Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C.[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:24]([C:29]([OH:31])=O)[C@H:25]([CH2:27][CH3:28])[CH3:26].O.[NH:40]1[CH2:54][CH2:53][CH2:52][C@@H:41]1[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:24]([C:29]([N:40]1[CH2:54][CH2:53][CH2:52][C@H:41]1[C:42]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:43])=[O:31])[C@H:25]([CH2:27][CH3:28])[CH3:26]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 85 %

Procedure:
While cooling on ice, DCC (1.24 g, 6.0 mmol) and triethylamine (0.70 ml, 4.0 mmol) were added to DMF (10 ml) containing Boc-L-Ile-OH.1/2 H2O (1.39 g, 6.0 mmol), H-D-Pro-OBzl-HCl (956 mg, 4.0 mmol), and HOBt.H2O (613 mg, 4.0 mmol). After stirring for 8 hours, DMF was removed by evaporation, the residue was dissolved in ethyl acetate, and then successively washed with an aqueous 10% citric acid solution, an aqueous 4% sodium bicarbonate solution, and saturated saline. After drying over MgSO4 and concentrating, the resulting oily substance was purified by flash silica gel chromatography (4×30 cm, 1% methanol/chloroform). to obtain the oily title compound (1.63 g, 3.38 mmol, 85% yield). TLC: Rf=(CHCl3/MeOH=9/1)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1([CH:16]=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>CS(C)=O>[C:6]1([C:16]2[C:2]3[NH:1][C:5](=[CH:4][CH:3]=3)[C:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)=[C:5]3[N:1]=[C:2]([CH:3]=[CH:4]3)[C:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)=[C:2]3[NH:1][C:5]([CH:4]=[CH:3]3)=[C:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)[C:5]3=[N:1][C:2]=2[CH:3]=[CH:4]3)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: c1cc[nH]c1
Solvent: CS(C)=O
Product: C1=Cc2nc1c(-c1cccc3ccccc13)c1ccc([nH]1)c(-c1cccc3ccccc13)c1nc(c(-c3cccc4ccccc34)c3ccc([nH]3)c2-c2cccc3ccccc23)C=C1

Procedure:
Tetra-(1-naphthyl) porphine (designated TNP) was prepared from the following reactants in a DMSO solvent: pyrrole and 1-naphthaldehyde. Prior to mixing the reactants, pyrrole was distilled under an argon atmosphere with the fraction boiling at 130° C. collected. The 1-naphthaldehyde was distilled under vacuum to purify. A mixture of 6.0 g of pyrrole, 13.7 g of 1-naphthaldehyde, and 120 ml or DMSO were heated at reflux for 2 hours. The reaction solution was cooled and the DMSO solvent partially removed under vacuum. The solid that was present was filtered off and washed with 60 ml of methanol, 60 ml of hot water, and 12 ml of cold methanol. The resulting solid was then dried in a vacuum oven at ambient temperature overnight.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[C:22]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])[C:23]4[S:27][CH:26]=[N:25][C:24]=4[CH:28]=3)=[N:18][CH:19]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.[O:47]1[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[O:47]1[CH2:52][CH2:51][CH:50]([N:11]2[CH2:10][CH2:9][N:8]([C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:21]=[C:22]([O:29][C@@H:30]([C@H:32]5[CH2:36][NH:35][C:34](=[O:37])[CH2:33]5)[CH3:31])[C:23]5[S:27][CH:26]=[N:25][C:24]=5[CH:28]=4)=[N:18][CH:19]=3)[CH2:13][CH2:12]2)[CH2:49][CH2:48]1
Reactant: O=C1CCOCC1
Reactant: C[C@@H](Oc1cc(-c2ccc(N3CCNCC3)cn2)cc2ncsc12)[C@H]1CNC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@@H](Oc1cc(-c2ccc(N3CCN(C4CCOCC4)CC3)cn2)cc2ncsc12)[C@H]1CNC(=O)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
The crude TFA salt of (R)-4-((R)-1-(5-(5-(piperazin-1-yl)pyridin-2-yl)benzo[d]thiazol-7-yloxy)ethyl)pyrrolidin-2-one (4.23) described above (0.06 mmol) was dissolved in THF (1 mL) and iPr2NEt (21 μL, 0.12 mmol) was added followed by dihydro-2H-pyran-4(3H)-one (28 μL, 0.30 mmol) and sodium triacetoxyborohydride (57 mg, 0.27 mmol). The reaction mixture was stirred at 50° C. for 18 h and was diluted with water (1 mL), 5% aqueous Na2CO3 (2 mL), and EtOAc (2 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (4×1.5 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (0-25% MeOH in DCM) to yield (R)-4-((R)-1-(5-(5-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyridin-2-yl)benzo[d]thiazol-7-yloxy)ethyl)pyrrolidin-2-one (4.26). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H34N5O3S: 508.24; found: 508.41. 1H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.40-8.36 (m, 1H), 8.18 (d, J=1.2 Hz, 1H), 7.77-7.72 (m, 1H), 7.71 (s, 1H), 7.29 (dd, J=8.8, 3.0 Hz, 1H), 5.84 (s, 1H), 4.88-4.74 (m, 1H), 4.10-3.99 (m, 2H), 3.57-3.49 (m, 1H), 3.46-3.35 (m, 3H), 3.34-3.29 (m, 4H), 2.97-2.85 (m, 1H), 2.80-2.74 (m, 4H), 2.62-2.43 (m, 3H), 1.86-1.78 (m, 2H), 1.69-1.56 (m, 2H), 1.44 (d, J=6.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8](OC2CCCCO2)[C:9]([C:11]2[O:12][C:13]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]=2O)=[NH:10])[CH:5]=[CH:6][CH:7]=1.C[OH:30]>>[NH2:21][C:20]1[C:13]2[O:12][C:11]([C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:10][OH:30])=[CH:15][C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: N=C(c1oc2c(N)cccc2c1O)N(OC1CCCCO1)c1cccc(Cl)c1
Reactant: CO
Product: Nc1cccc2cc(C(=NO)Nc3cccc(Cl)c3)oc12
Yield: 62 %

Procedure:
To a methanol solution of 32 mg of N-(3-chloro-phenyl)-hydroxy-7-amino-N-(tetrahydro-pyran-2-yloxy)-benzofuran-2-carboxamidine was 200 mg of acidic Dowex resin. The resulted solution was stirred at reflux temperature for 1 h. The reaction mixture was filtered and concentrated under vacuum. The crude product was purified using a chromatotron and eluting with 5-10% methanol/dichloromethane to give 18 mg of 7-amino-N-(3-chloro-phenyl)-N′-hydroxy-benzofuran-2-carboxamidine in 62% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:16][O:17][C:18]1[N:19]=[CH:20][C:21]([CH2:24][CH2:25][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:22][CH:23]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(OC)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-methoxy-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1)[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[O:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[CH:38]=[C:37]1B(O)O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.O.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>[CH3:1][O:2][C:3](=[O:35])[CH:4]([N:12]([CH:27]([C:37]1[O:36][C:40]2=[CH:41][CH:42]=[CH:43][C:44]2=[CH:39][CH:38]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COC(=O)C(Cc1ccccc1)N(Cc1ccc(I)cc1)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
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: O
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccccc1)N(C(c1ccccc1)c1ccc2cccc-2o1)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Temperature: 65 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a degassed solution of 2-[(4-Iodo-benzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid methyl ester (40 mg, 0.068 mmol) and benzofuran-2-boronic acid (20 mg, 0.124 mmol) in a mixture of DME (3 mL) and 2M aqueous Na2CO3 (1.5 mL), Pd(PPh3)4 (4 mg) was added and the reaction mixture was stirred at 65° C. for 2 h under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, dried (Na2SO4), concentrated. The residue was purified by column chromatography using ethyl acetate and hexane (1:9) to obtain 2-[(4-Benzofuran-2-yl-benzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid methyl ester (39 mg, 100%) as a thick syrup. 1H NMR (af-2783) (CDCl3, 400 MHz): δ7.2 (d, 2H), 7.62 (d, 1H), 7.55 (d, 1H), 7.30-7.15 (m, 7H), 7.12 (d, 2H), 6.96 (s, 1H), 6.51 (s, 1H), 4.72 (m, 3H), 3.80, 3.40 (2s, 6H), 3.28 (dd, 1H), 3.02 (dd, 1H), 2.71, 2.58, 2.12 (3s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[CH:3]=1.Br[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[N:29][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:29]1[CH:30]=[C:25]([CH2:24][N:20]2[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:13](=[O:14])[C:4]3[CH:3]=[C:2]([NH2:1])[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=3)[CH2:18][CH2:19]2)[CH:26]=[CH:27][C:28]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: BrCc1ccc(-c2ccccn2)nc1
Reactant: CCOc1nc(C(=O)NCC2CCNCC2)cc(N)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1nc(C(=O)NCC2CCN(Cc3ccc(-c4ccccn4)nc3)CC2)cc(N)c1C#N

Procedure:
The compound prepared in Example 334 (0.009 g), 5-(bromomethyl)-2,2′-bipyrdine (0.008 g, prepared according to the reported preparation in Journal of the American Chemical Society, 2006, 128(1), 250-256) and cesium carbonate (0.019 g) were heated to 80° C. for 16 hours in N,N-dimethylformamide (2 mL). The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organics were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 1-4% (9:1 methanol:ammonium hydroxide)/ethyl acetate) to furnish the title compound (0.006 g) having the following physical data.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl>C(OCC)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(Br)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Br)cc1
Reaction time: 2 h

Procedure:
To a suspension of anhydride zinc chloride (11.4 g, 83.8 mmol) in diethyl ether (200 ml) was added sodium borohydride (6.34 g, 168 mmol) by small portions, and the mixture was stirred for 2 hrs. The insoluble material was removed by filtration and washed with diethyl ether. The filtrate was ice-cooled, and a solution of ethyl 3-(4-bromophenyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (20 g, 41.9 mmol) in diethyl ether (50 ml) was added. The mixture was stirred at room temperature for 2 hrs. After cooling again, 2N hydrochloric acid was added to terminate the reaction. The obtained mixture was extracted with ethyl acetate (200, 100 ml), washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1-2:1) to give the objective substance (20 g, quantitative) as a colorless oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:63])([F:62])[C:25]1[CH:26]=[C:27]([CH:55]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:57]=1)[CH2:28][N:29]1[C:33]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[C:32]([C:39]([C:41]2[C:42](CO)=[N:43][O:44][C:45]=2[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[Cl:52])=[O:40])[N:31]=[N:30]1>ClCCl.CCOC(C)=O>[F:62][C:24]([F:23])([F:63])[C:25]1[CH:26]=[C:27]([CH:55]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:57]=1)[CH2:28][N:29]1[C:33]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[C:32]([C:39](=[O:40])[CH:41]([C:45](=[O:44])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[Cl:52])[C:42]#[N:43])[N:31]=[N:30]1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-n1ccnc1)c1c(CO)noc1-c1ccccc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#CC(C(=O)c1ccccc1Cl)C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-n1ccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add Dess-Martin periodinane (1.5 g, 3.54 mmol) to a solution of [1-(3,5-Bis-trifluoromethyl-benzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone (0.7 g, 1.17 mmol) in dichloromethane (10.0 mL). Stir at RT for 4 h, dilute with EtOAc and wash with 2N NaOH, water and brine, then dry, filter, and concentrate. Recyrstallize crude material from dichloromethane to give the title compound. (0.10 g, 15%). MS [ES] 567.0 (M+H)+, 565.0 (M−H); 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.70 (s, 2H), 7.69 (s, 1H), 7.25 (br s, 2H), 7.19 (m, 2H), 7.03 (s, 1H), 6.98 (m, 1H), 5.68 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].O1CCCC1.C(Cl)(Cl)=O.[OH-].[NH4+:23]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:23])=[O:5]
Reactant: [NH4+]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: O=C(Cl)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(F)c(F)cc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
A round-bottomed flask was charged with 2-amino-4,5-difluorobenzoic acid (2 g, 11.7 mmol) and 50 mL tetrahydrofuran (THF). The flask was cooled to 0° C., whereupon a 20% solution of phosgene (6.11 mL, 11.7 mmol) in toluene was added dropwise. The reaction was stirred for 15 min at 0° C., after which a large stoichiometric excess of ammonium hydroxide was added. The reaction was then warmed to room temperature, stirred for 18 h, then washed with water, and then extracted three times with ethyl acetate. Organic layers were combined and dried over sodium sulfate, then concentrated. The product was identified as 2-amino-4,5-difluorobenzamide (1.24 g, 7.2 mmol, 62% yield). MS: M(C7H6F2N2O)=172.13, (M+H)+=173.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:3]=12.[F:25]C1C=CC(C2C=C(N)N(C)N=2)=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:25])=[CH:19][CH:18]=3)[C:3]=12
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: Cn1nc(-c2ccc(F)cc2)cc1N
Product: Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 14 was synthesised following similar procedures outlined in Example 1 (Compound 37), starting from Step 2 using 3-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-amine instead of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24].[CH3:25][N:26](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:25]([C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24])#[N:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C#N)ccc1O2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CN)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, 0.17 mol). The slurry was heated to 90° C. for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5° C., stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:27])=O)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1C=CC=CC=1>[CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:27])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CC(N)=O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(CC#N)cc1

Procedure:
A solution of 2-(4-hexadecylaminophenyl)acetamide in benzene is cooled to 10° and a stream of dry hydrogen chloride gas is bubbled in. After one-half hour an excess of thionyl chloride is added and the reaction is heated to reflux for five hours. The reaction is then cooled in ice and poured into a slurry of ice and water. Cold 50% aqueous potassium hydroxide is slowly added until the mixture is basic to litmus. The layers are then separated and the aqueous portion is extracted with more benzene. The combined benzene extracts are washed with aqueous sodium carbonate and then with water. Evaporation of the solvent and recrystallization of the residue from hexane gives (4-hexadecylaminophenyl)acetonitrile.
Reaction SMILES: [C-:1]#[N:2].[K+].F[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=1[N+:20]([O-:22])=[O:21]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=1[N+:20]([O-:22])=[O:21])#[N:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(F)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
134 mg (2.06 mmol) of potassium cyanide were added to a solution of 500 mg (1.87 mmol) of tert-butyl (2E)-3-(4-fluoro-3-nitrophenyl)acrylate in 5.4 ml of DMF. The reaction mixture was stirred at RT overnight and then purified directly by flash chromatography on silica gel (mobile phase cyclohexane/ethyl acetate mixture). This gave 57 mg (11% of theory) of the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:14]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][C@H:9]1[C@H:14]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH2:13][CH2:12][NH:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CNCC[C@H]1N1CCOCC1
Yield: 93.5 %

Procedure:
A mixture of (+/−)-(3R,4R)-benzyl 3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidine-1-carboxylate (Isomer A, 0.43 g, 0.989 mmol) and Pd/C (0.063 g, 0.030 mmol) in methanol (20 mL) was hydrogenated at 30 psi overnight. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. (+/−)-4-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)morpholine (278 mg) was obtained as a colorless oil. The crude was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[C:37]([F:39])[C:36]([S:40](=[O:59])(=[O:58])[N:41](CC3C=CC(OC)=CC=3OC)[C:42]3[S:46][N:45]=[CH:44][N:43]=3)=[CH:35][C:34]=2[F:60])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3ON=[C:13]([N:16]([C:24](OC(C)(C)C)=[O:25])C(OC(C)(C)C)=O)[C:12]=3[CH:31]=2)[CH:7]=1.ClC1C=CC(OC2C(F)=CC(S(N(CC3C=CC(OC)=CC=3OC)C3SN=CN=3)(=O)=O)=C(F)C=2)=C(C2C=C3C(=CC=2)NC(=O)C3)C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[C:34]([F:60])=[CH:35][C:36]([S:40]([NH:41][C:42]3[S:46][N:45]=[CH:44][N:43]=3)(=[O:59])=[O:58])=[C:37]([F:39])[CH:38]=2)=[C:6]([C:8]2[CH:31]=[C:12]3[C:13](=[CH:10][CH:9]=2)[NH:16][C:24](=[O:25])[CH2:11]3)[CH:7]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Agent: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4c(c3)CC(=O)N4)cc2F)c(OC)c1
Product: O=C1Cc2cc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4ncns4)cc3F)ccc2N1
Yield: 53 %

Procedure:
Following the procedure as described in EXAMPLE 44, making non-critical variations to replace di-tert-butyl [5-(5-chloro-2-{4-[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)sulfamoyl]-2,5-difluorophenoxy}phenyl)-1,2-benzoxazol-3-yl]imidodicarbonate with 4-(4-chloro-2-(2-oxoindolin-5-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, 4-(4-chloro-2-(2-oxoindolin-5-yl)phenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide was obtained as an off-white solid in 53% yield over two steps (0.03 g): 1H NMR (300 MHz, DMSO-d6) δ10.48 (s, 1H), 8.52 (s, 1H), 7.74 (dd, J=9.9, J=6.4 Hz, 1H), 7.52 (d, J=2.6 Hz, 1H), 7.43 (dd, J=8.7, 2.6 Hz, 1H), 7.35 (br s, 1H), 7.31 (dd, J=8.1, 1.4 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 7.09 (dd, J=10.5, 6.5 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 3.47 (s, 2H), (NH not observed); MS (ES+) m/z 534.8 (M+1), 536.8 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[C-:12]#[N:13].[Na+].C(Cl)Cl.C([O-])(O)=O.[Na+]>CCO.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:12]#[N:13])[CH:5]=[N:4][C:3]=1[O:10][CH3:11]
Reactant: [C-]#N
Reactant: COc1ncc(CBr)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1ncc(CC#N)cc1Br
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 3-bromo-5-bromomethyl-2-methoxy-pyridine (1.42 g, 5.05 mmol) in EtOH (14 mL) and H2O (1.5 mL) was added sodium cyanide (0.25 g, 5.05 mmol), and the reaction was stirred at 50° C. overnight. The mixture was cooled to room temperature and worked up with CH2Cl2 and saturated aqueous NaHCO3. The combined organic layers were dried, filtered, and concentrated to give (5-bromo-6-methoxy-pyridin-3-yl)-acetonitrile.