Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@@H:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=2)=[O:30])[C:3]1=[O:20]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methylphenyl-isocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 208°-210° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:22][CH2:21][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:19][CH2:20]3)[CH2:17][O:16]4)=[CH:11][CH:10]=2)O1.Br[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2[O:43][C:42]([CH2:44][CH3:45])=[N:41][C:40]=2[CH3:46])=[O:38])=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(COC)OC>O.C(O)C>[CH2:44]([C:42]1[O:43][C:39]([C:37]([NH:36][C:33]2[CH:34]=[CH:35][C:30]([C:9]3[CH:10]=[CH:11][C:12]([C:15]45[CH2:22][CH2:21][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:19][CH2:20]4)[CH2:17][O:16]5)=[CH:13][CH:14]=3)=[CH:31][CH:32]=2)=[O:38])=[C:40]([CH3:46])[N:41]=1)[CH3:45]
Reactant: CCc1nc(C)c(C(=O)Nc2ccc(Br)cc2)o1
Reactant: COC(=O)CC12CCC(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)(CC1)OC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CCc1nc(C)c(C(=O)Nc2ccc(-c3ccc(C45CCC(CC(=O)OC)(CC4)CO5)cc3)cc2)o1
Temperature: 80 °C
Yield: 142.1 %

Procedure:
A vial was charged with methyl 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (14 mg, 0.036 mmol), N-(4-bromophenyl)-2-ethyl-4-methyloxazole-5-carboxamide (22.4 mg, 0.072 mmol), PdCl2(dppf)-CH2Cl2adduct (4.44 mg, 5.44 μmol), potassium phosphate (15.4 mg, 0.072 mmol), dimethoxyethane (0.6 ml), ethanol (0.2 ml), and water (0.1 ml) at room temperature. The vial was sealed, flushed with nitrogen for three times and heated at 80° C. for 16 hours. The mixture was purified by flash chromatography (heptanes/acetone 1/1, washed with acetone/ethanol 1/1) to afford methyl 2-(1-(4′-(2-ethyl-4-methyloxazole-5-carboxamido)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (25 mg, 40% purity, 56% yield) as white solid. LC/MS, ESI-MS(+1) m/z 489.1, RT 1.53 (Condition E).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:9]=[C:10]([OH:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].S(O[CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(C1C=CC(C)=CC=1)(=O)=O>CC(N(C)C)=O>[CH3:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[O:17][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:32][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 77.9 %

Procedure:
Cesium carbonate (16.29 g, 50 mmoles, 2 equivalents) was added to a stirred solution of 3-methyl-4-nitrophenol (3.82 g, 25 mmoles, 1 equivalent) and tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate (10.16 g, 27.5 mmoles, 1.1 equivalent) in anhydrous DMA (25 ml). The stirred reaction mixture was then heated to 90° C. (thermostatically controlled heating mantle) for 22 hours. The reaction mixture was then allowed to cool to room temperature and was filtered through a plug of Celite. The reaction flask and the Celite were then washed with ethyl acetate (250 ml). The organic solution was then transferred to a separatory funnel and extracted with additional ethyl acetate (3×200 ml). The combined ethyl acetate solution was then washed with water (2×100 ml), saturated sodium chloride (2×100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a crude product. This material was triturated with diethylether to give a solid which was filtered off, washed with ether to give 6.82 g of tert-butyl 4-((3-methyl-4-nitrophenoxy)methyl)piperidine-1-carboxylate (yield=78%). 1H-NMR (400 MHz, DMSO-d6) δ 8.06 (d, 1H), 8.64 (d, 1H), 8.62 (s, 1H), 3.9 (s, 2H), 3.34 (m, 4H), 2.00 (m, 1H), 1.46 (m, 1.46), 1.42 (s, 9H). MS (EI): 351 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2].[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:31]([CH:28]2[CH2:30][CH2:29]2)=[O:32])[CH2:25][CH3:26])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OCC)c1
Product: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (5-chloro-2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:28])([F:27])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[CH2:21][NH2:22])=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:16]=[N:15][C:14]([C:13]([F:28])([F:27])[F:12])=[N:19][CH:18]=1)[CH2:23][CH:24]1[CH2:26][CH2:25]1)=[O:6]
Reactant: NCC(CC1CC1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1CC1)c1cnc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-trifluoromethyl-pyrimidin-5-yl)-3-cyclopropyl-propylamine. LCMS (MH+): m/z=418.1, tR (minutes, Method G)=2.55
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([NH:20][C:21]2[N:22]=[C:23]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:24]3=[N:25][CH:26]=2)=[O:19])[CH2:13]1.NN.CC(O)=O>CN(C=O)C>[NH2:3][C@H:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([NH:20][C:21]2[N:22]=[C:23]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:24]3=[N:25][CH:26]=2)=[O:19])[CH2:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)N[C@H]3CC[C@H](N4C(=O)c5ccccc5C4=O)C3)cnc21
Agent: NN
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)N[C@H]3CC[C@H](N)C3)cnc21
Yield: 68.6 %

Procedure:
Trans 1-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-cyclopentyl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.288 g, 0.50 mmol) was dissolved with heating in DMF (10 mL) and placed in a 45° C. oil bath. The flask was evacuated and refilled with nitrogen three times. Hydrazine (0.16 mL, 5.1 mmol) was added via syringe. After 30 minutes AcOH (0.6 mL) was added and the mixture heated for 30 minutes more before being evaporated. MeOH was added, filtered and the filtrate was evaporated. H2O was added, filtered and the filtrate was evaporated. The residue was purified by reverse phase column chromatography (20-80% MeOH in 0.1% aqueous AcOH) to give trans 1-(3-amino-cyclopentyl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.134 g, 60% yield).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]>ClCCl.C(N(CC)CC)C>[C:10]([C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=1[NH:7][C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])(=[O:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1ccccc1C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1NC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dichloroacetylchloride (88 ml) in dichloromethane (200 ml) was added dropwise to a stirred solution of 2-aminobenzophenone (157.6g) in dichloromethane (400 ml) and triethylamine (116 ml) while keeping the temperature between 20°-30°C by cooling in ice. On completion of the addition the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was washed with successive portions of distilled water-dilute hydrochloric acid and finally distilled water. After drying over anhydrous magnesium sulphate the solvent was removed under reduced pressure to leave a solid which on recrystallisation from absolute, ethanol gave 222 g of 2'-benzoyl-2,2-dichloroacetanilide, m.p. 112°-114°C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1)=[O:4].N12CCCN=C1CCCCC2.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>CN(C)C=O.C(#N)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[O:4])=[CH:7][C:8]=1[C:13]([F:16])([F:15])[F:14]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C(Cl)(Cl)Cl
Reactant: Nc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Nc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 115 °C
Yield: 74.2 %

Procedure:
2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl)phenyl)acetamide (25 g, 0.07338 mol) was dissolved in dimethyl formamide (75 ml). 1,8-diazabicyclo[5.4.0]undec-7-ene (17.5 ml, 0.11731 mol) and 4-amino phenol (9.6 g, 0.0879 mol) were added in one lot. The reaction mass was heated to 110-120° C. for 18-20 hours, cooled to room temperature and quenched in water (750 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water. It was then dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in acetonitrile (300 ml) at ambient temperature and filtered to give 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (18 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.CCO.C([O-])([O-])=O.[Na+].[Na+].[N+:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>COCCOC.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.O>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([CH3:17])([C:5]1[CH:6]=[CH:7][C:2]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:27]([O-:29])=[O:28])[CH:35]=2)=[CH:3][CH:4]=1)[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
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: O
Solvent: COCCOC
Solvent: CCO
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Temperature: 150 °C
Yield: 66.8 %

Procedure:
2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) (100 mg, 0.33 mmol) was weigh out in a microwave vial and dissolved in 3 ml of DME, 2 ml of EtOH and 1.5 ml of water followed by addition of Na2CO3 (70 mg, 0.66 mmol) and 3-nitrophenylboronic acid (67 mg, 0.4 mmol). Pd(PPh3)4 (8 mg, 6.6 μmol) was then added and the tube was immediately sealed. The reaction mixture was heated in a Smith Synthesizer at 150° C. for 5 min. The solution was filtered and the compound purified by preparative HPLC to yield 75 mg (67%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (dd, 2H), 5.2 (broad, 1H), 7.5(d, 2H), 7.6 (d, 3H), 7.9 (d, 1H), 8.2 (dd, 1H), 8.4 (d, 1H). MS (M+H, 341).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[C:22]([CH3:24])[C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:25][NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[C:22]([CH3:24])[C:18]([C:19]([N:26]([CH3:25])[CH:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNC1CCN(C)CC1
Reactant: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1C(=O)O
Product: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1C(=O)N(C)C1CCN(C)CC1

Procedure:
The title compound was prepared in a manner similar to Example 412 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)-4-methylnicotinic acid and N,1-dimethylpiperidin-4-amine. ESI-MS m/z (M+H)+ calc'd for C24H26N6O2, 431.21. found 431.5.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[C:6]=2[N:7]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[CH3:22][N:23]1[CH:27]=[C:26]([C:2]2[N:3]=[CH:4][C:5]3[N:10]=[N:9][N:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)[C:6]=3[N:7]=2)[CH:25]=[N:24]1
Reactant: Clc1ncc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: Cn1cc(-c2ncc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 80 °C
Yield: 28.6 %

Procedure:
To a solution of 6-((5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)quinoline (393 mg, 1.33 mmol) in DME (8 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (415 mg, 1.99 mmol) and Cs2CO3 (1.30 g, 3.98 mmol) in H2O (1.3 mL). The reaction mixture was degassed twice. The palladium catalyst Pd(dppf).CH2Cl2 (63 mg, 0.077 mmol) was added and the reaction mixture was degassed for two more times, and heated to 80° C. for 15 h under nitrogen. After cooling to room temperature, the solvent was removed under reduced pressure. Flash chromatography of the residue over silica gel, using 50% hexane in EtOAc to 100% EtOAc to 10% MeOH in EtOAc, gave the desired product (130 mg, 29%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.00 (s, 3H), 6.04 (s, 2H), 7.39-8.29 (m, 7H), 8.92 (m, 1H), 9.44 (s, 1H); LCMS (APCI) m/z 343.0 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH:8]([CH3:34])[C@H:9]([NH:29][C:30](=[O:33])[O:31][CH3:32])[C:10](=[O:28])[N:11]1[C@H:16]([C:17]2[NH:18][C:19]([C:22]#[C:23][Si](C)(C)C)=[CH:20][N:21]=2)[CH2:15][C@@H:14]2[C@H:12]1[CH2:13]2>CO>[C:22]([C:19]1[NH:18][C:17]([C@@H:16]2[CH2:15][C@@H:14]3[C@@H:12]([CH2:13]3)[N:11]2[C:10](=[O:28])[C@@H:9]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:8]([CH3:34])[CH3:7])=[N:21][CH:20]=1)#[CH:23]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc([C@@H]2C[C@H]3C[C@H]3N2C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Potassium carbonate (34.3 mg, 0.248 mmol) was added to a solution of methyl(S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate (200 mg, 0.497 mmol) in methanol (5 mL) and the reaction was flushed with nitrogen, sealed and then heated at 50° C. for 4 h. and then stirred at rt overnight. The reaction was concentrated to dryness and then purified on a BIOTAGE® Horizon (12 g SiO2, 70-90% EtOAc/hexanes) to yield methyl(S)-1-((1R,3S,5R)-3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (151 mg) as a yellow glass. LC-MS retention time 1.788 min; m/z 331.32 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 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 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:10][O:11][C:12]([NH:14][C:15](=NC(OC)=O)SC)=[O:13]>CO.C(O)(=O)C>[CH3:10][O:11][C:12](=[O:13])[NH:14][C:15]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=2[N:1]=1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: Nc1ccc(O)cc1N
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(O)ccc2[nH]1
Yield: 109.7 %

Procedure:
6 g of 3,4-diaminophenol were combined with 9.8 g of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in 50 ml methanol and 30 ml acetic acid. The reaction mixture was refluxed for 4 hours. Solvents were then evaporated under reduce pressure yielding 10.8 g crude (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester. The residue was subjected to flash chromatography eluting with a mixture of dichloromethane-methanol (9:1; v/v) to give 5.6 g of a beige solid. Mass spectrum: 208 [M+H]+, retention time=0.56 minute.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 101 %

Procedure:
To a solution of (2R,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (9.81 g: 40 mmole) in dichloromethane (49 ml) in a nitrogen atmosphere under ice cooling, triethylamine (6.67 ml: 48 mmole) and methanesulfonyl chloride (3.70 ml: 48 mmole) are added. The mixture is stirred for 20 minutes to give (2R,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as a crude oil (13.05 g). Yield: 101%. NMR δ(CDCl3) ppm: 1.46(d, J=9.6 Hz, 9H), 2.5(m, 2H), 3.02(s, 3H), 3.76(s, 3H), 3.8(m, 2H), 4.3 to 4.6(m, 1H), 5.2 to 5.3(m, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:17]([OH:19])=O)[C:13](=[O:16])[NH:14][N:15]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2].CN(C=O)C.C(N(CC)CC)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[C:35]([NH2:40])[CH:34]=1>O>[NH2:40][C:35]1[CH:34]=[C:33]([Cl:32])[CH:38]=[CH:37][C:36]=1[NH:39][C:17]([C:12]1[C:13](=[O:16])[NH:14][N:15]=[C:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=2)[CH:11]=1)=[O:19]
Reactant: CCNc1nccc(-c2cc(C(=O)O)c(=O)[nH]n2)n1
Reactant: Nc1ccc(Cl)cc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCNc1nccc(-c2cc(C(=O)Nc3ccc(Cl)cc3N)c(=O)[nH]n2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 110 mg of 6-(2-ethylaminopyrimidin-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 2 ml of DMF and 0.17 ml of triethylamine is mixed with 192 mg of Hatu and stirred at room temperature for 30 minutes. Then 66 mg of 4-chloro-phenylenediamine are added, and the mixture is stirred at room temperature overnight. 5 ml of water are added to the mixture, and the precipitate is briefly stirred and then filtered off with suction and dried.
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]([NH:29][CH2:30][CH2:31][O:32][CH2:33][C:34]#[CH:35])=[O:28]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(O)(=O)C>[F:25][C:26]([F:36])([F:37])[C:27]([NH:29][CH2:30][CH2:31][O:32][CH2:33][C:34]#[C:35][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1)=[O:28]
Reactant: C#CCOCCNC(=O)C(F)(F)F
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=C(NCCOCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 5-iodo-2'-deoxyuridine (3.54 g, 10 mmol), copper(1) iodide (0.19 g, 1 mmol) and tetrakis(triphenylphosphine)palladium(O) (0.58 g, 0.5 mmol) is dried in vacuo at 60° for 3 hours and placed under argon. A suspension of the mixture in dry DMF (20 ml) is stirred under argon and treated with dry triethylamine (1.7 ml, 12 mmol) followed by 3-(2-Trifluoroacetamidoethoxy)propyne (3.17 g, 16 mmol). The mixture is cooled at room temperature in a water bath and stirred for 17 hours. The mixture is treated with 2% acetic acid (100 ml), the catalyst is removed by filtration and washed with 50% methanol. The filtrates are combined and passed onto a LiChroprep RP-18 column (5×25 cm), the column is washed, then eluted with 1% acetic acid in 50% (v/v) methanol. The fractions with the main product are combined, evaporated, and dried in vacuo. The resultant foam is stirred with 150 ml of ether to give crystalline product; yield 3.6 g (85%); m.p. 145°-152°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]2[C:21]([O:26][CH3:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.C(=O)([O-])[O-:29].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:29])=[CH:14][C:13]=2[C:20]2[C:21]([O:26][CH3:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: COc1ncccc1-c1cc(C#N)ccc1Oc1cnc(C2CC2)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1cnc(C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
To a solution of 4-(5-chloro-6-cyclopropylpyridin-3-yloxy)-3-(2-methoxypyridin-3-yl)benzonitrile (Preparation 39, 478 mg, 1.27 mmol) in dimethyl sulfoxide (5 mL) was added potassium carbonate (1.05 g, 7.62 mmol) followed by a 30% aqueous solution of hydrogen peroxide (650 μL, 6.35 mmol). The reaction was stirred 1 hour at room temperature. Water (50 mL) was added and the solution was extracted by ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 3% methanol in dichloromethane to afford the title compound as a white solid (528 mg, 87%).