Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([CH3:18])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([C:30]3[N:31]=[C:32]4[C:38]([C:39](O)=[O:40])=[CH:37][N:36]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:33]4=[N:34][CH:35]=3)=[N:25][N:26]2[CH3:29])=[CH:22][CH:21]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(#N)C.C(OCC)(=O)C.O>[F:17][C@H:14]1[CH2:15][CH2:16][N:12]([C:10](=[O:11])[C@H:9]([NH:8][C:39]([C:38]2[C:32]3[C:33](=[N:34][CH:35]=[C:30]([C:24]4[C:23]5[C:27](=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=5)[N:26]([CH3:29])[N:25]=4)[N:31]=3)[N:36]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:37]=2)=[O:40])[CH3:18])[CH2:13]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: C[C@@H](N)C(=O)N1CC[C@H](F)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
(R)-2-Amino-1-((S)-3-fluoro-pyrrolidin-1-yl)-propan-1-one trifluoroacetate (crude from Step 2) was dissolved in acetonitrile (4 ml) to which was then added 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (60 mg, 0.13 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (63 mg, 0.197 mmol) and N,N-diisopropylethylamine (0.092 ml, 0.52 mmol). The reaction was stirred at room temperature for 18 h and then water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford 55 mg (70%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-amide. 1H NMR (300 MHz, CDCl3) δ: 9.29 (s, 1H), 8.88-8.93 (m, 1H), 8.85 (d, J=8.1 Hz, 1H), 8.32 (s, 1H), 7.43-7.46 (m, 1H), 7.35-7.39 (m, 1H), 5.70-5.74 (m, 2H), 5.21-5.26 (m, 1H), 4.15 (s, 3H), 3.61-4.00 (m, 5H), 3.54-3.61 (m, 2H), 2.06-2.46 (m, 2H), 1.59 (d, J=6.6 Hz, 3H), 0.90-0.97 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][N:26]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH2:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCN
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of compound 4 (1.0 g, 2.4 mmol) in ethanol (20 mL) was added 10% Pd/C (0.3 g) and acetic acid (0.3 mL). The resulting mixture was stirred under an atmosphere of hydrogen for 16 hours and then filtered to remove Pd/C. The filtrate was concentrated in vacuo and the residue was loaded onto a silica gel gravity column (100 g) and eluted with CH2Cl2:MeOH 20:1 to 10:1 (v/v) to afford compound 5 as a oil (0.90 g, 96%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=3)[C:14]([NH:16][C:17]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18]3)=[O:15])[CH:9]=2)[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.[CH3:36]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.CCOC(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>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:3]2[O:4][C:5]3=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=4)[C:14]([NH:16][C:17]4([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:18][CH2:19]4)=[O:15])[CH:9]=[C:10]3[C:2]=2[CH3:36])=[CH:34][CH:33]=1
Reactant: O=C(NC1(c2ccccc2)CC1)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reactant: CB1OB(C)OB(C)O1
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: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
Pd(Ph3P)4 (16 mg, 0.014 mmol) was added to a stirring solution of 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-N-(1-phenylcyclopropyl)benzamide (75 mg, 0.14 mmol), trimethylboroxine (40 μL, 0.28 mmol), and Na2CO3 (45 mg, 0.43 mmol) in DMF (1.3 mL) and Water (0.13 mL) at room temperature. It was subjected to microwave irradiation: 180° C. for 30 min. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N-(1-phenylcyclopropyl)benzamide (61 mg, 0.132 mmol, 93% yield) consistent by LCMS. LC-MS retention time: 1.81 min; m/z (MH+): 463. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)[CH2:26][CH2:25]2)[CH:19]=1)=[O:16]
Reactant: O=Cc1ccnc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccnc4ccccc34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-quinolinecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 388.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26]([F:44])[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26]([F:44])[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Reaction time: 96 h
Yield: 78.6 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate (0.19 g, 0.29 mmol, 1 equiv) in MeOH (6 mL) was added 10% Pd/C (62 mg, 0.058 mmol, 0.2 equiv). The reaction was then stirred under a balloon of H2 for 4 d. More 10% Pd/C (62 mg, 0.058 mmol, 0.2 equiv) was added. After 5 h, the reaction was then filtered through Celite eluting with MeOH. The filtrate was then concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (0.15 g, 79%) as a colorless glass. LCMS (ESI, M+1): 658.5.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH:31]=O)([CH2:18][CH2:19][CH2:20][CH2:21][B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:31][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH2:18][CH2:19][CH2:20][CH2:21][B:22]1[O:23][C:24]([CH3:30])([CH3:29])[C:25]([CH3:27])([CH3:28])[O:26]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C(C=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CN1CCCCC1)NC(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A solution of ethyl 2-(benzyloxycarbonylamino)-2-formyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (0.503 g, 1.13 mmol), piperidine (0.39 mL, 4 mmol) and acetic acid (0.23 mL, 4 mmol) in 1,2-dichloroethane (20 mL) was stirred for 15 minutes then treated with sodium triacetoxyborohydride (0.85 g, 4 mmol). After stirring for 2 h at 65° C. the solution was cooled to room temperature and concentrated. The resulting residue was purified using a combiflash system (12 g silica gel column, 10-100% ethyl acetate in heptanes) to give ethyl 2-(benzyloxycarbonylamino)-2-(piperidin-1-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (300 mg, 52%). 1H NMR (CDCl3) δ: 7.36 (m, 5H), 6.05 (bs, 1H), 5.14 (d, 1H), 5.03 (d, J=11.2 Hz, 1H), 4.19 (m, 2H), 3.06 (d, J=13.8 Hz, 1H,), 2.59 (d, J=13.8 Hz, 1H), 2.34 (m, 4H), 2.15 (m, 1H), 1.78-1.70 (m, 1H), 1.45-1.25 (m, 12H), 1.22 (s, 12H), 1.02 (m, 1H), 0.73 (t, J=7.8 Hz, 2H). MS found for C28H45BN2O7 m/z[517(M+1)].
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Br[C:13]1[CH:22]=[CH:21][C:16]([NH:17][C:18](=[O:20])[CH3:19])=[CH:15][CH:14]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[C:18]([NH:17][C:16]1[CH:21]=[CH:22][C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:15]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: CC(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol, 2.0 mol %), phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and 4′-bromoacetanilide (214 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 182 mg (86%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1>[Ni].O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)=[N:6][CH:7]=1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2[N+](=O)[O-])cc1)C(=O)O
Agent: [Ni]
Solvent: C1COCCO1
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2N)cc1)C(=O)O
Yield: 54.9 %

Procedure:
20 g of Raney nickel catalyst are added to a solution of 196 g of 2-(4-(5-chloro-3-nitropyridin-2-yloxy)phenoxy)propionic acid in 615 g of dioxane, and hydrogenation is subsequently carried out at 20°-22° C. under normal pressure. After separating the catalyst the solvent is removed, giving 98 g of 2-(4-(5-chloro-3-aminopyridin-2-yloxy)phenoxy)propionic acid as crude product (55% of theory) which has a melting point of 152°-154° C. and can be recrystallised from toluene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:11]/N(C)C)/[CH:9]=O)=[CH:4][CH:3]=1.Cl.[NH2:16][C:17]([NH2:19])=[NH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:18][C:17]([NH2:19])=[N:16][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CN(C)/C=C(\C=O)c1ccc(Br)cc1
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ncc(-c2ccc(Br)cc2)cn1
Temperature: 80 °C
Yield: 96 %

Procedure:
A mixture of (Z)-2-(4-bromophenyl)-3-(dimethylamino)acrylaldehyde (1.27 g, 5 mmol), guanidine hydrochloride (0.525 g, 5.5 mmol) and potassium carbonate (1.38 g, 10 mmol) in ethanol (10 mL) was heated at 80° C. overnight. After cooling, the reaction mixture was filtered, washed with methanol and water, and dried under high vacuum to give the desired product (1.2 g, 96%). LCMS: (M+H)=249.9/251.9.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH:8]=[CH:13][C:14]([OH:16])=[O:15])=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(C=O)c(Cl)nc1C
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1cc(C=CC(=O)O)c(Cl)nc1C
Yield: 87 %

Procedure:
A mixture of 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (16.85 g), malonic acid (11.45 g), piperidine (10 ml) and pyridine (100 ml) was heated under reflux for 1 hour and evaporated to an oil. This oil was dissolved in sodium hydroxide solution and was extracted with chloroform, the residual aqueous phase was acidified with hydrochloric acid and extracted with chloroform. The second chloroform extracts were washed with water and evaporated to give 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylic acid (18.3 g, 87%), m.p. 150°-8°. This acid was esterified using ethanol and sulphuric acid to give the ethyl ester, m.p. 85°-8°.
Reaction SMILES: CS(O)(=O)=O.C(OC([N:13]1[CH2:18][CH2:17][C:16]2=[N:19][N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:21](=[O:22])[C:15]2([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:14]1)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][C:15]12[C:21](=[O:22])[N:20]([CH2:23][C:24]([F:26])([F:27])[F:25])[N:19]=[C:16]1[CH2:17][CH2:18][NH:13][CH2:14]2
Reactant: CC(C)(C)OC(=O)N1CCC2=NN(CC(F)(F)F)C(=O)C2(Cc2ccccn2)C1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1N(CC(F)(F)F)N=C2CCNCC12Cc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Methanesulfonic acid (11.6 g, 121 mmol) was added dropwise to a solution of the product from step B (10 g, 24.2 mmol) in CH2Cl2 (100 mL) over about 30 minutes. The reaction mixture was stirred for about 1 hour, then cooled to about 0° C., and then triethylamine (18.6 mL, 133.1 mmol) was added through an addition funnel. The mixture was allowed to warm to room temperature over about 1 hour, diluted with additional CH2Cl2 and washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated in vacuo to afford the product as a white solid (7.2 g). 1H-NMR (CDCl3) δ: 2.51-2.72 (m, 4H), 3.35 (m, 2H), 3.49 (m, 2H), 4.03 (m, 1H), 4.25 (m, 1H), 7.08 (d, 2H), 7.51 (t, 1H), 8.37 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:12]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:12][O:10][C:9]([C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([Cl:8])[N:4]=1)=[O:11]
Reactant: Nc1ccc(Cl)nc1C(=O)O
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1nc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Amino-6-chloro-pyridine-2-carboxylic acid (636 mg) was suspended in methanol (8 mL) and toluene (22 mL) was added. A solution of (trimethylsilyl)diazomethane (2.0 M in hexane, 2.4 mL) was added slowly to the reaction mixture. After 1 hour stirring at room temperature, another portion of (trimethylsilyl)diazomethane (550 μl) was added and the mixture was stirred for additional 45 minutes. The reaction mixture was quenched with water and extracted 3× with ethyl acetate. The combined organic layer was washed with 2N hydrochloric acid, saturated bicarbonate solution and brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica gel 60, choroform/ethyl acetate=50:1, Rf=0.30) to afford 365 mg of the title compound of the formula
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:42][S:43][CH2:44][C@H:45]([O:61][C:62](=[O:74])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:46][O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:41])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])([F:32])[F:31])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.C1(C)C=CC=CC=1>C(#N)C>[NH2:18][C@@H:19]([CH2:42][S:43][CH2:44][C@H:45]([O:61][C:62](=[O:74])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:46][O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:41])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])([F:32])[F:31]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Temperature: 25 °C

Procedure:
To a solution of diethyl(12R,16R)-12-(((9H-fluoren-9-yl)methoxy)carbonylamino)-16-(dodecanoyloxy)-1,1-difluoro-11,19-dioxo-4,7,18-trioxa-14-thia-10-azatriacontylphosphonate (1 eq) was added 20% piperidine (50 eq) in acetonitrile The resulting mixture was stirred at 25° C. until the smarting material disappeared. To the mixture was added toluene and then concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 100% EtOAc then 0-10% MeOH/DCM to give the product as a colorless oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:22]=[CH:21][C:11]3[NH:12][C:13]([C:15]4[C:19]([NH2:20])=[CH:18][NH:17][N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C1COCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:11](=[CH:21][CH:22]=2)[N:12]=[C:13]2[N:14]3[C:23](=[O:24])[NH:20][C:19]3[C:15]2=[N:16][NH:17][CH:18]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Solvent: C1CCOC1
Product: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a mixture of 3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (3.2 g, 10.7 mmol) in anhydrous THF (50 mL) stirring at ambient temperature was added 1,1′-carbonyldiimidazole (1.78 g, 11 mmol). The mixture was heated at reflux for 14 h and then cooled to ambient. The solid formed was collected by filtration, washed with THF (20 mL) and dried in vacuo to give 7-morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[a]fluoren-5-one (2.34 g, 67%) as a pink solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1

Procedure:
For example, N-benzyloxycarbonyl-L-aspartic acid is dissolved in a large excess of acetic anhydride, the acetic acid formed by the reaction and the excess acetic anhydride are distilled off under reduced pressure and the effect of any acetic acid remaining in the residue is removed by the addition of an organic solvent to give N-benzyloxycarbonyl-L-aspartic anhydride [J. Am. Chem. Soc., 81, 167-173 (1959)].
Reaction SMILES: [N:1]1[CH:6]=[C:5]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[C:16]([S@:20]([NH2:22])=[O:21])([CH3:19])([CH3:18])[CH3:17]>ClC(Cl)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:17][C:16]([S@:20](/[N:22]=[CH:12]/[C:11]1[CH:14]=[CH:15][C:8]([O:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[CH:9][CH:10]=1)=[O:21])([CH3:19])[CH3:18]
Reactant: O=Cc1ccc(Oc2cncnc2)cc1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(Oc2cncnc2)cc1
Temperature: 55 °C
Yield: 82.8 %

Procedure:
A mixture of 4-(pyrimidin-5-yloxy)benzaldehyde (666 mg, 3.33 mmol), (R)-(+)-tert-butanesulfinamide (450 mg, 3.71 mmol) and copper sulfate (796 mg, 4.99 mmol) in anhydrous in dichloroethane (7.648 mL) and under argon was heated at 55° C. for ˜21 hours. The reaction mixture was allowed to cool to room temperature. The slurry was filtered through a celite pad, eluted with DCM (5×10 mL). The combined filtrates were concentrated under reduced pressure and the resulting yellowish oil was purified by column chromatography [SiO2, 24 g, heptane/ethyl acetate] providing (R,E)-2-methyl-N-(4-(pyrimidin-5-yloxy)benzylidene)propane-2-sulfinamide (836 mg) as a pale viscous oil. LCMS m/z 304.0 (M+H)+, Rt 0.79 min.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27](=[NH:29])[NH2:28])[CH3:23]>C(O)C>[CH2:22]([O:24][C:25]([C:26]1[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:4]([OH:3])=[O:21])=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:28][C:27]=1[NH2:29])=[O:30])[CH3:23]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(c2ccccc2)=C(C(=O)O)C1c1ccccc1
Yield: 48 %

Procedure:
Upon boiling a solution of 14.0 g of benzylidene-benzoylacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2-amino-4,6 -diphenyl-1,4-dihydropyridine-3,5-dicarboxylic acid ethyl ester of melting point 183° C. (ethanol) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]([CH2:17][CH2:18][CH3:19])[C:8]=2[CH3:20])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[C:27]([O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:17][CH2:18][CH3:19])[C:8]([CH3:20])=[C:7]2[CH2:6][C:5]1[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:29])[CH3:28])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(C)c(Cc2ccc(Cl)cc2)c2cc(O)ccc21
Product: CCCn1c(C)c(Cc2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 3-(4-chlorobenzyl)-2-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.