CH:17]=[C:19]([N:23]5[CH2:22][CH2:21][NH:20][C@H:19]([CH2:17][CH3:18])[CH2:24]5)[N:20]=4)[C:7]=3[CH:21]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC[C@@H]1CNCCN1C(=O)OC(C)(C)C
Product: CC[C@@H]1CN(c2cccc(-n3ncc4cnc(-c5cnn(CC)c5)cc43)n2)CCN1
Yield: 10 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and (R)-tert-butyl 2-ethylpiperazine-1-carboxylate, 142 was obtained as an off-white solid (12.7 mg, 10%) over 2 steps. 1H NMR (400 MHz, DMSO) δ 9.18-9.06 (s, 1H), 8.67-8.59 (s, 1H), 8.56-8.49 (s, 1H), 8.31-8.25 (s, 1H), 7.95-7.90 (s, 1H), 7.78-7.70 (t, J=8.1 Hz, 1H), 7.23-7.15 (d, J=7.7 Hz, 1H), 6.84-6.76 (d, J=8.5 Hz, 1H), 4.27-4.15 (m, 4H), 3.10-3.03 (d, J=11.7 Hz, 1H), 3.01-2.93 (td, J=11.8, 3.0 Hz, 1H), 2.86-2.77 (td, J=11.6, 3.0 Hz, 1H), 2.68-2.56 (m, 2H), 1.48-1.38 (m, 5H), 0.94-0.87 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 403.2 [M+H]+
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].N([C:15]1[NH:16][CH2:17][CH2:18][N:19]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)=O>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH:4][C:15]1[NH:19][CH2:18][CH2:17][N:16]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: NCC(O)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CC(C)=O
Product: OC(CNC1=NCCN1)c1ccccc1
Temperature: 160 °C

Procedure:
A mixture of 15.8 parts β-hydroxy-phenethyl-amine, 13 parts 2-nitramino-2-imidazoline and 8 parts xylene is stirred and heated for 30 minutes at 160°C. (oil-bath). After cooling the reaction mixture to a temperature of about 70°C., there are added 40 parts acetone. The whole is filtered warm and after cooling the filtrate to room temperature, the precipicated product is filtered off and dried, yielding 2-(β-hydroxy-phenethyl-amino)-2-imidazoline; m.p. 147°-149°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[NH:20][CH2:19][C:18]2[CH:21]=[CH:22][O:23][C:17]=2[CH2:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH:15]([CH3:14])[CH2:16][C:17]4[O:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1Cc2occc2CN1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1Cc2occc2CN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-methyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]([OH:18])[CH:15]([CH3:17])[CH3:16])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]([OH:18])[CH:15]([CH3:16])[CH3:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(O)C1OCCN(Cc2ccccc2)C1=O
Solvent: C1CCOC1
Product: CC(C)C(O)C1CN(Cc2ccccc2)CCO1
Temperature: 60 °C
Yield: 96.6 %

Procedure:
To a stirred solution of 53 (1.97 g, 7.47 mmol) in tetrahydrofuran (50 ml) at room temperature under nitrogen was added borane-tetrahydrofuran complex (30 ml of a 1M solution, ca 4 eq.). The reaction was heated to 60° C. and followed by TLC-analysis. When all starting material had been consumed a few drops of methanol were added followed by a similar amount of 1N hydrochloric acid and heating was continued for another hour. Organic solvents were removed in vacuo and the remaining solution was poured onto 1M potassium carbonate solution (30 ml), extracted with diethyl ether. The organic layers were dried over magnesium sulphate and purified by column chromatography (gradient from 15% ethyl acetate in hexane [v/v]) gave 54 (1.8 g, 97%). MW 249.36; C15H23NO2; LCMS (6 min method): m/z 250 [M+H]+; RT=0.838.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:22][C:21]3[NH:20][CH:19]=[C:18]4[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=34)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-Chloro-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1carbaldehyde to give the title compound. MS m/z 315.2 [M++1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:9]2([OH:17])[O:14][CH2:13][C@@H:12]([CH3:15])[NH:11][C@H:10]2[CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[NH2:25][S:26]([C:29]1[C:30]([Cl:53])=[CH:31][C:32]([NH:46][CH2:47][C:48]2[O:49][CH:50]=[CH:51][CH:52]=2)=[C:33]([CH:45]=1)[C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43]Cl)=[O:41])=[O:35])(=[O:28])=[O:27]>C(#N)C>[NH2:25][S:26]([C:29]1[C:30]([Cl:53])=[CH:31][C:32]([NH:46][CH2:47][C:48]2[O:49][CH:50]=[CH:51][CH:52]=2)=[C:33]([CH:45]=1)[C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][N:11]1[C@H:12]([CH3:15])[CH2:13][O:14][C@:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)([OH:17])[C@@H:10]1[CH3:16])=[O:41])=[O:35])(=[O:27])=[O:28]
Reactant: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1
Reactant: NS(=O)(=O)c1cc(C(=O)OCCCC(=O)OCCl)c(NCc2ccco2)cc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1COC(=O)CCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1

Procedure:
A solution of the free base of (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (20a (0.023 mole) (U.S. Pat. No. 5,104,870), triethylamine (0.025 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoate (315) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give (2S,3S,5R)-4-[4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoyloxymethyl]-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (620). See eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10]O)[CH2:2][CH:3]([CH3:5])[CH3:4].N1C=CC=CC=1.P(Br)(Br)[Br:19]>C(Cl)(Cl)Cl>[Br:19][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: BrP(Br)Br
Reactant: CC(C)CCOCCCCO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)CCOCCCCBr
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 6.4 g (0.4 mol) of 4-isopentyloxy-butanol and 0.32 g (0.004 mol) of pyridine in 40 ml of chloroform are added over a period of 15 minutes with stirring at 0° , 1.42 ml (0.015 mol) of phosphorus tribromide. The mixture is stirred for a period of one hour at 20° and then for 20 hours at 60°C. After cooling to room temperature, the reaction mixture is poured into an ice cold saturated aqueous sodium bicarbonate solution and the reaction product is extracted with chloroform. The chloroform extract is then first washed with water and then with saturated aqueous sodium chloride solution and afterwards dried with sodium sulphate. The chloroform is then evaporated off under reduced pressure. The residue is chromatographed on a silica gel column with hexane/ethyl acetate (99:1 to 98.2) as eluent. After fractional distillation of the practically pure chromatographic fractions, pure 1-bromo-4-isopentyloxy-butane is obtained, as a colourless oil. (Boiling point 40° to 46° 0.03 mm Hg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:1]([O-:4])=[O:2])[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1
Reactant: Fc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1F
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
40.8 g of 100% nitric acid were added dropwise at from 0 to 5° C. to a solution of 118.9 g of 3-chloro-2-(4-fluorophenyl)-5-trifluoromethylpyridine in 563 ml of 96% sulfuric acid, and the mixture was then stirred at from 0 to 5° C. for 11/2 hours. For work-up, the reaction mixture was poured into 2 l of ice water, and the product was then extracted with ethyl acetate (3×300 ml). The combined organic phases were washed twice with 100 ml of water in each case, dried over sodium sulfate and then evaporated. Yield: 134.5 g (97%) of a colorless oil which crystallized slowly.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]12([NH2:36])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>C(#N)C>[C:26]12([NH:36][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[C:16]5[S:17][CH:18]=[CH:19][C:15]=5[O:14][N:13]=4)[CH:7]=3)[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCCNC23CC4CC(CC(C4)C2)C3)cc(-c2noc3ccsc23)c1
Temperature: 75 °C
Yield: 43.7 %

Procedure:
Mix 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole (0.250 g, 0.739 mmol), potassium carbonate (0.205 g, 1.48 mmol), 1-adamantanamine (0.560 g, 3.70 mmol) and acetonitrile (4.0 mL) and heat at 75° C., overnight. Cool the reaction mixture and filter through a Waters Sep-Pak (1 g) silica gel cartridge (ethyl acetate). Combine the appropriate fractions and concentrate to give a residue. Purify the residue by column (10 g silica) chromatography using a step gradient from 40% ethyl acetate in dichloromethane to 100% ethyl acetate to 20% methanol in ethyl acetate to give the title compound (132 mg, 44% yield). Purity by LC/MS (APCI)=98%, [M+H]+=409.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.CSC.Cl[Si](C)(C)C.[O:24]=[C:25]([CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:26]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([C:28]([CH3:30])([CH3:29])[CH2:27][C:25](=[O:24])[CH3:26])[CH:7]=1
Reactant: CC(=O)C=C(C)C
Reactant: COc1ccc(F)cc1Br
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CSC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(C)=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 85 %

Procedure:
To a stirred solution of 2-bromo-4-fluoro anisole (3.24 mL, 25 mmol) in anhydrous THF (40 mL) cooled to −78° C. and maintained under argon was added n-butyl lithium (17.2 mL of 1.6 M solution in hexanes, 27.5 mmol). After stirring at −78° C. for 45 minutes, the reaction mixture was treated with a solution of cuprous iodide in dimethyl sulfide (4.76 g in 15 mL, 25 mmol) and stirred for 15 minutes at −78° C. Then chlorotrimethylsilane (6.4 mL, 50 mmol) was added, followed by a solution of mesityl oxide (2.9 mL, 25 mmol) in anhydrous THF (5 mL). The reaction was stirred at −78° C. to −60° C. for 4 hours and then quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of methylene chloride. The combined extracts were washed with three 25 mL portions of water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as a light brown liquid (85% yield) which was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:13]([CH3:17])([C:15]#[CH:16])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][C:13]([CH3:17])([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)[C:15]#[CH:16]
Reactant: C#CC(C)(C)Cl
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CC(C)(C)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
1.62 g of 4-(trifluoromethyl)phenol, 1.53 g of 2-chloro-2-methyl-3-butyne and 10 g of potassium carbonate were heated at reflux in 50 ml of acetone. After 18, 42 and 66 hours further batches of 1 53 g of 2-chloro-2-methyl-3-butyne were added. 72 hours after the final addition the mixture was allowed to cool to room temperature and was partitioned between diethyl ether and water. The organic phase was washed with aqueous sodium hydroxide solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 5% (v/v) ethyl acetate/petroleum ether for the elution. 1.8 g of 4-(1,1-dimethyl-2-propynyloxy)trifluoromethylbenzene were obtained as a yellow oil.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)C[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1.NCC1(N(CC2C=CC=CC=2)CC2C=CC=CC=2)C[O:51][CH2:50]1>>[NH2:8][C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][C:36]([O:51][CH3:50])=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:10][O:11][CH2:12]1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Product: COc1ccc2c(c1)S(=O)(=O)CCN(c1cc(NCC3(N)COC3)c3ccccc3n1)C2

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloroquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloroquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm 7.91-7.74 (m, 2 H), 7.58-7.38 (m, 3 H), 7.22-7.03 (m, 2 H), 6.23 (s, 1 H), 5.12 (brs, 2 H), 4.70-4.46 (m, 6 H), 3.81 (s, 3 H), 3.70 (s, 2 H), 3.65-3.52 (m, 2 H).
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16]([O:18]C)=O)=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[O:18])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)C2=C(O)c3c(c4ccccc4n3C)S(=O)(=O)N2C)n1
Yield: 88 %

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-(4-methyl-2-thiazolyl)-1, 2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from methyl 2,5-Dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide and 2-amino-4-methyl-thiazole with a yield of 88% of theory; M.p.: 270° C. (decomposition).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[S:20](Cl)(=[O:23])(=[O:22])[NH2:21]>CN(C=O)C>[NH2:21][S:20]([NH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)(=[O:23])=[O:22]
Reactant: NS(=O)(=O)Cl
Reactant: NCc1csc2cncn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)NCc1csc2cncn12
Temperature: -25 °C
Reaction time: 4 h

Procedure:
A 770 mg potin of 3-aminomethylimidazo[5,1-b]thiazole was dissolved in 15 ml of DMF, and 4.78 ml of N,N-diisopropylethylamine and 1.04 g of sulfamoyl chloride were further added at -60° C., followed by stirring at -30 to -20° C. for 4 hours. The reaction solution was concentrated under reduced pressure and then dissolved in 30 ml of water, and the solution was adjusted to pH 7.5 with an aqueous sodium hydrogencarbonate solution. After purification by Diaion HP-20 Resin, crystallization was carried out from methanol to obtain 636 mg of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[CH:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:34][C:35]([NH:37][C@H:38]([C:44](OC2C=CC([N+]([O-])=O)=CC=2)=[O:45])[CH2:39][CH2:40][C:41]([NH2:43])=[O:42])=[O:36])=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C)C=O>[NH:37]([C:35]([O:34][CH2:33][C:30]1[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=1)=[O:36])[C@H:38]([C:44]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:45])[CH2:39][CH2:40][C:41](=[O:42])[NH2:43]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1

Procedure:
550 mg of H-Asp(OtBu)-Phe-OCH3.HCl together with 574 mg of Z-Gln-ONP are dissolved in 2.5 ml of absolute N,N-dimethylformamide and stirred with 0.20 ml of triethylamine for 15 hours at 30°-33° C. bath temperature. Thereafter the product is extracted by shaking with a large amount of ethyl acetate as described under 19 and the solution is dried and evaporated.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:16][C:17]([C:19]2[NH:20][N:21]=[C:22]([Cl:24])[N:23]=2)=[O:18])[CH2:9][C@@H:10]([CH2:14][OH:15])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.Cl.[CH3:32][O:33][CH2:34][CH2:35]O>O1CCOCC1>[CH3:32][O:33][CH2:34][CH2:35][O:12][C:11](=[O:13])[C@H:10]([CH2:14][OH:15])[CH2:9][C@H:8]([NH:16][C:17]([C:19]1[NH:20][N:21]=[C:22]([Cl:24])[N:23]=1)=[O:18])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:2][CH:3]=1
Reactant: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](CO)C(=O)O)c1nc(Cl)n[nH]1
Reactant: COCCO
Agent: Cl
Solvent: C1COCCO1
Product: COCCOC(=O)[C@H](CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nc(Cl)n[nH]1
Temperature: 80 °C
Yield: 95 %

Procedure:
(2S,4S)-5-Biphenyl-4-yl-4-[(5-chloro-2H-[1,2,4]-triazole-3-carbonyl)-amino]-2-hydroxymethyl-pentanoic acid (10 mg, 23 μmol, 1.0 eq.) was dissolved in 2-methoxyethanol (0.8 mL) followed by the addition of 4 M of HCl in dioxane (117 μL). The resulting mixture was heated and maintained at 80° C. for about 3.5 hours. The mixture was concentrated and purified by preparative HPLC to yield the title compound (7.2 mg, 95% purity). MS m/z [M+H]+ calc'd for C24H27ClN4O5, 487.17. found 487.4.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C1C=CC=CC=1>O>[N:8]1([C:4]2[CH2:5][CH2:6][S:1][CH2:2][CH:3]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCSCC1
Reactant: C1CCNC1
Solvent: c1ccccc1
Solvent: O
Product: C1=C(N2CCCC2)CCSC1

Procedure:
A solution of 103 g (0.89 mole) of tetrahydrothiopyran-4-one, 95 g (1.33 moles) of pyrrolidine, and one l. of anhydrous benzene is heated under reflux in a nitrogen atmosphere for 2 hours until the theoretical amount of water has collected in a Dean-Stark trap. The solvent is distilled, and the residue is fractionated under reduced pressure to provide 5,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran as a colorless liquid, b.p. 124° (0.01 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>[Ni].CO>[CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][Cl:20]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Yield: 94.9 %

Procedure:
In a 50 mL volume pressure-resistant vessel were placed 2.02 g (6.58 mmol) of methyl 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoate (purity: 99%) obtained in Reference Example III-4, 2.0 g of a developed Raney nickel, and 40 mL of methanol. The atmosphere in the vessel was replaced with hydrogen, and the vessel was closed. The reaction was carried out at 90-100° C. for 24 hours at a hydrogen pressure of 0.9 MPa (gauge pressure). After the reaction was complete, the reaction mixture was filtered. The filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 1.71 g (reaction yield: 95.0%) of methyl 5-methoxy-4-(3-chloropropoxy)anthranilate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C.O>[Br:21][C:11]1[O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(-c2ccco2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(Br)o2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Referring now to Scheme 5 above, to a chilled (ice/water bath) solution of 2-(4-cyanophenyl)furan (28.25 g, 0.167 mol) in DMF (100 ml) was added portionwise NBS (31.20 g, 1.05 eq., freshly recrystallized from nitromethane) with stirring (approximately 1 g portions over course of approximately 40 minutes). The resulting solution was stirred for 2 h at room-temperature, at which point TLC showed consumption of starting material. During the course of the reaction, the color went from yellow to orange and then finally to red. The solution was then diluted with water (approximately 300 ml) to give a pink/red solid, which was collected, washed with water, and air dried. Yield: 39.0 g, 94%. A small sample was recrystallized from MeOH/water to give a pale red crystalline solid, mp 96.5-97° C. 1H NMR (DMSO-d6): 6.80 (d, J=3.6 Hz, 1H), 7.29 (d, J=3.6 Hz, 1H), 7.87 (m, 4H). IR (cm−1): 3142, 3128, 3060, 2226, 1613, 1515, 1475, 1015, 929, 833, 787, 545.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13]C)[CH:8]=2)[N:3]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)cc(C)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)nc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
A solution of 2-chloro-6-methoxy-4-methylquinoline (0.20 g) in dichloromethane (15 mL) was cooled to −78° C., followed by addition of a solution (5.3 mL) of 1 M boron tribromide in dichloromethane, and the mixture was stirred for 12 h while slowly heating to room temperature. To the reaction mixture was added a saturated sodium hydrogencarbonate solution to make it basic, and the mixture was extracted with chloroform. The aqueous layer was reextracted with a mixture solution of ethyl acetate and n-butanol, then the organic layer was combined and concentrated under reduced pressure, and the resulting solids were washed with diethyl ether to obtain 2-chloro-6-hydroxy-4-methylquinoline (0.15 g).