Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH:12]=[O:13])=[C:10]3[C:14]([CH3:21])([C:19]#[N:20])[CH2:15][C:16]([CH3:18])([CH3:17])[C:9]3=[C:8]2[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:24].[K+].N1C=CC=CC=1>O>[C:1]1([N:7]2[C:11]([C:12]([OH:24])=[O:13])=[C:10]3[C:14]([CH3:21])([C:19]#[N:20])[CH2:15][C:16]([CH3:17])([CH3:18])[C:9]3=[C:8]2[CH3:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1c2c(c(C=O)n1-c1ccccc1)C(C)(C#N)CC2(C)C
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1c2c(c(C(=O)O)n1-c1ccccc1)C(C)(C#N)CC2(C)C

Procedure:
Following a procedure similar to that described in Example 13C, 17.48 g. (0.06 mole) of 2-phenyl-3-formyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carbonitrile was oxidized with 18.9 g. (0.12 mole) of potassium permanganate in 120 ml. of pyridine and 90 ml. of water to give 4.03 o 2-phenyl-3-carboxy-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carbonitrile which was esterified by reaction of 9.83 g. (0.032 mole) of the acid with 1.713 g. (0.035 mole) of a 50% mineral oil dispersion of sodium hydride followed by 2.23 ml (0.036 mole) of methyl iodide. There was thus obtained 4.18 g. of 2-phenyl-3-carbomethoxy-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carbonitrile.
Reaction SMILES: F[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:12]2=[O:15])=[CH:8][CH:7]=1.[CH2:22](OC1C=C2C(CCC2=O)=CC=1)C(C)C.C(OC)(=O)C=C>>[CH2:4]([O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:12]2=[O:15])=[CH:8][CH:7]=1)[CH:3]([CH3:22])[CH3:2]
Reactant: O=C1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=O
Reactant: CC(C)COc1ccc2c(c1)C(=O)CC2
Solvent: C=CC(=O)OC
Product: CC(C)COc1ccc2c(c1)C(=O)C1(CCC(=O)CC1)C2
Yield: 72 %

Procedure:
The title compound (3.02 g, 72% yield) was prepared using the method described for Intermediate 63 starting from 6-isobutoxy-2,3-dihydro-1H-inden-1-one (Intermediate 66, 3.0 g, 14.7 mmol) and methyl acrylate (2.92 mL, 32.3 mmol): 1H NMR (400 MHz, CDCl3) δ ppm 1.04 (m, 8H) 1.86 (m, 2H) 2.11 (dt, 1H) 2.21 (m, 2H) 2.47 (m, 3H) 2.70 (m, 2H) 3.15 (s, 2H) 3.76 (m, 3H) 7.20 (m, 1H) 7.25 (m, 1H) 7.38 (d, 1H); MS (ES+) m/z 287 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:22]4[N:23]=[C:24]([NH:26][C:27]([CH:29]5[CH2:31][CH2:30]5)=[O:28])[N:25]=[C:21]4[CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>C(OCC)(=O)C>[N:2]1[NH:32][N:33]=[N:34][C:1]=1[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:22]4[N:23]=[C:24]([NH:26][C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[N:25]=[C:21]4[CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2cccc(-c3ccc(OCc4ccc(-c5nn[nH]n5)nc4)cc3)n2n1)C1CC1
Reaction time: 16 h
Yield: 5.7 %

Procedure:
A solution of cyclopropanecarboxylic acid {5-[4-(6-cyano-pyridin-3-ylmethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amide (143 mg, 0.35 mmol, 1 equiv), sodium azide (46 mg, 0.7 mmol, 2 equiv), ammonium chloride (38 mg, 0.7 mmol, 2 equiv) was stirred at 0° C. under nitrogen for 30 minutes. Afterwards the mixture was subjected for 100° C. for 16 hours. The crude of the reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over MgSO4, filtered, and dried under vacuum. The crude was diluted with DMSO and submitted for preparative HPLC purification: UPLC system (XBridge™ Prep C18, 5 μm, 19×100 mm column); 8 min LC; flow: 20 mL/min; gradient: from 30% to 70% acetonitrile in water 0.1% TFA; to afford the final pure product (9 mg, 6% yield).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:47]([N:54]1[CH:62]=[C:61]2[C:56]([CH:57]=[C:58]([C:63]3[CH:64]=[C:65]([CH:73]4[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]4)[N:66]4[C:71]=3[C:70]([NH2:72])=[N:69][CH:68]=[N:67]4)[CH:59]=[CH:60]2)=[N:55]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:24][CH2:23][CH2:22][CH:18]1[C:19]([N:76]1[CH2:77][CH2:78][CH:73]([C:65]2[N:66]3[C:71]([C:70]([NH2:72])=[N:69][CH:68]=[N:67]3)=[C:63]([C:58]3[CH:59]=[CH:60][C:61]4[C:56]([CH:57]=3)=[N:55][N:54]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:62]=4)[CH:64]=2)[CH2:74][CH2:75]1)=[O:21])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N,N-Diisopropylethylamine (35.0 μL, 0.200 mmol, 2.0 eq.) was added to N-(tert-butoxycarbonyl)-L-proline (23.7 mg, 0.110 mmol, 1.1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.2 mg, 0.100 mmol, 1.0 eq), 1-hydroxybenzotriazole (13.5 mg, 0.100 mmol, 1.0 eq) and 1 mL of anhydrous DMF. The reaction was cooled to 0° C. and shaken for 30 minutes. Then to this mixture was added 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (42.3 mg, 0.1 mmol, 1.0 eq.) in 1 mL of anhydrous DMF. The reaction was shaken for 5 minutes at 0° C. The reaction was slowly warmed to rt and shaken over night. The product was purified by acidic HPLC on a Sunfire column (5% to 90%, 12 min).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]=[CH:4]1)[CH3:2].S(Cl)(Cl)=O.N1C=CC=CC=1.[CH2:21]([C:23]1[C:28]([NH2:29])=[CH:27][N:26]=[CH:25][N:24]=1)[CH3:22]>C1COCC1>[CH2:21]([C:23]1[C:28]([NH:29][C:8]([C:6]2[N:5]=[CH:4][N:3]([CH2:1][CH3:2])[CH:7]=2)=[O:10])=[CH:27][N:26]=[CH:25][N:24]=1)[CH3:22]
Reactant: CCn1cnc(C(=O)O)c1
Reactant: CCc1ncncc1N
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCc1ncncc1NC(=O)c1cn(CC)cn1

Procedure:
A solution of 1-ethyl-1H-imidazole-4-carboxylic acid (2.5 g, 17.8 mmol) and thionyl chloride (65 mL) is refluxed for 1.5 h. The thionyl chloride is removed in vacuo using toluene to azeotrope thionyl chloride. To a suspension of the residue is added THF (60 mL) and pyridine (3.2 mL, 39.2 mmol), followed by 4-ethyl-5-pyrimidineamine (2.2 g, 17.8 mmol). The reaction mixture is refluxed for 17 h, and concentrated in vacuo. The residue is taken up in water (100 mL), and the pH of the solution is adjusted to 8.0 by the addition of solid potassium carbonate. The aqueous layer is extracted with methylene chloride (3×100 mL). The organic extracts are combined, dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (300 g) using 3% MeOH in CH2Cl2 as eluent. The product fractions are combined and the solvent removed. The resultant material is triturated with ether+MeOH (19+1) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(O)c(C(=O)O)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1

Procedure:
A solution of 5.0 g. (0.03 mole) of 2-hydroxy-5-methoxybenzoic acid in 50 ml. of dimethylformamide is treated with 2.5 g. (0.06 mole) of sodium hydride in a 56.6% oil suspension, followed by the addition of 7.6 g. (0.06 mole) of benzyl chloride. The resulting mixture is heated at 98°-103° C. for one hour, after which the insolubles are filtered, the filtrate diluted with 100 ml. of water and the aqueous solution extracted with ether. The aqueous phase is discarded and the ether phase dried over sodium sulfate and evaporated to provide the intermediate, benzyl 2-benzyloxy-5-methoxybenzoate, as an oil, 5.0 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9](I)[CH:10]=1)=[O:4].[CH2:19]([NH2:21])[CH3:20].C1CCN2C(=NCCC2)CC1.C1C[O:36][CH2:35]C1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([C:35](=[O:36])[NH:21][CH2:19][CH3:20])[CH:10]=1)=[O:4]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Reactant: CCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Yield: 50 %

Procedure:
A 20 mL of vial was charged with 5-iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester (500 mg, 1.42 mmol), Pd(OAc)2 (9.6 mg, 0.043 mmol), Mo(CO)6 (413.5 mg, 1.566 mmol), ethylamine (2.0 M in MeOH, 1.068 mL, 2.136 mmol), DBU (426 uL, 2.848 mmol) and dry THF (10 mL). The vial was immediately capped with a Teflon septum under air and irradiated with microwaves to 100° C. for 15 minutes. After cooling, the reaction mixture was filtered through a short celite pad and the solvent, and excess DBU was removed under reduced pressure. The residue was purified by preparative HPLC to afford 210 mg of 5-ethylcarbamoyl-4′-methyl-biphenyl-3-carboxylic acid methyl ester (yield 50%). MS (M+H)=298.
Reaction SMILES: Cl.[S:2]1[N:6]=[CH:5][C:4]([C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8])=[N:3]1>O1CCOCC1>[S:2]1[N:6]=[CH:5][C:4]([C:7]([NH:9][NH2:10])=[O:8])=[N:3]1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1cnsn1
Agent: Cl
Solvent: C1COCCO1
Product: NNC(=O)c1cnsn1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
4M HCl (6.60 ml, 26.4 mmol) in 1,4-dioxane was added to 1,1-dimethylethyl 2-(1,2,5-thiadiazol-3-ylcarbonyl)hydrazinecarboxylate (I118) (1.29 g, 5.28 mmol). The reaction mixture was stirred at room temperature for 7 h. The solvent was evaporated under reduced pressure. The crude product was purified by SCX cartridge (2 batches of 500 mg each—MeOH/2M NH3 in MeOH to afford the desired product in 361.4 mg as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.C[C:23]1[CH:30]=[C:29](O)[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26]>>[CH:25]([C:24]1[CH:27]=[CH:28][C:29]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:30][CH:23]=1)=[O:26]
Reactant: Cc1cc(O)ccc1C=O
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCOc2ccc(C=O)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and methyl 4-hydroxybenzaldehyde: 1H NMR (300 MHz, CDC3) δ 9.89 (s, 1H), 7.88-7.80 (m, 2H), 7.68 (d, J=8.9 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.02 (dd, J=8.8, 2.7 Hz, 1H, partially overlapped with 6.99-6.93), 6.99-6.93 (m, 2H), 4.31 (t, J=5.2 Hz, 2H), 4.20 (q, J=8.5 Hz, 2H), 4.05 (t, J=5.2 Hz, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[O:18])[N:14]([O:16][CH3:17])[CH3:15])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.CO>[NH2:7][C@@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([N:14]([O:16][CH3:17])[CH3:15])=[O:18]
Reactant: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CON(C)C(=O)[C@@H](N)C(C)(C)C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
To a solution of [1(S)-(methoxy-methyl-carbamoyl)-2,2-dimethylpropyl]-carbamic acid-tert-butyl ester (1.686 g, 6.15 mmol) in dichloromethane (20 mL) at 0° C. was added trifluoroacetic acid (17 mL). The reaction was allowed to stand for 16 hours at <5° C. before the solvents were removed in vacuo to give a bright yellow oil. The residue was dissolved in methanol (30 mL) and was treated portionwise with Dowex 1X8-400 basic resin until pH 9. Filtration and removal of the solvents in vacuo gave the title compound as a pale yellow oil (990 mg, 92%). The material was used without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1.C(OC([N:23]=[C:24]([N:26](C(OC(C)(C)C)=O)[O:27][CH2:28][CH2:29][NH:30][C:31](=[O:54])[CH2:32][C:33]1[C:38]([C:39]#[N:40])=[CH:37][CH:36]=[C:35]([NH:41][CH2:42][C:43]([F:52])([F:51])[C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=2)[C:34]=1[F:53])[NH2:25])=O)(C)(C)C>C(Cl)Cl>[C:24]([NH:26][O:27][CH2:28][CH2:29][NH:30][C:31](=[O:54])[CH2:32][C:33]1[C:38]([C:39]#[N:40])=[CH:37][CH:36]=[C:35]([NH:41][CH2:42][C:43]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=2)([F:51])[F:52])[C:34]=1[F:53])(=[NH:23])[NH2:25]
Reactant: CC(C)(C)OC(=O)N=C(N)N(OCCNC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2cccc(Cl)c2)c1F)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NCC(F)(F)c2cccc(Cl)c2)c(F)c1CC(=O)NCCONC(=N)N
Reaction time: 10 h
Yield: 84.1 %

Procedure:
A solution of TFA (7.5 mL, 97 mmol) and anisole (3.0 mL, 27.6 mmol) in DCM (23 mL) was added to N-[2-(N′,N″-bis(tert-butoxycarbonyl)amidinoaminooxy)ethyl]-2-{3-[(2,2-difluoro-2-(3-chlorophenyl)ethyl)amino]-6-cyano-2-fluorophenyl}acetamide (2.18 g, 3.26 mmol), as prepared in the preceding step, at room temperature. The dark yellow solution was stirred for 10 h, and then concentrated. The residue was subjected to flash chromatography (DCM/MeOH saturated with gaseous NH3; 95:5→90:10) to yield 1.286 g (84%) of the title compound as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.57-7.55 (m, 1H), 7.51-7.40 (m, 3H), 7.27 (dd, J=8.6 Hz, 1.3 Hz, 1H), 6.77 (t, J=8.4 Hz, 1H), 3.93 (t, J=13.6 Hz, 2H), 3.80 (t, J=5.4 Hz, 2H), 3.74 (d, J=2.0 Hz, 2H), 3.43 (t, J=5.4 Hz, 2H). LC/MS (ESI) calcd for C20H21ClF3N6O2 (MH+) 469.1. found 469.2.
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=O)=O.[N-:23]=[N+]=[N-].[Na+].C(O)C>CN(C=O)C.[Pd]>[NH2:23][CH2:6][CH:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC(COS(C)(=O)=O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Pd]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CN)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)ethyl methanesulfonate (Intermediate 23) (535 mg, 1.53 mmol) in DMF (8 mL) was treated with sodium azide (199 mg, 3.06 mmol) and the mixture was heated at 80° C. for 1 hour. The mixture was cooled and allowed to stir at room temperature overnight. The solution was partitioned between ethyl acetate and water. The organic layer was washed twice with water then dried with magnesium sulfate, filtered and concentrated until the final volume was approximately 5 mL. Ethanol (20 mL) and 10% palladium on carbon (75 mg, 0.07 mmol) were added. The resulting suspension was stirred under an atmosphere of hydrogen at ambient pressure and temperature for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 2-amino-1-(4-chlorophenyl)ethylcarbamate as a gum (410 mg, 99%).
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH2:5]([CH2:7][NH2:8])[OH:6].Cl.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>O.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>[OH:6][CH2:5][CH2:7][NH:8][C:10](=[O:2])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: NCCO
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCO)c1ccncc1

Procedure:
To a mixture of 1.69 g of the nitric ester of monoethanolamine nitrate in 5 ml of water, 3.8 ml of 35% potassium carbonate solution and 17 ml of tetrahydrofuran were added alternately 3 g of isonicotinyl chloride hydrochloride and 11.2 ml of 35% potassium carbonate aqueous solution over 30 minutes under stirring at 0° to 5° C. The reaction mixture was stirred for an additional 15 minutes, and the organic layer was separated. The aqueous layer was extracted with tetrahydrofuran and the extract was combined with the previously separated organic layer. The combined organic layers were dried over anhydrous sodium sulfate and filtered. Evaporation of the solvent in vacuo and crystallization of the residue afforded the nitric ester of N-(2-hydroxyethyl) isonicotinamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([NH:48][CH:49]2[CH2:51][CH2:50]2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>O1CCCC1>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([N:48]([C:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:10])[CH:49]2[CH2:50][CH2:51]2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: O=C(O)c1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2-chloropyrimidine-5-carboxylic acid (2.00 g), ethyldiisopropylamine (6.39 mL), and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (4.21 g) in tetrahydrofuran (15 mL) is stirred for 45 min at room temperature prior to the addition of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (2.94 g). The resulting mixture is stirred at room temperature for 1 h. The solvent is evaporated in vacuo and the residue purified by HPLC(H2O/MeOH/TFA). LC (method 3): tR=1.89 min; Mass spectrum (ESI+): m/z=381/383 (Cl) [M+H]+.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]/[C:4]#[N:5].[C:7](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:21])[CH2:8][C:9](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:10].CCOCC>COCCOCCOC>[OH:21][C:7]1[C:3]([C:4]#[N:5])=[C:2]([CH3:6])[NH:1][C:9](=[O:10])[CH:8]=1
Reactant: C/C(N)=C\C#N
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: COCCOCCOC
Solvent: CCOCC
Product: Cc1[nH]c(=O)cc(O)c1C#N
Temperature: 120 °C

Procedure:
A mixture of (E)-3-aminobut-2-enenitrile (9.7 g, 118 mmol) and bis(2,4,6-trichlorophenyl) malonate (58.4 g, 126 mmol) in diglyme (120 ml) was heated to 120° C. for 2.5 hr. The mixture was cooled to RT and poured into Et2O and filtered to collect the precipitate. The precipitate was washed with Et20 to obtain 4-hydroxy-2-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile. MS ESI calc'd. for C7H7N2O2 [M+H]+ 151. found 151.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]1([CH2:41][O:42][C:43]2[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([CH2:41][O:42][C:43]2[CH:44]=[C:45]([C:2]3[CH:35]=[CH:34][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:21]=[CH:22][C:23]([N:26]6[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]6)=[CH:24][CH:25]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:11]=4)=[CH:4][CH:3]=3)[CH:46]=[CH:47][CH:48]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: OB(O)c1cccc(OCC2CCCC2)c1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4cccc(OCC5CCCC5)c4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 3-(cyclopentylmethoxy)phenylboronic acid (44 mg, 0.2 mmol, prepared according to general procedure H) to give 5-{4-[2-(3′-cyclopentylmethoxy-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCc1cc(OC)ccc1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(O)ccc1F
Temperature: -15 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
To a solution of ethyl 3-(2-fluoro-5-methoxyphenyl)propanoate (100 mg) in dichloromethane (3.0 mL) was added dropwise a 1.0 M solution of boron tribromide in dichloromethane (0.15 mL) at −15° C., and the mixture was stirred at −15° C. for 5 hr. Water (20 ml) was added dropwise to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (60 mg) as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C@@H:22]2[CH2:26][C:25]([F:28])([F:27])[CH2:24][N:23]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[N:8]([CH3:21])[C:9](=[O:20])[C:10]=1[O:11]C(=O)C1C=CC=CC=1)=O.[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1>CO>[CH2:32]([O:31][C:29]([N:23]1[CH2:24][C:25]([F:28])([F:27])[CH2:26][C@H:22]1[C:7]1[N:8]([CH3:21])[C:9](=[O:20])[C:10]([OH:11])=[C:5]([C:3]([NH:45][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([F:39])=[CH:41][CH:42]=2)=[O:2])[N:6]=1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc([C@@H]2CC(F)(F)CN2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Solvent: CO
Product: Cn1c([C@@H]2CC(F)(F)CN2C(=O)OCc2ccccc2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
Methyl-5-(benzoyloxy)-2-{(2S)-1-[(benzyloxy)carbonyl]4,4-difluoropyrrolidin-2-yl}-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate in dry MeOH was treated with 4-fluorobenzyl amine (2.5 eq.) at reflux for 2 hours. Solvent was removed in vacuo and the residue was taken up in ethyl acetate, washed with HCl 1N, brine, dried over Na2SO4. The filtrate was concentrated in vacuo and triturated with ethyl ether to obtain the title compound as a 1.5:1 mixture of two rotamers by NMR.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]#[CH:12])=[C:4]([N+:13]([O-])=O)[CH:3]=1>[Fe].O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]#[CH:12])=[C:4]([NH2:13])[CH:3]=1
Reactant: C#CCCOc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: C#CCCOc1ccc(Br)cc1N
Yield: 89.3 %

Procedure:
4-Bromo-1-but-3-ynyloxy-2-nitro-benzene (82% pure, 4.22 g, 12.5 mmol) was heated in a mixture of IMS (Industrial Methylated Spirits, 40 mL) and glacial acetic acid (2 mL) at approx. 50° C. until a solution was formed. Iron powder (5.05 g, 89.8 mmol) and iron (III) chloride hexahydrate (0.56 g, 1.56 mmol) were added and the mixture was heated under reflux for 18 h. The cooled mixture was filtered through Celite®, and washed through with ethyl acetate. The filtrate was washed with water, followed by brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 10 to 20% ethyl acetate in cyclohexane) to give 5-Bromo-2-but-3-ynyloxy-phenylamine as an orange oil (2.68 g, 89%). LCMS: RT=4.10 min, M+H+=240/242.