Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12](Br)=[C:11]([C:15]#[N:16])[C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH:2]=[CH2:3].[CH3:25][O:26][C:27]1[CH:47]=[CH:46][C:30]([CH2:31][N:32]([C:36]2[CH:41]=[C:40]([Sn](C)(C)C)[CH:39]=[CH:38][N:37]=2)[C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=1.O1CCOCC1>CCOC(C)=O.C(Cl)Cl.[Cu]I.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>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:40]2[CH:39]=[CH:38][N:37]=[C:36]([N:32]([CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:47][CH:46]=3)[C:33](=[O:35])[CH3:34])[CH:41]=2)=[C:11]([C:15]#[N:16])[C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH:2]=[CH2:3]
Reactant: COc1ccc(CN(C(C)=O)c2cc([Sn](C)(C)C)ccn2)cc1
Reactant: C=CCn1ccnc1-c1sc(Br)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CCn1ccnc1-c1sc(-c2ccnc(N(Cc3ccc(OC)cc3)C(C)=O)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.2 %

Procedure:
The mixture of 5-(1-allyl-1H-imidazol-2-yl)-2-bromo-4-(2,4-dichlorophenyl)thiophene-3-carbonitrile (0.840 g, 1.91 mmol), N-(4-methoxybenzyl)-N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (0.992 g, 2.37 mmol) Lithium chloride (0.232 g, 5.46 mmol), Copper(I) iodide (0.104 g, 0.546 mmol) and Tetrakis(triphenylphosphine)palladium(0) (0.210 g, 0.182 mmol) in dry 1,4-Dioxane (50 mL, 600 mmol) was heated under N2 to reflux for 1 hour. The mixture was cooled to r.t., evaporated in rotavapor. The residue was quenched with aqueous saturated NaHCO3, extracted with DCM (2×150 mL), washed with water, brine, dried over Na2SO4, filtered, evaporated in rotavapor to give a brown solid. The solid was heated in EtOAc/DCM (50 mL/15 mL) to reflux for 15 min, cooled to r.t., filtered and washed with small amount of EtOAc. The filtrate was purified on a silica column using hexane as solvent A and hexane:concentrated aqueous NH4OH:MeOH:DCM (67%:0.5%:10.5%:22%) as solvent B (A/B from 100/0 to 0/100 in 5 min then 100% B for 10 min) to give a solid product (1.32 g, 75% pure by LCMS, yield 84.2%). LCMS: (AA) ES+, 614, 616. The product was used for next step without further purification.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:36])[CH3:35])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[C:38]1([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:35])[CH3:36])[CH:28]=3)[CH2:21]2)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)Oc1cccc(CC(=O)N2CC[C@](CCOS(C)(=O)=O)(c3cccc4ccccc34)C2)c1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: CC(C)Oc1cccc(CC(=O)N2CC[C@@](CCN3CCC(N4CCCCC4)CC3)(c3cccc4ccccc34)C2)c1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(1-naphthyl)-1-[(3-isopropoxyphenyl)acetyl)pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [C:1]1([C:7]2[O:8][N:9]=[C:10]3[C:15]([CH2:16][C:17]#[N:18])=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:19].[K+].O>C(O)(C)(C)C>[C:1]1([C:7]2[O:8][N:9]=[C:10]3[C:15]([CH2:16][C:17]([NH2:18])=[O:19])=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: N#CCc1cccc2c(-c3ccccc3)onc12
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: NC(=O)Cc1cccc2c(-c3ccccc3)onc12
Yield: 11.7 %

Procedure:
A slurry of 4.0 g (0.017 mole) of 3-phenyl-2,1-benzisoxazol-7-acetonitrile in 175 ml of t-butanol was heated to reflux and treated with 5 g (0.09 mole) of powdered potassium hydroxide. The deep blue colored reaction mixture was heated at reflux for 0.5 hr, cooled and poured into 800 ml of water. The mixture was extracted with three 100 ml portions of methylene chloride. The combined extracts were washed with water, dried over sodium sulfate, and concentrated to give a brown solid as residue. The solid was recrystallized from 2-propanol (charcoal) and then subjected to vacuum sublimation at 160°-170° C. to yield 0.5 g (12%) of an off-white powder, m.p. 191°-192° C. after recrystallization from absolute ethyl alcohol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]2([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17]2)[C:13]([F:25])([F:24])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C:13]([F:24])([F:25])[C@@H:14]([C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)[CH2:15]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)CC2(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1C[C@H](C2(C(=O)O)CC2)C(F)(F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
1-Benzyloxycarbonyl-4-(R)-(1-ethoxycarbonylcyclopropyl)-3,3-difluoropyrrolidine (2.287 g, 6.472 mmol) was dissolved in ethanol (65 ml) to which, while cooling in an ice bath, was added dropwise a 10 N sodium hydroxide aqueous solution (6.5 ml). The reaction solution was stirred at room temperature for 16 hours and then ethanol was evaporated under reduced pressure. The thus obtained residue was mixed with water (50 ml) and washed with dichloromethane (50 ml×2), and the thus separated aqueous layer was cooled in an ice bath, acidified by adding dropwise concentrated hydrochloric acid and then extracted with diethyl ether (100 ml×5), subsequently drying the extract over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the thus obtained residue was dissolved in benzene (100 ml) and again concentrated under reduced pressure. This azeotropic treatment with benzene was repeated 3 times to obtain 1.956 g (92.9%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[N:29]1([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[N:34]=2)[CH2:32][CH2:31][CH2:30]1>>[N:29]1([C:33]2[N:34]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[C:7]([CH2:12][N:13]5[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]5)[N:8]4[CH3:11])=[C:4]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[N:3]=3)[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: c1ccc2[nH]c(N3CCC3)nc2c1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N4CCC4)nc4ccccc43)nc21

Procedure:
2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (75 mg) was reacted with 2-(azetidin-1-yl)-1H-benzo[d]imidazole (33 mg) via General Procedure I for Buchwald coupling to give 35.9 mg 455 following reverse phase purification. MS (Q1) 546.3 (M)+
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:21])[CH2:4][CH2:5][CH2:6][N:7]([CH3:20])[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=1.O=S(Cl)Cl.[F:26][C:27]1[CH:28]=[C:29]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:30][O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][N:36]=[C:35]2[NH2:41]>C1COCC1.CN(C=O)C.N1C=CC=CC=1>[F:26][C:27]1[CH:28]=[C:29]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:30][O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][N:36]=[C:35]2[NH:41][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([N:7]([CH2:6][CH2:5][CH2:4][N:3]([CH3:2])[CH3:21])[CH3:20])=[CH:9][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1n[nH]c2ccc(OCc3cc(F)cc(F)c3)cc12
Reactant: CN(C)CCCN(C)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C)CCCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(OCc4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1
Temperature: 4 °C
Yield: 6.4 %

Procedure:
4-[(3-Dimethylamino-propyl)-methyl-amino]-2-nitro-benzoic acid hydrochloride (500 mg, 1.57 mmol) in dry THF (15 mL) was treated with one drop of DMF and with neat SOCl2 (0.34 mL, 4.69 mmol). The reaction mixture was refluxed for 0.5 hours, evaporated. The residue was taken in toluene (10 mL) and evaporated to dryness to afford a yellow solid that was suspended in dry pyridine (15 mL), cooled to 4° C. and treated with 5-(3,5-difluoro-benzyloxy)-1H-indazol-3-ylamine (360 mg, 1.31 mmol) in pyridine (5 mL). The solution was left at 4° C. over night and evaporated. The residue was dissolved in DCM (250 mL), washed with saturated NaHCO3 solution, water and brine. After drying over sodium sulfate and removal of the solvent, the crude was purified over silica gel (DCM: NH3 7N in MeOH 93:7) to afford 45 mg of title compound as an amorphous yellow solid (yield: 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@:20]([N:25]=[C:26]=[O:27])([CH3:24])[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@:20]([NH:25][C:26]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:27])([CH3:24])[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C1CCNC1
Reactant: C[C@@]1(N=C=O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Solvent: CN1CCCC1=O
Product: C[C@@]1(NC(=O)N2CCCC2)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1

Procedure:
A solution of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3R)-3-isocyanato-3-methylcyclohexyl)pyrimidin-4-amine, 52m, (0.035 g, 0.087 mmol) in 3 mL of NMP with 0.5 mL of pyrrolidine was warmed to 200° C. in a microwave for 30 minutes. The reaction was then concentrated in vacuo and purified by reverse phase HPLC chromatography, yielding 8.7 mg of desired product as a tan solid.
Reaction SMILES: [C:1]([C:5]1O[C:7]([O:10]CC)=[CH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>>[CH2:18]([O:17][C:13](=[O:16])[C:14]1[C:7]([OH:10])=[CH:8][N:9]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:15]=1)[CH3:19]
Reactant: CCOc1cnc(C(C)(C)C)o1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)c1cc(C(C)(C)C)ncc1O
Temperature: 100 °C
Yield: 51.1 %

Procedure:
2-tert-Butyl-5-ethoxy-oxazole (16.6 g, 98.1 mmol) was dissolved in freshly distilled ethyl acrylate (11.7 mL, 108 mmol). The solution was heated in a sealed tube to 100° C. for 24 h. Upon cooling, the remaining starting materials were distilled away from the product which was further purified by filtration through a plug of silica-gel (methylene chloride) and concentrated to provide 2-tert-butyl-5-hydroxy-isonicotinic acid ethyl ester (11.2 g, 54%) as a pale yellow oil.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][C:8]=3[C:7]=2[C:26]#[N:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C1C[O:33]CC1>>[O:33]=[C:9]1[C:8]2[C:7]([C:26]#[N:27])=[C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: C1CCOC1
Reactant: Cc1ccc(-c2cc(N3CCCC3)c(C#N)c3c2-c2ccccc2C3)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(-c2cc(N3CCCC3)c(C#N)c3c2-c2ccccc2C3=O)cc1
Temperature: 2.5 °C
Yield: 76 %

Procedure:
A solution of 2-(pyrrolidin-1-yl)-4-p-tolyl-9H-fluorene-1-carbonitrile (350 mg) in THF was added sodium hydride (42 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Red solid; yield 76%; mp 162-164° C.; ESMS 365 (M++1); IR (KBr) 1716 cm−1 (CO) 2214 (CN).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.[CH3:45][N:46]([CH3:50])[C:47](Cl)=[O:48]>C(Cl)Cl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][C:47](=[O:48])[N:46]([CH3:50])[CH3:45])[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36].[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CNC(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (16 mg, 0.029 mmol) and triethylamine (20 μL, 0.14 mmol) in methylene chloride (1 mL) was added N,N-dimethylcarbamoyl chloride (3.2 μL, 0.034 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/min) to give the desired compound as TFA salt (3.4 mg, 30%) as TFA salt. LCMS calculated for C20H28N5O2S (M+H)+: m/z=402.2. Found: 402.2.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(OC(C)C)(=O)C.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A solution of 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-amine (Intermediate A) (20 g, 87.0 mmol) in isopropyl acetate (240 mL) was added to a stirred solution of sodium carbonate (11.3 g, 106 mmol) in water (80 mL). After 10 min phenyl chloroformate (12.1 mL, 96 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (160 mL), the layers were separated and the organics were washed with water (2×80 mL), brine (80 mL), dried (MgSO4) and concentrated in vacuo. The resulting yellow solid was suspended in 10% ether/iso-hexane (320 mL) and stirred until a uniform suspension was obtained. The solid was collected by filtration and washed with iso-hexane to yield the subtitle compound phenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate as a white powder (27.3 g, 88%); Rt 2.65 min (Method 1); m/z 350 (M+H)+ (ES+); 1H NMR δ:1.29 (9H, s), 2.37 (3H, s), 6.35 (1H, s), 7.10-7.23 (3H, overlapping m), 7.33-7.46 (6H, overlapping m), 9.99 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:3]=1.[CH3:19][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:3]=1
Reactant: COc1ccccc1-c1ccc(C(=O)O)c(Cl)n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2OC)nc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
500 mg (1.90 mmol) of 2-chloro-6-(2-methoxyphenyl)pyridine-3-carboxylic acid were initially charged in a mixture of 20 ml of methanol and 8 ml of toluene and admixed with 8 ml (16 mmol) of a 2 molar solution of trimethylsilyldiazomethane in hexane. The mixture was stirred at RT for 15 h and then 1 ml of acetic acid was added. The solvent was removed fully under reduced pressure, and the resulting solid was used without further purification. 502 mg (87% of theory) of the product were obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11](Cl)[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)=[C:11]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1c(Cl)c(Cl)c(OCc2ccccc2)nn1Cc1ccccc1
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: Cc1ccccc1
Product: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c(OCc2ccccc2)nn1Cc1ccccc1
Temperature: 100 °C
Reaction time: 36 h
Yield: 68.6 %

Procedure:
To a round bottom flask was added 2-benzyl-6-(benzyloxy)-4,5-dichloropyridazin-3(2H)-one (20 gm, 55.4 mmol), 4-chlorophenylboronic acid (19.07 gm, 121.88 mmol), 2N sodium carbonate (124.7 ml, 249.3 mmol), toluene (200 ml) and Pd(PPh3)4 (3.2 gm, 2.77 mmol). The reaction was stirred at 100° C. for 36 hrs. After this time, the solution was cooled to rt and the organic layer was separated. The organic layer was washed with water (100 ml), saturated aqueous NaCl (100 ml). The organic layer was dried (MgSO4), filtered and concentrated. The crude material was recrystallized from methanol (150 ml) at −25° C. The solid was collected by filtration to give the title compound, 2-benzyl-6-(benzyloxy)-4,5-bis(4-chlorophenyl)pyridazin-3(2H)-one, (19.5 gm, 70% yield) as light yellow solid. MS (M+H)=513.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:25]=1.[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]([C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([CH:8]3[CH2:7][C:6]4[CH:25]=[C:2]([N:29]5[CH2:28][CH2:27][N:26]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30]5)[CH:3]=[CH:4][C:5]=4[O:9]3)[CH2:11][CH2:12]2)=[N:21][CH:20]=1)[CH2:23][CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCc1cnc(N2CCC(C3Cc4cc(Br)ccc4O3)CC2)nc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1cnc(N2CCC(C3Cc4cc(N5CCN(C(=O)OC(C)(C)C)CC5)ccc4O3)CC2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a degassed solution of 2-(4-(5-bromo-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)-5-propylpyrimidine (280 mg, 0.522 mmol), tert-butyl piperazine-1-carboxylate (389 mg, 2.088 mmol), t-BuONa (251 mg, 2.61 mmol), and BINAP (6.5 mg, 10.44 μmol) in toluene (5 mL) was added Pd2(dba)3 (28.7 mg, 0.031 mmol). Upon completion of addition, the reaction mixture was stirred in a sealed vial at 80° C. overnight. At the conclusion of this period, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was diluted with water (3 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with aqueous NaHCO3 (saturated, 5 mL) and then brine (5 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, CH2Cl2/EtOAc gradient 0 to 50% EtOAc) to afford Compound 9C as a light yellow solid (201 mg, 76% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.15 (s, 2 H), 6.83 (d, J=1.9 Hz, 1 H), 6.70-6.75 (m, 1 H), 6.66-6.69 (m, 1 H), 4.80 (dd, J=13.2, 2.5 Hz, 2 H), 4.48-4.56 (m, 1 H), 3.53-3.61 (m, 4 H), 3.18 (dd, J=15.5, 8.9 Hz, 1 H), 2.94-3.02 (m, 4 H), 2.80-2.90 (m, J=12.9, 12.9, 7.6, 2.8 Hz, 2 H), 2.40 (t, J=7.4 Hz, 2 H), 2.00-2.07 (m, 1 H), 1.91 (dddd, J=11.5, 8.0, 7.7, 3.6 Hz, 1 H), 1.74 (br. s., 1 H), 1.53-1.62 (m, 2 H), 1.47-1.51 (m, 9 H), 1.32-1.43 (m, 2 H), 0.94 (t, J=7.3 Hz, 3 H). LC/MS (m/z)=508 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[C:21]([CH:23]=1)[NH2:22]>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[C:21]([NH:22][C:12](=[O:13])[CH2:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)[CH:23]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: COc1ccc(C)c(NC(=O)CC23CC4CC(CC(C4)C2)C3)c1
Yield: 14.6 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.2 g) and 5-methoxy-2-methylaniline (0.13 g) to give the title compound as a white solid (0.043 g).