Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[CH2:14][NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=CC=1.[H-].[Na+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CS(C)=O.C(OCC)(=O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:24][C:25]1[CH:26]=[CH:27][C:30]([N:15]([CH2:14][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:8]=2)[S:16]([CH2:19][CH3:20])(=[O:17])=[O:18])=[CH:31][CH:32]=1
Reactant: COc1cccc(CBr)c1
Reactant: CCS(=O)(=O)NCc1cnccc1-c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(OCc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of N-(4-(4-hydroxyphenyl)-N-(ethanesulfonyl) pyrid-3-ylmethylamine (1.0 equiv.) in DMSO (0.15 M) was cooled to 0° C. Sodium hydride (1.1 equiv.; 60% dispersion in oil) was added; after 20 minutes at 0° C. 3-methoxybenzyl bromide (Aldrich; 1.3 equiv.) was added and the reaction warmed to ambient temperature. After stirring overnight the reaction was diluted with ethyl acetate and washed with 0.1 M potassium carbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative HPLC eluting with 90:10 to 70:30 DCM/ethyl acetate to give the title compound. Anal Calcd for C22H24N2O4S.0.1H2O: C, 64.06; H, 5.86; N, 6.79. Found: C, 63.78; H, 5.89; N, 6.76. MS found 413.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[S:12][C:13]([CH2:17][NH2:18])=[C:14]([CH3:16])[N:15]=1>>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:18][CH2:17][C:13]2[S:12][C:11]([CH3:10])=[N:15][C:14]=2[CH3:16])[CH:7]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cc1nc(C)c(CN)s1
Product: Cc1nc(Cl)cc(NCc2sc(C)nc2C)n1

Procedure:
The title compound was prepared from 4,6-dichloro-2-methylpyrimidine and (2,4-dimethylthiazol-5-yl)methanamine according to the protocol outlined in Example 1, to afford 3A-1 as a solid. LRMS (ES) (M+H)+: observed=269.1, calculated=269.7.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([OH:22])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[N:8]=[C:7]1[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=[O:5])=[O:4].N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>C1(C)C=CC=CC=1>[Si:23]([C:7]1[N:6]([S:3](=[O:4])(=[O:5])[N:2]([CH3:30])[CH3:1])[CH:10]=[C:9]([CH:11]([O:22][C:37](=[O:39])[CH3:38])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[N:8]=1)([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:25])[CH3:24]
Reactant: CN(C)S(=O)(=O)n1cc(C(O)c2ccnc3ccccc23)nc1[Si](C)(C)C(C)(C)C
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC(c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.1 %

Procedure:
To 2-(tert-Butyldimethylsilyl)-4-(hydroxyquinolin-4-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (example 8, step A) (0.750 g, 1.62 mmol) in 8 ml of anhydrous toluene at 0° C., pyridine (0.16 ml, 1.94 mmol) was added followed by acetyl chloride (0.14 ml, 1.94 mmol). The solution was stirred at room temperature for two hours. It was cooled to 0° C. and ice cubes were added. The reaction mixture was partitioned between toluene (5 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure and column purified (hexanes:EtOAc; 1:4) to give 0.84 g (100%) of the product.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:13](Cl)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:16]([O:20][C:21]([N:23]1[CH2:27][C@@H:26]([CH2:28][N:29]([CH:46]([CH3:48])[CH3:47])[C:30](=[O:45])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[C@H:25]([CH2:49][NH:50][CH:51]2[CH2:53][CH2:52]2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([O:20][C:21]([N:23]1[CH2:27][C@@H:26]([CH2:28][N:29]([CH:46]([CH3:47])[CH3:48])[C:30](=[O:45])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[C@H:25]([CH2:49][N:50]([CH:51]2[CH2:52][CH2:53]2)[C:13]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:14])[CH2:24]1)=[O:22])([CH3:18])([CH3:19])[CH3:17]
Reactant: O=C(Cl)N1CCCC1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)N2CCCC2)C2CC2)C(C)C)ccc1OC
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Triethylamine (99 μL, 0.714 mmol) followed by 1-pyrrolidinecarbonyl chloride is added to a solution of ((3R*,4R*)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (254 mg, 0.476 mmol) in CH2Cl2 (20 mL). The resulting solution is stirred at RT for 2 h and at 60° C. for another 24 h. Evaporation of the solvent affords the crude product which is purified by preparative HPLC (Waters C18 ODB, eluent: H2O/CH3CN 20 to 100%) to give the title compound. MS (LC-MS): 631.1 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 6.31 min.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[C:7]1([C:13]2[O:17][C:16]([C:18]3[C:19]([NH2:30])=[N:20][CH:21]=[C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:23]=3)=[N:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([S:3]([N:27]1[CH2:28][CH2:29][N:24]([C:22]2[N:23]=[C:18]([C:16]3[O:17][C:13]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:14][N:15]=3)[C:19]([NH2:30])=[N:20][CH:21]=2)[CH2:25][CH2:26]1)(=[O:5])=[O:4])[CH3:2]
Reactant: Nc1ncc(N2CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethanesulfonyl chloride (37.51 mg, 27.64 μL, 0.2917 mmol) was added to a solution of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-piperazin-1-yl-pyrazin-2-amine (116 mg, 0.2652 mmol) and triethylamine (53.67 mg, 73.93 μL, 0.5304 mmol) in dichloromethane (5 mL) at 0° C. and the resulting solution stirred at room temperature for 1.5 hours. The mixture was diluted with dichloromethane, washed with water and the aqueous layer extracted further with dichloromethane. The organics were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel by flash column chromatography (3% MeOH/DCM) to afford the title compound still impure. This was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (25.2 mg, 18% Yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])[F:11])[NH2:5].[CH3:13][C:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:17]([C:14]2([CH3:13])[CH2:16][CH2:15]2)=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:11])[F:12]
Reactant: Nc1ccc(OC(F)F)c(Br)c1
Reactant: CC1(C(=O)Cl)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1(C(=O)Nc2ccc(OC(F)F)c(Br)c2)CC1
Yield: 96 %

Procedure:
In the same manner as in Example 3 but using 3-bromo-4-difluoromethoxyaniline (2.4 g) and 1-methylcyclopropanecarbonyl chloride (1.2 g) with pyridine (0.8 g) as the hydrogen chloride-eliminating agent and ethyl acetate as the solvent, the operations were effected to give N-(3-bromo-4-difluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (3.1 g). M.P., 71°-71.5° C.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([O-:3])=[O:2].C([O:11][CH:12](O)[C:13]([F:16])([F:15])[F:14])C.C(=O)([O-])[O-].[K+].[K+]>CC(=O)OCC>[N+:1]([CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[CH:12]([OH:11])[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2]
Reactant: CCOC(O)C(F)(F)F
Reactant: CCCCC[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCC(C(O)C(F)(F)F)[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a stirred solution of 1-nitropentane (1.0 g, 8.5 mmol) and trifluoroacetaldehyde ethyl hemiacetal (1.2 mL, 8.5 mL) was added potassium carbonate (K2CO3 ) (0.06 g, 0.43 mmol). The reaction mixture was heated at 60° C. under Ar for 3 h. The mixture was cooled to R.T., then taken up in EA (50 mL). The organic layer was washed with 1 N HCl (2×10 mL), sat. NaCl (2×10 mL), dried (MgSO4), filtered and concentrated to give (2SR)-(3SR)-3-nitro-1,1,1-trifluoro-2-heptanol as a crude oil (1.7 g, 93%): 1H NMR (CDCl3, 300 MHz) δ 0.91 (t, 3H, J=7.2 Hz), 1.24-1.43 (m, 4H), 2.04-2.11 (m, 2H), 4.08-4.77 (m, 3H) ppm.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[OH:4])#[N:2].[Cl:18][C:19]([Cl:29])=[CH:20][C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:18][C:19]([Cl:29])=[CH:20][C@@H:21]1[C@H:23]([C:24]([O:4][CH:3]([C:1]#[N:2])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=2)=[O:25])[C:22]1([CH3:27])[CH3:28]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 106.1 %

Procedure:
A mixture of 468.6 g (2.08 moles) (cyano)(3-phenoxyphenyl)methanol and 2500 ml toluene was placed in a flask and heated to 40° C. During an 80-85 minute period, 509 g (2.24 moles) of (cis)-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride prepared as described in Step B, and 186 g (2.35 moles) of pyridine were added under nitrogen. Upon completion of the addition, the reaction mixture was stirred 2.5 hours at 40° C. After cooling, the reaction mixture was washed successively with 1000 ml of water, 1000 ml of 1 N hydrochloric acid, 1000 ml of 1 N sodium hydroxide, twice with water, and once with an aqueous solution of sodium chloride. After being dried over magnesium sulfate, the solution was filtered through Celite and the solvent stripped using a rotary evaporator. Residual solvent was removed in a vacuum oven. A total of 918.3 g of 93.6% (cyano)(3-phenoxyphenyl)methyl cis-3-(2,2dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate was obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[C:22]([N:26]([CH2:36][CH3:37])[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[CH2:36]([N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)[CH:21]=1)[S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:37]
Reactant: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(=O)(=O)c1ccccc1
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN(c1cccc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c1)S(=O)(=O)c1ccccc1
Yield: 64.4 %

Procedure:
A mixture of 0.33 g (1.70 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.61 g (1.70 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-benzenesulfonamide in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 535 mg of N-ethyl-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-benzenesulfonamide as a yellow solid (yield 64.4%).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2.C(N(CC)CC)C.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36]([Cl:38])=[O:37]>CN(C=O)C>[ClH:38].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH:23][C:36]([C:32]4[O:31][CH:35]=[CH:34][CH:33]=4)=[O:37])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2
Reactant: Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30 mg (0.08 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-amino-1-benzothiophene-2-carboxamide dihydrochloride are dissolved in 1 ml of DMF, and 33.5 μl (0.24 mmol) of triethylamine are added. At 0° C., 15.7 mg (0.12 mmol) of furan-2-carbonyl chloride are added. After 3 h of stirring at RT, the reaction mixture is separated by preparative HPLC. The product fraction is concentrated under reduced pressure and codistilled with 4M HCl in dioxane. 12 mg (34.7% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:49][CH2:48][CH2:47][C@H:5]1[C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:46][CH2:45][CH2:44][C@H:14]1[C:15]([NH:17][N:18]([C:20]([O:22][CH:23]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][NH:28]C(OCC1C=CC=CC=1)=O)=[O:21])[CH3:19])=[O:16])=[O:12])[CH3:10])=[O:7])(=[O:3])[CH3:2].[ClH:50].[H][H]>[Pd]>[ClH:50].[C:1]([N:4]1[CH2:49][CH2:48][CH2:47][C@H:5]1[C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:46][CH2:45][CH2:44][C@H:14]1[C:15]([NH:17][N:18]([C:20]([O:22][CH:23]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])=[O:21])[CH3:19])=[O:16])=[O:12])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CCCCNC(=O)OCc1ccccc1)OC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)C(CCCCN)OC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O

Procedure:
A mixture of 0.01 moles of 5-benzyloxycarbonylamino1-ethoxycarbonylpentyl acetylprolylalanylprolyl-2-azaalaninate and 0.2 gm of 10% Pd/C in 200 ml of 1.0 N-ethanolic hydrogen chloride is hydrogenated at room temperature. When the required amount of hydrogen has been taken up the reaction mixture is filtered and concentrated in vacuo to give 5-amino-1-ethoxycarbonylpentyl acetylprolylalanylprolyl-2-azaalaninate hydrochloride.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: C[Si](C)(C)CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 2-(trimethylsilyl)ethanol (7.3 mL) and triethylamine (25 mL) in dichloromethane (80 mL). Cool in an ice bath. Add dropwise chloroacetyl chloride (6.9 g). After the addition is complete warm the reaction mixture to ambient temperature After 5 hours, add chloroacetyl chloride (2.8 g), After 2 hours, filter the reaction mixture and extract with a saturated aqueous solution of sodium bicarbonate and then water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Distill the residue to give 2-(trimethylsilyl)ethyl chloroacetate: bp 150° C. at 28 mm of Hg.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)(=[O:10])=[O:9])[CH2:4]1.[C:18]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26]2)=[CH:22][C:21]=1[F:34])#[N:19].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO>[F:34][C:21]1[CH:22]=[C:23]([CH2:24][N:25]2[C:29]([CH2:30][NH:2][C@@H:3]3[CH2:7][CH2:6][N:5]([S:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=4)(=[O:10])=[O:9])[CH2:4]3)=[CH:28][N:27]=[CH:26]2)[CH:32]=[CH:33][C:20]=1[C:18]#[N:19]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: N[C@@H]1CCN(S(=O)(=O)c2cccc(O)c2)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CN[C@@H]2CCN(S(=O)(=O)c3cccc(O)c3)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-Amino-1-(3-hydroxyphenylsulfonyl)pyrrolidine hydrochloride, as described above in Step F. (360 mg, 1.29 nimol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described in Example 1, Step G. (326 mg, 1.42 mmol) were stirred in MeOH (8 mL) and N,N-diisopropylethylamine was added dropwise adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hour at ambient temperature then NaCNBH3 (97 mg, 1.54 mmol) was added and stirring was continued for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (10 mL) and CHCl3 (20 mL). The aqueous layer was extracted further with CHCl3 (3×15 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of EtOAc—5% MeOH—0.5% NH4OH to EtOAc—10% MeOH—1% NH4OH to yield the titled product as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH:14]([NH2:20])[CH2:13]2>C1(C)C=CC=CC=1.C1COCC1>[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH:14]([NH:20][C:10]([NH:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)=[O:11])[CH2:13]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)NC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dichlorophenyl isocyanate (1.88 g, 10 mmol) in toluene (20 ml) was added at 0° to 1-azabicyclo[2.2.2]octan-3-amine (3-aminoquinuclidine) (1.26 g, 10 mmol) in THF (40 ml). The mixture was stirred at room temperature overnight and evaporated to dryness. The residue was partitioned between ether and dilute hydrochloric acid. The aqueous phase was basified with potassium carbonate and extracted with ethyl acetate. The dried (Na2SO4)ethyl acetate phase was evaporated and the residue (1.64 g) converted to the 1:1 oxalate, quarter hydrate, mp 208°-209° C. (dec).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([O:23][C:24]([F:27])([F:26])[F:25])[CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([O:23][C:24]([F:27])([F:26])[F:25])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2OC(F)(F)F)sc2ccc(F)cc12
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2OC(F)(F)F)sc2ccc(F)cc12
Yield: 73.6 %

Procedure:
This compound was prepared in analogy to example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethoxy-phenyl)-amide (0.075 g) and 4-pyridineboronic acid (0.029 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.25 ml) and 2 M aqueous sodium carbonate solution (0.6 ml) with tetrakis(triphenylphosphine)palladium (0.009 g) to obtain the title compound (0.055 g) as a colorless solid. MS (ISP): 483.0 (M+H)+
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O.O>[O:1]([CH2:8][CH2:9][C:10]([N:13]=[N+:14]=[N-:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCOc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)CCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
Phenoxypropionyl chloride (9.23 g, 0.05 mol) is dissolved in 100 ml acetone and cooled with an ice bath as sodium azide (3.6 g, 0.055 mol) in 10 ml water is added dropwise. After addition is completed, the reaction mixture is warmed to room temperature and stirred for 30 minutes. The solution is decanted and concentrated. The residue is dissolved in 100 ml ether and washed with saturated sodium bicarbonate and brine. The organic phase is separated, dried (MgSO4) and concentrated to give 6.52 g (68.0% yield) of phenoxypropionyl azide as a yellow oil which solidifies on cooling. IR (KBr) cm-1 : 2137 (N3), 1718 (C=O); 1H nmr (CDCl3) δ: 7.31 (m, 2H, phenyl H), 6.98 (t, 1H, J=7.5 Hz, phenyl H), 6.92 (m, 2H, phenyl H), 4.26 (t, 3H, J=6.3 Hz, CH2O), 2.84 (t, 3H, J=6.3 Hz, CH2C=O); 13C nmr (CDCl3) δ: 178.0, 159.0, 129.5(2C), 121.2, 114.7(2C), 62.9, 36.9.
Reaction SMILES: [CH3:1][C:2]([O:16][C:17](=[O:24])[CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:20]([N:19]([CH2:22][CH3:23])[C:18]1[C:17](=[O:24])[O:16][C:2]([CH3:15])([CH3:1])[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH3:21]
Reactant: CCN(CC)CC(=O)OC(C)(C)C(=O)c1ccc(S(C)(=O)=O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)C1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Temperature: 25 °C
Yield: 31 %

Procedure:
Sodium hydride, 60% dispersion (0.478 g, 11.96 mmol) was washed in hexane and suspended in DMF (5 mL). This suspension was added to a 0° C. solution of 2-(diethyl amino)acetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one-2-yl ester (1.70 g, 4.78 mmol) in DMF (20 mL). The resulting mixture was warmed to RT for 15 minutes. The mixture was diluted with ethyl acetate and quenched with water. The organic layer was washed with brine, dried over MgSO4 and concentrated to dryness. The residue was purified by swishing in ether/hexanes to give 500 mg of crystalline solid on filtration.