Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=C[C:21](C#N)=[C:20](N=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=2)[C:13](=[O:40])[C@@H:12]1[CH2:41][CH2:42][S:43][CH3:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:45]1[CH:50]=[N:49][CH:48]=[N:47][CH:46]=1.C(O)(=O)C>C(O)C>[NH2:45][C:50]1[C:21]2[C:46](=[CH:23][C:18]([CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[C@@H:12]([CH2:41][CH2:42][S:43][CH3:44])[C:13]3=[O:40])=[CH:19][CH:20]=2)[N:47]=[CH:48][N:49]=1
Reactant: CSCC[C@H]1C(=O)N(Cc2ccc(C#N)c(N=C(c3ccccc3)c3ccccc3)c2)CCN1C(=O)OCc1ccccc1
Reactant: c1ncncn1
Solvent: CCO
Solvent: CC(=O)O
Product: CSCC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)OCc1ccccc1
Yield: 39 %

Procedure:
To a solution of 4-benzyloxycarbonyl-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-3-(S)-(2-methylsulfanyl-ethyl)-piperazin-2-one (1.17 g, 2.67 mmol) in 15 ml of ethanol is added 1,3,5-triazine and glacial acetic acid (3.1 ml, 53.4 mmol). The resulting solution is refluxed for 20 hours, concentrated under vacuum. The residue is dissolved in ethyle acetate, washed with 1N hydrochloric acid, a saturated aqueous NaHCO3 solution, water, brine. The solution is dried over MgSO4, concentrated. The resulting crude product is purified by column chromatography eluting with a gradient of 5% MeOH:CH2Cl2 to 10% MeOH:CH2Cl2. The title compound (489 mg, 39% yield) is obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)=[O:4].S(Cl)(Cl)=O.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:40][CH3:41])=[C:24]([S:26]([N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH2:39])[CH:37]=3)[CH2:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH:25]=1.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:4])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:10](=[O:12])[NH:39][C:36]2[CH:37]=[C:38]3[C:33]([CH2:32][CH2:31][CH2:30][N:29]3[S:26]([C:24]3[CH:25]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=3[O:40][CH3:41])(=[O:28])=[O:27])=[CH:34][CH:35]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc(N)cc21
Reactant: COC(=O)Cc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C(=O)Nc2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCC3)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
4-Methoxycarbonylmethyl-benzoic acid (52.00 mg, 0.27 mmol) was suspended in dichloromethane (2.00 mL) and treated with thionyl chloride (95.57 mg, 0.80 mmol). The mixture was stirred at 50° C. for 18 hours, and the volatiles were evaporated. The residue was redissolved in tetrahydrofuran (2.00 mL) and treated with 1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-7-ylamine (94.48 mg, 0.27 mmol) and 4-dimethylaminopyridine (66.76 mg, 0.54 mmol). The mixture was warmed to 75° C. and stirred for 2.5 hours. The mixture was treated with HCl 1 N and the slurry extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (dichloromethane/methanol gradient) to yield {4-[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-7-ylcarbamoyl]-phenyl}-acetic acid methyl ester as an off-white solid, 134.20 mg (95%), MS (ISP): m/e=529.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14](O)[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.P(Cl)(Cl)([Cl:19])=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)C>[Cl:19][C:14]1[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=[C:2]([CH3:1])[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2ccc3cccnc3c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(Cl)c2ccc3cccnc3c2n1
Temperature: 25 °C

Procedure:
To a 500 mL round-bottomed flask equipped with a reflux condenser containing 2-methyl-[1,10]phenathrolin-4-ol, (10.20 g, 48.5 mmol), was slowly added phosphorus oxychloride (200 mL) and the mixture was refluxed for 3 hours. The reaction flask was allowed to cool down to room temperature and the solvent was removed in a rotary evaporator. The solid obtained was treated with methylene chloride (200 mL) and saturated NaHCO3 (200 mL) and transferred to a separatory funnel. The aqueous layer was further extracted with methylene chloride (200 mL) and the combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue obtained was treated with ethyl ether (100 mL), filtered and dried yielding a light brown solid (9.00 g). A second crop of 0.60 g of material was obtained from the mother liquors as a light yellow solid, with an overall yield of 9.60 g (87% yield).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:24]1([C@@H:30]([NH2:33])[CH2:31][CH3:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:34]([O:38][C:39]([NH:41][C@@H:42]([CH2:48][CH2:49][CH2:50][CH3:51])[C@H:43]([OH:47])[C:44](O)=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]>ClCCl>[C:34]([O:38][C:39]([NH:41][C@@H:42]([CH2:48][CH2:49][CH2:50][CH3:51])[C@H:43]([OH:47])[C:44]([NH:33][C@H:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:31][CH3:32])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)O
Reactant: CC[C@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)N[C@@H](CC)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
229 mg of 1-hydroxybenzotriazole monohydrate, 287 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 148 mg of (S)-(−)-1-phenylpropylamine were added in sequence to a solution of 260 mg of 3(S)-(tert-butoxyformamido)-2(S)-hydroxyheptanoic acid in 10 ml of dichloromethane. The mixture was stirred at room temperature for 3 hours, then diluted with dichloromethane and washed in sequence with 5% citric acid solution, saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated to give 285 mg of 3(S)-(tert-butoxyformamido)-2(S)-hydroxy-N-(1(S)-phenylpropyl)heptanamide, MS: m/e 379.1 [M+H]+.
Reaction SMILES: Cl[P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4](Cl)[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[OH:27])([CH3:17])[CH3:16]>C(N(CC)CC)C>[CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]([CH3:17])[CH3:16])[C:19]=1[O:27][P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4]([O:27][C:19]2[C:20]([CH:24]([CH3:25])[CH3:26])=[CH:21][CH:22]=[CH:23][C:18]=2[CH:15]([CH3:17])[CH3:16])[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:26])[CH3:25]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: CC(C)(C)N1P(Cl)N(C(C)(C)C)P1Cl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1OP1N(C(C)(C)C)P(Oc2c(C(C)C)cccc2C(C)C)N1C(C)(C)C

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-di-tert-butyl-1,3,2,4-diazadiphosphetidine, 2,6-diisopropylphenol and triethylamine to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[Si:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:18])[CH:3]=1.C([Li])CCC.[F:24][C:25]([F:36])([F:35])[C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:27]>O1CCCC1>[F:36][C:25]([F:24])([F:35])[C:26]([C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)([C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[Si:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:18])[CH:3]=1)[OH:27]
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Reactant: Cc1cc(Br)cc(C)c1N([Si](C)(C)C)[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)(c2ccc(F)cc2)C(F)(F)F)cc(C)c1N([Si](C)(C)C)[Si](C)(C)C

Procedure:
To a solution of 2-(4-bromo-2,6-dimethyl-phenyl)-1,1,1,3,3,3-hexamethyl-disilazane (Example II) (1.72 g, 5.0 mmol) in tetrahydrofuran (12 ml) under a nitrogen atmosphere was slowly added a solution of n-butyl lithium in hexanes (1.6 M) (3.3 ml, 5.28 mmol) at −70° C. The reaction mixture was stirred at −70° C. for 30 minutes before addition of 2,2,2,4′-tetrafluoroacetophenone (commercially available) (1.01 g, 5.25 mmol) at −70° C. The cooling bath was removed after 15 minutes. Once the reaction mixture had reached ambient temperature, it was poured onto water. The mixture was extracted with diethyl ether. The organic phase was washed with water and brine, dried over sodium sulfate, and then concentrated. The title compound was isolated as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[N:9]=[CH:10][C:3]=12.[NH2:18][CH2:19][C:20]([OH:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+].C(O)=O>O>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[C:3]2[CH:10]=[N:9]1
Reactant: NCC(=O)O
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: O=C(O)CNc1ncnc2c1cnn2-c1ccccc1Cl
Yield: 82.7 %

Procedure:
4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (1.3 g, 4.90 mmol) was added to a stirred solution of glycine (0.72 g, 9.59 mmol) and anhydrous sodium carbonate (0.58 g, 5.48 mmol) in water (10 mL). The reaction was refluxed for 2 hrs. The reaction mixture was acidified by the addition of formic acid. The precipitate was filtered, washed with water and dried in vacuo to give the title compound as a colourless solid (1.23 g), 1H NMR (300 MHz, CD3OD) δ 8.32 (s, 1H), 8.24 (s, 1H), 7.66 (m, 1H), 7.54 (m, 3H), 4.34 (s, 2H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CI.[CH:17]([N-]C(C)C)(C)C.[Li+]>>[CH3:17][C:8]1([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1CCC2(CC1)OCCO2
Agent: [Li+]
Solvent: CI
Product: COC(=O)C1(C)CCC2(CC1)OCCO2

Procedure:
According to the process described in the literature (JP83-118577), methyl 1,4-dioxaspiro [4.5]decan-8-carboxylate was reacted with methyl iodide in the presence of LDA (lithium diisopropylamide) to obtain methyl 8-methyl-1,4-dioxaspiro [4.5]decan-8-carboxylate (the compound (1) of the above figure).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(O[K])(C)(C)C.F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].CCOC(C)=O>CS(C)=O>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([O-:25])=[O:24]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of imidazole (0.997 g, 14.65 mmol) and tert-BuOK (1.722 g, 15.35 mmol) was put under Ar in a 100 mL and dissolved in dry DMSO (15 mL) to give a colorless solution. After 5 min, 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (2.04 mL, 14.58 mmol) was added within 30 s, immediately leading to a darkening of the rm to black. A temperature rise was also noted. The black solution was stirred at RT for 20 min. Ice water (60 mL) and EtOAc (50 mL) were added, the organic layer was isolated, and the aqueous phase was extracted twice with 20 mL EtOAc. The organic layer was washed with H2O (2×30 mL), brine, dried, filtered and evaporated to give the title compound as an orange oil. Yield: 3.66 g (97%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[B:10].C(=O)([O-])[O-].[Na+:15].[Na+]>C(OCC)C.O>[Na+:15].[F:9][C:4]1[CH:3]=[C:2]([B-:10]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)[C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: [B]
Reactant: Fc1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Fc1cc(F)cc([B-](c2cc(F)cc(F)c2)(c2cc(F)cc(F)c2)c2cc(F)cc(F)c2)c1
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A dried flask made of Pyrex glass (capacity of 500 ml) provided with a reflux condenser was charged with an inert gas to purge the air from theflask. Then, metallic magnesium (4.65 g) and anhydrous diethyl ether (100 ml) were fed to the flask, and the resulting solution was stirred and cooled by ice bath. A solution prepared separately by adding anhydrous diethylether (50 ml) to 1-bromo-3,5-difluorobenzene (43.52 g) was added dropwise thereto over one hour, and the resulting solution was left still for three hours. At the end of the reaction, a liquid containing boron trifluorideethercomplex (4.542 g) in anhydrous diethyl ether was added dropwise over 40 minutes, and left still for 16 hours with stirring at the room temperature. Then, an aqueous solution of sodium carbonate (30 g) in pure water (100 g) was dropped with 30 minutes. After the solution was kept stirring at the room temperature for 24 hours, the water phase and the organic phase were separated from each other. The separated organic phase was dried with sodium sulfate and filtered; the filtrate was put into an evaporator (oil bath temperature: 70° C.); and diethyl ether was evaporated, thereby obtaining a liver-brown colored solid. The liver-brown colored solid was further purified with silica gel, and a white solid of tetrakis(3,5-difluorophenyl)borate sodium salt (10.3 g) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[I:11].[OH-].[K+].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].Cl>CS(C)=O.O>[I:11][C:3]1[C:2]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[N:7][CH:6]=[C:5]([CH:4]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(I)c1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
6-Chloro-5-iodo-3-pyridinecarboxylic acid (CAN 59782-87-5, 4.7 g, 16.6 mmol) was dissolved in DMSO (49.5 ml). Potassium hydroxide pellets (2.79 g, 49.7 mmol) and 2,2,2-trifluoroethanol (2.16 g, 1.55 ml, 21.6 mmol) were added slowly at room temperature under argon. The reaction mixture was stirred for 2 h at rt; water (35 mL) was added and the mixture was cooled to 0-5° C. Concentrated HCl solution (8 mL) was added drop by drop and the precipitated solid was collected, washed with cold water and dried. The crude material was purified by flash chromatography (silica gel, 150 g, 0% to 20% i-propyl acetate in n-heptane +10% of acetic acid) to give the title compound (1.6 g, 28%) as colorless solid; MS (ESI) 345.7 (M−H)−.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)[C:35]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A solution of triphenylphosphine (288 mg, 1.1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (196 mg, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (175 mg, 0.55 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (275 mg, 2.75 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (25 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide (80 mg, 36%) as an amorphous white solid: EI-HRMS m/e calcd for C19H21FN6OS (M+) 400.1482, found 400.1476.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17](I)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]([OH:27])[CH2:24][C:25]#[CH:26].Cl>C(NCC)C.CN(C=O)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([C:26]#[C:25][CH2:24][CH2:23][OH:27])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CCNCC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C#CCCO)cc2c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxamide (Example No. 2) (1.00 g) in diethylamine (28 mL) is added copper iodide (0.128 g) and Pd(PPh3)2Cl2 (0.032 g) followed by addition of 3-butyn-1-ol (0.20 mL). The reaction is stirred at rt for 18 h. The reaction mixture is partitioned between H2O (100 mL) and ethyl acetate (100 mL). The organic layer is removed, and the aqueous layer is extracted with ethyl acetate (2×100 mL). Combined organic layers are dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown oil is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a brown solid. This material is dissolved in DMF (15 mL) and 2N HCl is added until a precipitate forms. The resulting tan solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2, 95:5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.183 g (21%) of the title compound as a yellow, crystalline solid.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: COc1cc(OC)cc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 59.7 %

Procedure:
6-(3,5-Dimethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (55 mg, 60%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3,5-dimethoxyphenylboronic acid (62.5 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]12[NH:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N:18]2[CH:12]3[CH2:17][CH2:16][CH:15]2[CH2:14][CH2:13]3)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: C1CC2CCC1N2
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 255.1 %

Procedure:
To a solution of 2-bromo-4-fluoro-1-nitro-benzene (250 mg, 1.14 mmol) in DMSO (2 mL) was added 7-azabicyclo[2.2.1]heptane (182 mg, 1.36 mmol) portion-wise. The reaction was stirred at 80° C. for 24 h. The reaction was quenched with water and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with 1 N HCl, dried over MgSO4, filtered and concentrated in vacuo to provide 7-(3-bromo-4-nitrophenyl)-7-azabicyclo[2.2.1]heptane (864 mg, 98% yield). LC/MS m/z 298.5 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[O:30]1[CH2:33][C:32](=O)[CH2:31]1.C(N(C(C)C)C(C)C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:29]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][CH:32]3[CH2:33][O:30][CH2:31]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCNC3COC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a stirred of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,3-diamine (84 mg, 0.2 mmol, prepared in analogy to Example 9-3), oxetan-3-one (15 mg, 0.21 mmol) and ethyldiisopropylamine (43 μL, 0.25 mmol) in dichloromethane (10 mL) was added molecular sieves (4 Å, 84 mg) followed by sodium triacetoxyborohydride (63.6 mg, 0.3 mmol). After being stirred at room temperature overnight, another batch of sodium triacetoxyborohydride (63.6 mg, 0.3 mmol) was added and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 26 mg of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(oxetan-3-yl)propane-1,3-diamine as a white solid. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J=7.6 Hz, 1 H), 7.87 (d, J=7.6 Hz, 1 H), 7.34 (s, 1 H), 7.68 (t, J=14.8 Hz, 1 H), 7.58-7.51 (m, 2 H), 7.45 (d, 1 H), 5.99 (s, 1 H), 5.24 (s, 2 H), 4.85 (t, J=3.3 Hz, 2 H), 4.85 (t, J=13.6 Hz, 2 H), 4.55 (m, 4 H), 4.06-4.00 (m, 1 H), 3.67 (s, 2 H), 3.50 (t, J=13.2 Hz, 2 H), 2.74 (t, J=13.6 Hz, 2 H), 2.45 (s, 3 H), 1.98-1.91 (m, 2 H).
Reaction SMILES: [CH:1]([Si:3]([Cl:6])(Cl)[Cl:4])=[CH2:2].[CH3:7][SiH:8]([Cl:10])[Cl:9]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH3:7][Si:8]([Cl:10])([Cl:9])[CH:2]1[CH2:1][Si:3]([Cl:6])([Cl:4])[CH:2]([Si:8]([CH3:7])([Cl:10])[Cl:9])[CH2:1][Si:3]1([Cl:6])[Cl:4]
Reactant: C[SiH](Cl)Cl
Reactant: C=C[Si](Cl)(Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C[Si](Cl)(Cl)C1C[Si](Cl)(Cl)C([Si](C)(Cl)Cl)C[Si]1(Cl)Cl
Yield: 51.2 %

Procedure:
In the same manner as that of Embodiment 1, 80 g (0.50 mol) of vinyltrichlorosilane, 171.4 g (1.49 mol) of methyldichlorosilane, and 14.7 g of tetrabutylphosphonium chloride were put in a 500 ml stainless steel tube and reacted at 180° C. for six hours. The reactant was vacuum-distilled to obtain 61.4 g (yield: 51.2%) of 2,5-bis(methyldichlorosilyl)-1,1,4,4-tetrachloro-1,4-disilacyclohexane. The obtained product was analyzed with 300 MHz 1H magnetic resonance.