Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH:13]=[C:12]([CH3:14])[CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.C([O+](CC)CC)C.[N+](=[CH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N-]>C(Cl)Cl>[CH2:1]([CH:8]1[CH:13]=[C:12]([CH3:14])[CH2:11][CH2:10][CH:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C=[N+]=[N-]
Reactant: CC1=CC(Cc2ccccc2)C(=O)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1=CC(Cc2ccccc2)C(=O)C(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of the above ketone (19) (8.18 g) in methylene chloride (18 mL) at -78° C. was added a cold solution of triethyloxonium tetrafluoroborate (28 mL, 1N in CH2Cl2). Immediately afterwards t-butyl diazoacetate (4.1 mL) was added and the reaction stirred for 15 min at -78° C. then allowed to slowly warm up in an ice bath. After the cessation of gas evolution (~15 min), the reaction was quenched by the addition of aqueous saturated NaHCO3 (150 mL) and stirred an additional 15 min. The organic phase was removed and the aqueous phase re-extracted with fresh CH2Cl2. The CH2Cl2 phases were then combined, dried over MgSO4 and evaporated. The product (20) was obtained by silica gel chromatography (5.0×100 cm) eluting with 2.5% ethyl acetate in n-hexane (2.11 g, 17.4%). Another later eluting fraction was obtained which corresponded to the other regioisomer (21) (3.71 g, 30.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([C:19]2[CH:20]=[N:21][C:22]([NH:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[CH:3]=1.CCN(C(C)C)C(C)C.[F:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[CH:47][C:46]([C:52](O)=[O:53])=[CH:45]2.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CN(C=O)C.CS(C)=O>[F:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[CH:47][C:46]([C:52]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:22]3[N:21]=[CH:20][C:19]([C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]5[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=5)[N:5]=4)=[CH:24][CH:23]=3)[CH2:27][CH2:28]1)=[O:53])=[CH:45]2
Reactant: O=C(O)c1cnc2ccc(F)cc2c1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCNCC3)nc2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCN(C(=O)c4cnc5ccc(F)cc5c4)CC3)nc2)c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
4-Methyl-N6′-(piperidin-4-yl)-N6-(4-(trifluoromethyl)pyridin-2-yl)-2,3′-bipyridine-6,6′-diamine (30 mg, 0.07 mmol) was dissolved in DMF (500 μL). The solution was then treated with DIEA (24 μL, 0.14 mmol), 6-fluoroquinoline-3-carboxylic acid (20 mg. 0.11 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (42 μL, 0.07 mmol). The reaction was warmed to 40° C. and stirred for 16 hours. The reaction was allowed to cool to room temperature: The mixture was diluted with DMSO (1.0 mL) and purified by mass-triggered reverse phase high pressure liquid chromatography, eleuting with a 1% ammonium hydroxide buffered water/acetonitrile gradient over a Waters X-Bridge C-18 column, to afford (6-fluoroquinolin-3-yl)(4-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)-2,3′-bipyridin-6′-ylamino)piperidin-1-yl)methanone. MS ESI calcd. for C32H28F4N7O [M+H]+ 602. found 602. 1H NMR (600 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.60 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.11 (dd, J=5.4, 9.2 Hz, 1H), 8.00 (dd, J=2.4, 8.8 Hz, 1H), 7.86 (dd, J=2.9, 9.3 Hz, 1H), 7.73 (m, 1H), 7.20 (s, 1H), 7.14 (d, J=5.1 Hz, 1H), 7.07 (s, 1H), 6.87 (d, J=7.6 Hz, 1H), 6.56 (d, J=8.8 Hz, 1H), 4.37 (s, 1H), 4.06 (s, 1H), 3.32 (s, 1H), 2.47-2.45 (m, 1H), 2.27 (s, 3H), 2.04 (s, 1H), 1.90 (s, 1H), 1.49 (s, 1H), 1.42 (s, 2H). rhSyk IC50=8 nM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@H:36]2[CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:41])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:41][C@H:37]2[CH2:38][CH2:39][CH2:40][C@@H:36]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: O[C@H]1CCC[C@@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Yield: 33.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 500 mg, 1.12 mmol), (1S*,2R*)-2-phenylcyclopentanol (200 mg, 1.23 mmol), sodium hydride (63%; 100 mg, 2.63 mol) and DMSO (5.0 mL), to yield the title compound (220 mg, 33%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:17])[CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Tl].I[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>C(Cl)(Cl)Cl>[CH3:23][CH:22]([CH3:24])[CH2:21][CH2:20][O:1][C:2]1[C:7]2[C:8](=[O:17])[CH:9]=[C:10]([C:12]([OH:14])=[O:13])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCI
Reactant: CCOC(=O)c1cc(=O)c2c(O)cccc2o1
Agent: [Tl]
Solvent: ClC(Cl)Cl
Product: CC(C)CCOc1cccc2oc(C(=O)O)cc(=O)c12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A stirred mixture of 21.87 parts of ethyl 5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate, thallium salt and 99 parts of 1-iodo-3-methylbutane was refluxed for one hour. After cooling, chloroform was added to the reaction mixture and the insoluble thallium salts were removed by filtration. The chloroform filtrate was washed with cold N sodium hydroxide solution, then washed with water and the volatile components were removed by evaporation. Sodium bicarbonate solution was added to the oily residue obtained and the mixture was stirred at 100°C for two hours. After cooling, the solution was extracted with chloroform and the aqueous layer was separated. This aqueous extract was acidified with 2N hydrochloric acid and the solid which precipitated was collected by filtration, washed with water and dried to give 6.16 parts of 5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid, m.p. 181°-183°C (after crystallisation from ethyl acetate/light petroleum).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:12][CH:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[N:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]1=[O:31].O>CS(C)=O>[NH2:12][C:13]1([CH2:3][CH2:2][C:1]#[N:4])[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[N:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]1=[O:31]
Reactant: COc1ccc2c(c1)N(c1ccc(F)cc1)C(=O)C2N
Reactant: C=CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)N(c1ccc(F)cc1)C(=O)C2(N)CCC#N
Temperature: 25 °C
Reaction time: 9 h

Procedure:
Under argon atmosphere, 1.2 ml of acrylonitrile and 4.48 g of potassium carbonate were added to a stirred suspension of 5.00 g of 3-amino-1-(4-fluorophenyl)-2,3-dihydro-6-methoxy-1H-indol-2-one hydrochloride in dimethyl sulfoxide (30 ml), and the mixture was stirred at room temperature for 9 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the extract was washed, dried and then filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform-ethyl acetate (1:1)] to afford 3.48 g of 3-[3-amino-1-(4-fluorophenyl)-2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl]propanonitrile as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][S:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])(=[O:7])=[O:6].C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[CH3:1][O:2][CH:3]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][S:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][S:43]([CH3:42])(=[O:45])=[O:44])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCCCCCO)OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCCCCCOS(C)(=O)=O)OC
Temperature: 25 °C

Procedure:
In 30 ml of dichloromethane are dissolved 1.77 g of 6-hydroxyhexyl 2-methoxy-3-octadecyloxypropyl sulfone and 0.64 ml of triethylamine, to which 0.35 ml of methanesulfonyl chloride is added dropwise with stirring at room temperature. Thereafter, the mixture is stirred at room temperature for 2 hours and the solvent is distilled off under reduced pressure. The residue is dissolved in ethyl acetate and washed successively with dilute hydrochloric acid, water, an aqueous sodium bicarbonate solution and water. After drying, the solvent is distilled off to leave 1.98 g of the captioned compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6]
Reactant: C1CCNCC1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCl)N1CCCCC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
4-Chlorobutyryl chloride in dichlormethane was added to an ice cooled solution of piperidine (1.8 ml; 17.6 mmol) and triethylamine (2.5 ml) in dichloromethane (40 ml) under an atmosphere of nitrogen. The mixture was stirred for 5 min whilst being cooled, then stirred at ambient temperature for 3 h. The solution was washed with water, dried over sodium sulfate and evaporated to give 1-(4-chloro-1-oxobutyl)piperidine as a pale yellow oil (2.1 g).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.C1CCCCC1.[CH3:20][CH:21]([C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH3:22].[CH3:28][C:29](=[C:32]([CH3:34])[CH3:33])[CH2:30]Br.[Br-].Cl>C1COCC1>[CH3:20][CH:21]([C:23](=[O:27])[C:24]([CH3:26])([CH3:25])[CH2:30][C:29]([CH3:28])=[C:32]([CH3:34])[CH3:33])[CH3:22]
Reactant: CC(C)=C(C)CBr
Reactant: CC(C)C(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)=C(C)CC(C)(C)C(=O)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
On a three neck flask containing 50 ml of dry THF, at −70° C., were added 65 ml of a 1.5 M solution of LDA THF in cyclohexane (96 mmoles). To said solution were added, dropwise, 10 g of 2,4-dimethyl-3-pentanone (87.5 mmoles). After one hour stirring, the medium temperature was left to warm up to 0° C., and then 14.3 g of 2,3-dimethyl-1-bromo-2-butene (87 mmoles) were added dropwise so as to maintain the reaction temperature between 0° and 10° C. At the end of the addition of the bromide, the temperature was risen to room temperature. After one hour stirring the reaction medium was poured into an excess of a 2 M aqueous HCl solution. The mixture thus obtained was extracted with 100 ml of cyclohexane and the organic layer washed with water until neutrality.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[C:5]([C:19]([OH:21])=[O:20])[CH:4]=1.[N+](=[CH2:24])=[N-]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[C:5]([C:19]([O:21][CH3:24])=[O:20])[CH:4]=1
Reactant: COc1cc(C(=O)O)cc2c1C(=O)c1ccccc1CC2
Reactant: C=[N+]=[N-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(c(OC)c1)C(=O)c1ccccc1CC2

Procedure:
4-Methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a.d]cycloheptene-2-carboxylic acid (4.0 g) is dissolved in dimethylformamide (30 ml) and to the solution is added excess ethereal diazomethane. The mixture is evaporated to low volume, poured into water and extracted with ethyl acetate. The extract is washed, dried and evaporated to yield methyl 4-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylate. 1.0 G of this compound is refluxed for 1 hour in carbon tetrachloride (50 ml) containing N-bromosuccinimide (0.635 g) while irradiating the mixture with a 100 watt incandescent lamp. The solution is cooled, filtered and evaporated. The residue is dissolved in dimethylformamide (10 ml) and 1,5-diazabicyclo[4.3.0]non-5-ene (1.0 ml) is added. The mixture is heated to 70° for 30 minutes then cooled and poured into water. The solution is extracted with ethyl acetate, and the extract washed, dried and evaporated to afford methyl 4-methoxy-5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylate. This material is refluxed for 3 hours in water (10 ml) and methanol (2.5 ml) containing sodium hydroxide (0.5 g). The cooled solution is acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated. The residue is recrystallized from aqueous methanol to afford 4-methoxy-5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid, mp 252°-253°.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[OH:29][S:30]([OH:33])(=[O:32])=[O:31]>C(O)C.O>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[S:30]([O-:33])([O-:32])(=[O:31])=[O:29]
Reactant: O=S(=O)(O)O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])[O-]
Temperature: 22.5 °C

Procedure:
100.0 g (245.5 mmoles) of sitagliptin base were dissolved at 20-22° C. in a mixture of 750 ml of absolute ethanol and 120 ml of water. A previously prepared solution of 98.1% H2SO4 (24.9 g, 240.9 mmoles) in ethanol (760 ml) was slowly added to said solution, maintaining the temperature between 20-25° C. When approximately ⅔ of the total volume of the acid solution had been added, the addition was stopped and 1.0 g (1.978 mmoles) of crystalline form M of sitagliptin sulfate obtained by means of any of the processes described in Examples 1 and 3-5 was added to the reaction mixture. The presence of a white precipitate that remains undissolved was immediately noticed. The addition of the acid solution was continued and once this ended, the mixture obtained was maintained at a temperature of 20-25° C. for 4 hours. The solid obtained was filtered and washed in the filter with absolute ethanol (2×100 ml). The wet product was dried in a vacuum oven at 40° C. for 22 hours to yield 97.1 g (192.1 mmoles) of a white crystalline solid (77.6%). XRPDs both of the wet product (FIG. 3) and of the dry product (FIG. 2) which correspond with form M of sitagliptin sulfate were performed. The DSC of the wet product (FIG. 9) shows an endothermic signal at 216.7° C. whereas the dry product showed an endothermic signal at 215.5° C. (FIG. 8). The water content determined by TGA (FIG. 13) is 0.02%. The product thus obtained had a particle size distribution (PSD) corresponding to D90: 254.21 μm, D50: 141.64 μm, D10: 5.32 μm. By adjusting the grinding conditions a product with a particle size distribution (PSD) corresponding to D90 120.84 μm, D50: 6.01 μm, D10: 1.50 μm could be obtained and it was found that the ground product is still the crystalline form of sitagliptin sulfate object of the present invention.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](O)=[O:8].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([Cl:14])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)C(C(=O)O)C1(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)C(C(=O)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.50 g, 3.5 mmol) in 18 mL of methylene chloride at 0° C. was added oxalyl chloride (0.61 mL, 7.0 mmol) and a catalytic amount of dimethylformamide (2 drops). The solution was stirred at ambient temperature for 1 hour, and then concentrated under reduced pressure to provide 0.56 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:18].[F:19][C:20]1[CH:21]=[C:22]([OH:35])[CH:23]=[CH:24][C:25]=1B1OC(C)(C)C(C)(C)O1.CCOCC>O.C1COCC1.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>[F:19][C:20]1[CH:21]=[C:22]([OH:35])[CH:23]=[CH:24][C:25]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:18]
Reactant: OCCCc1ccc(-c2ccc(Br)c(F)c2)cc1
Reactant: CC1(C)OB(c2ccc(O)cc2F)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OCCCc1ccc(-c2ccc(-c3ccc(O)cc3F)c(F)c2)cc1

Procedure:
16.5 g (59 mmol) of sodium metaborate octahydrate and 1.3 g (1.8 mmol) of bis(triphenylphosphine)palladium(II) chloride are initially introduced in 150 ml of water and 50 ml of THF, 12.5 g (38.5 mmol) of 3-(4′-bromo-3′-fluorobiphenyl-4-yl)propan-1-ol are added, and a solution of 12.5 g (0.053 mol) of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol in 50 ml of THF is subsequently added dropwise. The batch is heated under reflux overnight, taken up in MTB ether and washed three times with water. The org. phase is dried over sodium sulfate, the solvent is removed in vacuo, and the crude product is recrystallised from toluene/ethyl acetate (9:1), giving 2,2′-difluoro-4″-(3-hydroxypropyl)[1,1′;4′,1″]-terphenyl-4-ol as colourless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][CH:10]=O)=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]2[CH:9]=[CH:10][N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:4]=2[N:3]=1
Reactant: O=CCc1c(Cl)nc(Cl)nc1Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Clc1ccc(-n2ccc3c(Cl)nc(Cl)nc32)cc1

Procedure:
A solution of the product from step (ii) (2 g) and p-toluenesulfonic acid (catalytic) in methanol (30 ml) was stirred at room temperature for 2 h then evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether (2:1). Yield 0.5 g
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19](O)=[O:20])=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:24]1CCOCC1.ClC(OCC(C)C)=O.N>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([NH2:24])=[O:20])=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
2-(3-Benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (1.50 g, 4.72 mmol) and 4-methylmorpholine (0.60 mL, 5.45 mmol) in tetrahydrofuran (100 mL) was added isobutyl chloroformate (0.62 mL, 4.73 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 1 hour and followed by the addition of ammonia (7.0 N solution in methanol, 10 mL, 70 mmol). The reaction mixture was kept stirring at ambient temperature for 19 hours. The solvent was removed in vacuo and the residue was triturated with 10% sodium hydroxide solution. The solid was collected by filtration and washed with water to afford the title compound in 30% yield (0.47 g): mp 217-218° C. (water); 1H NMR (300 MHz, DMSO-d6) δ 7.42-7.27 (m, 7H), 4.40 (s, 2H), 3.93-3.88 (m, 2H), 3.48-3.42 (m, 2H), 2.42 (s, 3H); MS (ES+) m/z 317.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12]([N:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1)(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: C1CSCCN1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1Cl
Yield: 93.6 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88mmol), thiomorpholine (710 mg, 6.88 mmol) and triethylamine(l.92mL, 13.76mmnol) were reacted to form the desired product (2.30 g, 94%). 1H NMR (MeOD-d4): δ 7.95 (d, 1H), 7.85(d, 1H), 3.68 (t, 4H), 2.69 (t, 4H).
Reaction SMILES: [Br:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:34][S:35][C:36]1[O:37][C:38]2[CH:44]=[C:43]([CH:45]=O)[CH:42]=[CH:41][C:39]=2[N:40]=1>C(Cl)Cl>[Br:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH:6][CH2:45][C:43]2[CH:42]=[CH:41][C:39]3[N:40]=[C:36]([S:35][CH3:34])[O:37][C:38]=3[CH:44]=2)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Br)cc1[N+](=O)[O-]
Reactant: CSc1nc2ccc(C=O)cc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1nc2ccc(CNc3cc(Cl)c(Br)cc3[N+](=O)[O-])cc2o1
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 4-bromo-5-chloro-2-nitroaniline (550 mg, 2.19 mmol) from the previous step and TFA (2.26 mL) in DCM (10 mL) at −15° C. was added NaBH(OAc)3 (1.39 g, 5.37 mmol). Then a solution of 2-(methylthio)benzo[d]oxazole-6-carbaldehyde (465 mg, 2.41 mmol) in DCM (6 mL) was added to the mixture. After complete addition, the mixture was stirred at −10° C. to 0° C. for 2 h. The reaction mixture was diluted with DCM and washed sequentially with H2O, aq NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5:1 to 2:1 petroleum ether/DCM to give 4-bromo-5-chloro-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline as a yellow solid (451 mg, 48.2%). 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, 1H), 8.34 (s, 1H), 7.66 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.37 (d, J=6.9 Hz, 1H), 7.19 (s, 1H), 4.76 (d, J=6.3 Hz, 2H), 2.74 (s, 3H). LCMS (ESI) m/z 428 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C:10](=[N:14]O)[C:9]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[BH4-].[Na+].[OH-].[Na+]>CO.CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH2:14])[C:9]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCCC(=NO)c2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)OC(=O)N1CCCC(N)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 8-chloro-5-hydroxyimino-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (3.33 g, 11.2 mmole) and MoO3 (2.45 g, 17.0 μmmole) in MeOH (50.0 ml) was added a solution of sodium borohydride (2.13 g, 56.2 mmole) in DMF (50.0 ml). The reaction was stirred at room temperature overnight. To the reaction mixture was added 2.0N NaOH (aq) (100 ml). The precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate (5×100 ml). The combined organics was washed with brine (3×500 ml). Dried over Na2SO4, filtered and concentrated to 100 ml, which was then treated with 4.0N HCl in dioxane (3.50 ml). Removal of solvents in vacuo gave a white solid, which washed with ethyl ether and dried under vacuum to provide the titled compound as hydrochloride salt (2.87 g, 80%). MS (ES+): 283 (M+H).