Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](OCC)=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]([CH3:20])[N:9]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[C:12]([CH3:19])[N:11]=[C:10]([CH3:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc(C)nc1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: ClCCl
Product: Cc1nc(C)c(CO)c(-c2ccc(F)cc2)n1
Temperature: -78 °C
Yield: 79.3 %

Procedure:
To a solution of 46.5 g (0.169 mol) of ethyl 4-(4-fluorophenyl)-2,6-dimethyl-5-pyrimidinecarboxylate in 500 mL of dichloromethane at -78° C. under nitrogen was added 340 mL of a 1M solution of diisobutylaluminum hydride (0.339 mol) in dichloromethane. Theresulting mixture was stirred at -78° C. for one-half hour and then the reaction was quenched by the addition of a saturated aqueous solution of sodium sulfate (48.15 g, 0.34 mol). The cooling bath was removed and the mixture was vigorously stirred for twenty minutes and then filtered through Celite®. The filter cake was thoroughly washed with chloroformand the combined filtrate and washings were dried over anhydrous magnesium sulfate and evaporated to yield 31.14 g of 4-(4-fluorophenyl)-2,6-dimethyl-5-pyrimidinemethanol, mp 174°-176° C.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[C:16](Br)=[C:17]([CH:23]=[CH:24][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19].O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O1CCOCC1.C1(C)C=CC=CC=1.O>[Cl:14][C:15]1[CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:24][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2cccc3ccccc23)c(C(=O)OCC)cc1Cl
Yield: 64.9 %

Procedure:
51 g (298 mmol) of 1-naphthylboronic acid, 100 g (298 mmol) of diethyl chlorobromoterephthalate and 144 g (626 mmol) of potassium phosphate monohydrate are initially introduced in a mixture of 600 ml of dist. water, 400 ml of toluene and 200 ml of dioxane and saturated with N2 for 30 min. 5.4 g (18 mmol) of tri(o-tolyl)phosphine and 669 mg (3 mmol) of palladium(II) acetate are subsequently added, and the mixture is heated at the boil for 3 h. After dilution with toluene, the organic phase is separated off, washed twice with water, dried over Na2SO4 and evaporated in vacuo. The oil which remains is distilled in a thin-film evaporator (p=5×10−3 mbar, T=130° C.) and isolated in the form of a yellow oil (74 g, 65%), which, according to 1H-NMR, has a purity of >95%.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].OCN([CH2:29][OH:30])C>C(Cl)Cl.N1C=CC=CC=1>[OH:4][CH2:5][CH:10]([CH2:29][OH:30])[NH:11][S:16]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH:6]=1)(=[O:18])=[O:17]
Reactant: CN(CO)CO
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1Oc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(S(=O)(=O)NC(CO)CO)cc1Oc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(2,4-Dichlorophenoxy)-4-methylsulphonylaminobenzene-sulphonic acid chloride (1.8 g, 2.51 mmol) was dissolved in CH2Cl2 (5 ml) and at 0° C. added dropwise to a solution of bis(hydroxymethyl)methylamine (0.44 g, 4.8 mmol) in pyridine (20 ml). The mixture was stirred for 2 hours at 0° C. and then evaporated down. The residue was dried in vacuo and purified by chromatography (silica gel, chloroform/MeOH 19/1) Yield: 0.35 g=29% 13C (100 MHz, DMSO-d6) δ 150.17, 147.50, 138.39, 132.09, 130.34, 129.29, 129.10, 126.02, 123.25, 122.75, 122.51, 115.22, 60.36, 57.07, 40.94
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])([CH3:21])[CH3:20])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][Cl:42]>C(#N)C>[Cl:42][CH2:41][CH2:40][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]([NH:18][C:14]1[C:13](=[O:29])[N:12]([C:10]2[CH:11]=[C:6]([CH:7]=[C:8]([F:31])[C:9]=2[CH3:30])[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:32])[CH:17]=[CH:16][N:15]=1)([CH3:20])[CH3:21]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Temperature: 83 °C
Reaction time: 10 h

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (Example 252j, 7.08 g) dissolved in acetonitrile (150 mL) was treated with potassium carbonate (22.42 g) and 1-bromo-2-chloroethane (13.50 mL) under nitrogen. The resulting suspension was stirred at 83° C. for 10 h. The reaction mixture was evaporated to dryness, diluted with water (300 mL), and extracted with dichloromethane. The organic layer was dried (MgSO4) and evaporated. The crude product was triturated with 50% diethyl ether in iso-hexane to afford subtitle compound (7.58 g).
Reaction SMILES: [Si]([O:8][C:9]([CH3:44])([CH3:43])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][C:21]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:22]=3[CH2:23][NH:24][C:25]([NH:27][C:28]3[N:29]([CH3:37])[N:30]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:32]=3)=[O:26])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>ClCCl>[C:33]([C:31]1[CH:32]=[C:28]([NH:27][C:25]([NH:24][CH2:23][C:22]2[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:21]=2[O:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:11]([CH2:10][C:9]([OH:8])([CH3:44])[CH3:43])[N:12]=[CH:13]3)=[O:26])[N:29]([CH3:37])[N:30]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)NCc1cc(F)ccc1Oc1ccc2c(cnn2CC(C)(C)O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)NCc1cc(F)ccc1Oc1ccc2c(cnn2CC(C)(C)O)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 87.4 %

Procedure:
To a solution of -(2-{1-[2-(tert-butyldimethylsilanyloxy)-2-methyl-propyl]-1H-indazol-5-yloxy}-5-fluorobenzyl)-3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-urea (0.084 g, 0.135 mmol) in dichloromethane (3 mL) was added TBAF (0.70 mL of 1M in THF). The mixture was stirred at room temperature for 5 days. The reaction mixture was poured into NH4Cl and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed on silica eluting with acetone/hexanes (2:1) to afford 0.060 g of product (87% yield). MS (ESI+) m/z 509 (M+1) detected; 1H NMR (400 mHz, DMSO-D6) δ 8.45 (s, 1H), 7.98 (s, 1H), 7.74 (d, 1H), 7.17 (m, 3H), 7.08 (m, 1H), 6.85 (m, 2H), 5.95 (s, 1H), 4.66 (s, 1H), 4.33 (d, 2H), 4.30 (s, 2H), 2.50 (s, 3H), 1.18 (s, 9H), 1.12 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13].O>C(O)CO>[F:10][C:7]1[CH:6]=[C:3]2[C:4]([NH2:5])=[N:13][NH:12][C:2]2=[N:9][CH:8]=1
Reactant: NN
Reactant: N#Cc1cc(F)cnc1Cl
Solvent: O
Solvent: OCCO
Product: Nc1n[nH]c2ncc(F)cc12

Procedure:
A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was initially charged in 1,2-ethanediol (380 ml), and hydrazine hydrate (119.6 ml) was then added. With stirring, the mixture was heated at reflux for 4 h. Cooling resulted in the precipitation of a solid, which was admixed with water (380 ml) and extracted by stirring at RT for 10 min. The suspension was then filtered with suction through a frit, and the filter cake was washed with water (200 ml) and with THF at −10° C. (200 ml). The solid was dried under high vacuum over phosphorus pentoxide.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH:6]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1.C(N(CC)CC)C.O>C1COCC1>[C:1]([NH:5][C@@H:6]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(N)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Acetyl chloride (23 mg) was added to a solution of tert-butyl (6SR,7SR)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (90 mg) and triethylamine (33 mg) in THF (5 ml), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (93 mg).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Cl>C(OCC)C>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[OH:13])=[CH:10][CH:9]=1
Reactant: Brc1nccs1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)c1nccs1
Temperature: -30 °C
Reaction time: 1.1 h
Yield: 64.3 %

Procedure:
A solution of 5.003 g of 2-bromothiazole in 20 mL of diethyl ether was added dropwise to 23 mL of a 1.6-M n-butyllithium/n-hexane solution in 20 mL of diethyl ether under cooling at −30° C. After the mixture was stirred for 1.1 hours, a solution of 5.538 g of 4-chlorobenzaldehyde in 20 mL of diethyl ether was added dropwise thereto. It took 1.2 hours to bring back to a room temperature, and then the reaction solution was poured into a mixture of 72 mL of 1-N hydrochloric acid and ice. The insoluble matter was removed by filtration, and then the organic layer was collected by separation. The organic layer was washed with a saturated sodium bicarbonate water and with saturated saline solution in this order. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off. The raw product was purified by silica gel column chromatography (hexane/ethyl acetate (volume ratio)=2:1 to 3:2) to give the title compound (4.425 g (64%)).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:13]([F:27])=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:7][N:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:26][C:22]1[CH:21]=[C:20]([C:14]2[C:15]([O:18][CH3:19])=[CH:16][CH:17]=[C:12]([CH2:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:3][OH:2])=[N:6][CH:7]=3)[C:13]=2[F:27])[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(Cc2ccc(OC)c(-c3cccc(Cl)c3)c2F)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2ccc(CO)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic acid methyl ester (I-146, 100 mg, 0.259 mmol) and tetrahydrofuran (1.3 mL). The solution was cooled to 0° C. and then lithium aluminum hydride (39.3 mg, 1.04 mmol) was added resulting in strong gas evolution. Then mixture was stirred at 0° C. for 1 hour and then concentrated with a stream of nitrogen. The solid was diluted with dichloromethane (2 mL) and then slowly quenched with water (7 mL). The aqueous portion was extracted with DCM (3×6 mL), the organic portions were combined, filtered through Celite, dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 30% acetone/dichloromethane to produce 22 mg of P-599 as a pale orange viscous oil in 24% yield.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21](/[C:24](/[CH3:31])=[CH:25]/[C:26](OCC)=[O:27])=[CH:20][CH:19]=2)[CH:14]=[C:15]([Cl:17])[CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:19]=[CH:20][C:21](/[C:24](/[CH3:31])=[CH:25]/[CH2:26][OH:27])=[CH:22][CH:23]=2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2cc(Cl)cc(Cl)c2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2cc(Cl)cc(Cl)c2)cc1

Procedure:
The colourless oil (E)-3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-enoate as described for example 52b.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.Br[C:33]([CH3:39])([CH3:38])[C:34]([NH:36][CH3:37])=[O:35]>>[CH3:37][NH:36][C:34](=[O:35])[C:33]([CH3:39])([N:1]1[CH2:2][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:4]1)[CH3:38]
Reactant: CNC(=O)C(C)(C)Br
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Product: CNC(=O)C(C)(C)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1

Procedure:
Following General Procedure C, 4-(8-(azetidin-3-ylmethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 2-bromo-N,2-dimethylpropanamide were reacted to give 580. LCMS m/z: 259.7 (2M+H+)
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2.[NH:20]1[CH:24]=[C:23]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[N:22]=[CH:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>C1COCC1.C(OCC)(=O)C>[CH:28]([O:27][C:25]([C:23]1[N:22]([CH:2]2[C:3]3[C:8](=[CH:7][C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:5][CH:4]=3)[CH2:9][CH2:10][CH2:11]2)[CH:21]=[N:20][CH:24]=1)=[O:26])([CH3:30])[CH3:29]
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CC(C)OC(=O)c1c[nH]cn1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cncn1C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reaction time: 1 h

Procedure:
To a suspension of trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (5.0 g, 0.016 mol) and isopropyl 4-imidazolecarboxylate, which can be prepared as described in Example 1 (1.72 g, 0.011 mol) in THF (100 mL) at 0° C. is added triphenylphosphine (4.20 g, 0.016 mol) and dimethyl azodicarboxylate (40% wt. in, toluene, 5.85 g, 0.016 mol). After 1 hour, the mixture is diluted with ethyl acetate and washed with water. The organic phase is dried with Na2SO4, filtered, and concentrated to give a residue, which is purified by silica gel chromatography (elution with hexanes-ethyl acetate mixtures) to give 3-(6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, MeOD) δ ppm 1.37 (t, J=6.8 Hz, 6 H), 1.88-1.97 (m, 2 H), 2.27-2.34 (m, 2 H), 2.96 (dd, J=17.4, 6.3 Hz, 1 H), 3.11 (dd, J=17.4, 6.6 Hz, 1 H), 5.22 (t, J=6.8 Hz, 1 H), 6.36 (t, J=6.2 Hz, 1 H), 7.06 (d, J=8.8 Hz, 1 H), 7.19 (dd, J=8.8, 2.5 Hz, 1 H), 7.29 (d, J=2.5 Hz, 1 H), 7.58 (s, 1 H), 7.76 (d, J=1.0 Hz, 1 H).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([C:19]1[S:23][C:22]([NH:24]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:21][CH:20]=1)=[O:18])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O)=O>CCO>[C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([C:19]1[S:23][C:22]([NH2:24])=[N:21][CH:20]=1)=[O:18])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCc1cccc(Cl)c1NC(=O)c1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Solvent: O=CO
Solvent: CCO
Product: CC(C)(C)C(=O)OCc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Yield: 87.4 %

Procedure:
A mixture of compound 9a (8.90 g, 14 mmol) and formic acid (15 mL, 96% in H2O) in EtOH (150 mL) was refluxed for 24 h. After cooling, the solution was concentrated in vacuo. The residue was subjected to a short column using EtOAc in hexane (30% to 70%) to give the crude compound 10a which was triturated with 10% EtOAc in hexane to give compound 10a (4.50 g, 87% yield). 1H NMR (500 MHz, CDCl3) δ 1.17 (s, 9H), 5.09 (s, 2H), 7.20-7.39 (m, 5H), 8.01 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.CON(C)[C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36].Cl.O1CCOCC1>O>[Cl:25][C:5]1[CH:6]=[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:19]([CH3:20])[CH3:21])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[C:2]([C:29]([C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:37])=[N:3][CH:4]=1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(OC(C)C)cc1
Reactant: CON(C)C(=O)c1cccnc1C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-bromo-5-chloro-pyridin-3-yl)-4-isopropoxy-N-methoxymethyl-benzenesulfonamide (592 mg, 1.32 mmol) was placed in a dry 25 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (5 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (1.72 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 60 minutes, followed by the addition of N-methoxy-2,N-dimethyl-nicotinamide (379 mg, 2.11 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 M HCl in dioxane (6 mL, 24.0 mmol) and H2O (6.0 mL), and then stirred at 80° C. for two hours. The resultant solution was concentrated in vacuo and saturated sodium bicarbonate was added to adjust to neutral pH. The solution was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude sulfonamide was finally purified via automated flash chromatography to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 10.90 (s, 1H), 8.58 (d, 1H), 8.17 (m, 2H), 7.80 (d, 2H), 7.49 (d, 1H), 7.16 (m, 1H), 6.89 (d, 2H), 4.57 (sep, 1H), 2.34 (s, 3H), 1.33 (d, 6H); MS (ES) M+H expect 445.9. found 446.1.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[CH3:35][O:36][C:37]1C=C(C=[CH:43][CH:44]=1)C=O>>[CH3:35][O:36][C:37]1[CH:9]=[C:8]([CH:13]=[CH:43][CH:44]=1)[CH2:7][N:5]1[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[CH:23]=[N:22][N:21]([CH:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:19]=3[N:20]=2)[CH2:4]1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: COc1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)c1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 3-methoxybenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.27-7.21 (m, 1H), 6.96-6.92 (m, 2H), 6.81 (d, J=7.1 Hz, 1H), 4.82-4.76 (m, 1H), 4.14-4.08 (m, 2H), 3.85 (s, 3H), 3.79 (s, 1H), 3.62-3.54 (m, 3H), 3.39 (t, J=8.7 Hz, 1H), 3.00 (d, J=10.3 Hz, 1H), 2.81 (m, 1H), 2.53 (m, 1H), 2.42-2.28 (m, 3H), 1.94-1.82 (m, 3H), 1.20 (d, J=7.1 Hz, 3H). MS: (M+H m/z 424.1).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([CH3:32])=[CH2:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:29]=[N:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][N:25]=3)[CH2:22][CH2:23]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
4-(4-Benzyl-phthalazin-1-yl)-5′-isopropenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (50 mg, 0.118 mmol) is dissolved in MeOH (2 mL). Palladium hydroxide (25 mg) is added to the flask capped with a septum and balloon of hydrogen. The reaction is stirred 3 h at room temperature. Filter through a small pad of silica gel and wash behind with EtOAc. Concentrate the filtrate in vacuo. The residue is purified by flash chromatography on silica gel (EtOAc/Heptane) to afford the title compound (17.6 mg, 35%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>C1(C)C=CC=CC=1.CS(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:21][C:23]2[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(N)ccc1Oc1ncccc1-c1ccncn1
Reactant: Clc1nc2ccccc2o1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc(Nc2nc3ccccc3o2)ccc1Oc1ncccc1-c1ccncn1
Temperature: 100 °C

Procedure:
To 3-methyl-4-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzenamine (30 mg, 0.11 mmol) in toluene (2.0 mL) was added 2-chlorobenzo[d]oxazole (0.014 mL, 0.12 mmol). The resulting mixture was heated to 100° C. for 47 h. The mixture was diluted with DMSO and purified by Gilson reverse-phase HPLC. The product-containing fractions were combined, diluted with methylene chloride, and extracted with saturated sodium carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield the title compound as a tan solid. MS m/z=396 [M+H]+. Calc'd for C23H17N6O2: 395.42.