Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC.C(O)(=O)C.[OH-].[Na+]>ClC1C=CC=CC=1Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[NH:46][N:45]=[N:44][N:30]=4)=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccc(C#N)cc2)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Clc1ccccc1Cl
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(-c3nnn[nH]3)cc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
A solution of (R)-4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]benzene-nitrile from Step 1 (350 mg, 0.88 mmol) and tributyltin azide (1.17 g, 3.5 mmol) in 1,2-dichlorobenzene (4 mL) was stirred at 150° C. for 2 hours. The reaction mixture was then cooled to room temperature and acetic acid (0.5 mL) was added. After 15 min, aqueous 1N NaOH was added and the aqueous phase was washed 3 times with ether. The aqueous phase was then treated with 25% aqueous NH4OAc and 6N HCl to pH 7 before it was extracted twice with CH2Cl2. The organic phase was then dried (MgSO4) and evaporated to afford the title compound as a yellow solid (341 mg, 88%). 1H NMR (400 MHz, CDCl3): d 1.55 (m, 2H), 1.80 (m, 6H), 3.30 (m, 1H), 3.45 (m, 1H), 3.80 (s, 3H), 4.20 (m, 1H), 4.70 (m, 1H), 6.70 (s, 1H), 6.80 (m, 2H), 7.00 (d, 2H), 7.20 (d, 2H), 7.90 (d, 2H), 8.40 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([OH:10])=[CH:4][N:3]=1.[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:15][CH:14]=[C:13]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[C:5]([OH:10])=[CH:4][N:3]=2)[CH:12]=1
Reactant: Cn1c(Cl)ncc(O)c1=O
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cn1c(-c2cccc(-c3ccccc3)c2)ncc(O)c1=O
Temperature: 120 °C
Yield: 14.4 %

Procedure:
To a solution of 40 mg (0.249 mmol) 2-chloro-5-hydroxy-3-methylpyrimidin-4(3H)-one in 1 ml THF was added 20.3 mg (0.025 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct, 74 mg (0.374 mmol) biphenyl-3-boronic acid, and 0.747 ml (0.747 mmol) 1 M aq Cs2CO3. The reaction mixture was heated to 120° C. for 20 min in the microwave, then diluted with 2 ml water, extracted with 10 ml EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by HPLC gave 10 mg (14% yield) of 2-biphenyl-3-yl-5-hydroxy-3-methylpyrimidin-4(3H)-one. 1H NMR δ (ppm) (CH3OH-d4): 7.83-7.77 (2H, m), 7.67 (2H, d, J=7.69 Hz), 7.64-7.55 (2H, m), 7.53-7.42 (3H, m), 7.37 (1H, t, J=7.33 Hz), 3.50 (3H, s). HRMS (ESI positive) calc (M+H)+=279.1128 found 279.1127.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][N:40]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(N(CC)CC)C>COCCOC.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.Cl[Pd]Cl>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[N:40]=[CH:41][C:42]([C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[N:11]=[C:10]([C:18]5[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=5[F:25])[CH:9]=4)[CH:3]=3)=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Fc1ccc(Cl)cc1-c1cc(-c2cncc(Br)c2)c2cccnc2n1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cncc(-c4cc(-c5cc(Cl)ccc5F)nc5ncccc45)c3)cn2)CC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A slurry of 500 mg (1.21 mmol) 4-(5-bromo-pyridin-3-yl)-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine, 516 mg (1.33 mmol) 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester and 512 g (14.1 mmol) tri-potassium-phosphate-trihydrate in 30 ml 1,2-dimethoxyethane was heated to 80° C. under nitrogen. Then 85 mg (0.12 mmol) bis-(triphenylphosphine)-palladium(II)-chloride and 16 μl triethylamine were added. The reaction mixture was stirred for 5 hours at 80° C. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with ethylacetate/methanol as eluent yielding 4-{5′-[2-(5-Chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[3,3′]bipyridinyl-6-yl}-piperazine-1-carboxylic acid tert-butyl ester as yellow oil; HPLC-MS: 2.69 min, [M+H] 597.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15](OCC)=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH2:22][NH2:23].O>CCO>[F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]([NH:22][NH2:23])=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: NN
Reactant: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To the solution of ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (13.6 g, 45.0 mmol) in EtOH (200 mL), NH2NH2.H2O (80%, 14 mL, 225 mmol) was added. The reaction mixture was stirred at RT overnight. The desired compound precipitated from the reaction mixture, filtered and washed with EtOH (50 mL) to afford 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide as a light yellow solid (9.7 g, 75%). MS (ES+) C10H7F3N4O3 requires: 288. found: 289 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)(C)C>[C:5]([NH:18][C@H:19]([C:25]([O:27][CH:9]([CH3:10])[CH3:8])=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH:6]([CH3:7])[CH3:5])=[O:23])(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)OC(C)C)C(=O)OC(C)C
Yield: 195.3 %

Procedure:
7.24 g of thionyl chloride was gradually and dropwise added to 73.32 g of isopropyl alcohol, then 10.0 g of N-lauroylglutamic acid was added, and reacted at room temperature for 1 day. The reaction liquid was concentrated under reduced pressure to obtain 12.26 g of a white crystal of diisopropyl N-lauroylglutamate.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13]>C(#N)C>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[S:13])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc2sc(N)nc12
Solvent: CC#N
Product: Cc1cccc2sc(NC(=S)n3ccnc3)nc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
To 4-methylbenzo[d]thiazol-2-amine (1.1 g, 6.7 mmol) in acetonitrile (30 mL) was added 1,1′-thiocarbonyldiimidazole (1.552 g, 8.71 mmol). The reaction mixture was stirred at 50° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven (50° C.) for 1 hour to yield N-(4-methylbenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (900 mg, 3.28 mmol, 49% yield) and then used in the next step without any further purification or characterization.
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[C:6]=2[CH:5]=1)=[O:3].[NH3:20]>O1CCCC1>[O:13]=[C:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH2:9][O:8][C:7]2[CH:18]=[CH:19][C:4]([C:2]([NH2:20])=[O:3])=[CH:5][C:6]1=2
Reactant: N
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
Dissolve the acid chloride from Step A in 20 ml. of dry tetrahydrofuran and add this solution dropwise with stirring to a cooled (ice-bath) saturated solution of ammonia in 60 ml. of tetrahydrofuran. Pass ammonia through the reaction mixture simultaneously for 15 minutes. Stir at room temperature for an additional 15 minutes and evaporate the reaction mixture to dryness. Add a mixture of 12 ml. of ethanol and 60 ml. of water to the residue and stir at room temperature for an additional 30 minutes. Separate the solid by filtration and wash with water, then with ethanol and then with ether. Dry in vacuo to obtain the title product.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](CNC2C=CC=CC=2C)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:21]([NH2:23])[CH3:22]>C(O)C>[CH2:21]([NH:23][C:2]1[N:11]=[C:10]([NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:22]
Reactant: CCN
Reactant: Cc1ccccc1NCc1nc(Cl)nc2ccccc12
Solvent: CCO
Product: CCNc1nc(Nc2ccccc2C)c2ccccc2n1
Yield: 33 %

Procedure:
2-Chloro-4-(2-methylphenylaminomethyl)quinazoline (5.00 g, 0.0185 mol) and ethylamine in ethanol (33%, 30 ml) were dissolved in ethanol (35 ml) placed in a sealed vessel and heated for 5 hours at 130°. After cooling and removal of excess solvent in vacuo the residue afforded crystals of 2-ethylamino-4-(2-methylphenylamino)quinazoline (1.7 g, 33%) from ethanol/water, m.p. 127°-129°.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[S:7][C:8]([CH3:11])=[CH:9][N:10]=1)=[O:4].ClC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:36]1[S:37][C:38]([CH3:41])=[CH:39][CH:40]=1.[OH-].[NH4+].O>CN1CCCC1=O>[CH3:1][C:2]([CH3:13])([CH3:12])[C:3](/[N:5]=[C:6]1\[S:7][C:8]([CH3:11])=[CH:9][N:10]\1[C:36]1[S:37][C:38]([CH3:41])=[CH:39][CH:40]=1)=[O:4]
Reactant: Cc1cnc(NC(=O)C(C)(C)C)s1
Reactant: Cc1ccc(Br)s1
Agent: Clc1cc2cccnc2c2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(-n2cc(C)s/c2=N\C(=O)C(C)(C)C)s1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
In a 4 mL vial charged with a stir bar, 2,2-dimethyl-N-(5-methyl-1,3-thiazol-2-yl)propanamide (62 mg, 0.3 mmol, Example 87A) was added, followed by copper(I) trifluoromethanesulfonate benzene complex (31 mg, 0.06 mmol), 5-chloro-1,10-phenanthroline (26 mg, 0.12 mmol) and cesium carbonate (107 mg, 0.33 mmol). A loose cap with septum was placed on the vial and then the vial was placed under vacuum in a vacuum oven for 30 minutes. The mixture was purged with nitrogen gas a couple of times. Then 2-bromo-5-methylthiophene (58 mg, 0.33 mmol) dissolved in 1-methyl-2-pyrrolidinone (1.0 mL) was added to the solid mixture. The vial was capped and placed on a heater/stirrer and heated to 120° C. overnight. Then 1 mL of a solution of concentrated ammonium hydroxide/water (1:2) was added. The reaction was filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (C8, gradient 10-100% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH3:21]>CS(C)=O>[CH2:17]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 70 °C
Yield: 94.9 %

Procedure:
To a stirred solution of 4-(4-bromophenyl)phenol (25.5 g, 0.102 mol) in 400 mL of dimethylsulfoxide was added 2.5N NaOH (40.9 ml, 0.102 mol) followed by n-pentyl bromide (12.7 mL, 0.102 mol). The resulting mixture was heated at 70° C. for a period of 18 h. After cooling, the solution was partitioned between ethyl acetate (1000 ml) and water (500 ml). The organic phase was washed with water (3×) and brine and dried with magnesium sulfate. The solvent was removed in vacuo to give 30.9 g of 4-(4-n-pentoxyphenyl)-bromobenzene: 1H NMR (400 MHz, DMSO-d6) δ0.93 (t, 3H, J=7.2 Hz), 1.41 (m, 4H), 1.79 (m, 2H), 3.97 (t, 2H, J=6.6 Hz), 6.94 (d, 2H, J=8.8 Hz), 7.39 (d, 2H, J=8.6 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.51 (d, 2H, J=8.6 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](Cl)=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[NH3:14]>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7]([NH2:14])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C#N)c(Cl)nc1C
Reactant: N
Solvent: C1CCOC1
Product: CC(=O)c1cc(C#N)c(N)nc1C
Temperature: 80 °C

Procedure:
40 g (0.21 mol) of 5-acetyl-2-chloro-3-cyano-6-methyl-pyridine are dissolved in 800 ml of tetrahydrofuran, 200 ml of concentrated aqueous NH3 solution are added, and the mixture is heated at 80° C. in a stirred autoclave for two hours. After cooling, the mixture is concentrated and filtered, and the filter cake is extracted by boiling in acetonitrile and is filtered with suction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[N:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]([CH3:32])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:33][CH3:34])(=[O:10])=[O:9])=[C:4]([Cl:35])[CH:3]=1.[CH3:36][C:37]1[CH:38]=[C:39](B(O)O)[S:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(OCC)(=O)C>[Cl:35][C:4]1[CH:3]=[C:2]([C:39]2[S:40][CH:41]=[C:37]([CH3:36])[CH:38]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[N:17]=[C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]([CH3:32])[CH2:19]2)[CH:15]=[CH:14][C:13]=1[O:33][CH3:34])(=[O:10])=[O:9]
Reactant: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(Br)cc1Cl
Reactant: Cc1csc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1Cl

Procedure:
1,1-Dimethylethyl (2R,6S)-4-[6-{[(4-bromo-2-chlorophenyl)sulfonyl]amino}-5-(methyloxy)-2-pyridinyl]-2,6-dimethyl-1-piperazinecarboxylate (D13) (0.15 g, 0.254 mmol), 4-methylthiophene-2-boronic acid (0.054 g, 0.382 mmol), (1,1′-Bis(diphenylphosphino)ferrocene)palladium(II) chloride, DCM complex (9.2 mg, 0.0127 mmol), sodium carbonate (0.053 g, 0.508 mmol) were heated in DME (2 mL) and water (1 mL) at 120° C. in the microwave for 20 minutes. The reaction was then diluted with ethyl acetate (50 mL) and washed with saturated sodium hydrogen carbonate (2×30 mL) and brine (30 mL). The organic layer was dried (MgSO4) and evaporated to give a dark brown oil which was purified by chromatography [silica gel, eluting with 0 to 50% Ethyl acetate/pentane]. Product fractions evaporated to give a pale yellow foam (D14) (0.127 g) MS (ES+) m/e 607/609 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH3:24])=[O:4].C1C(=O)N([Br:32])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl.CCCCC>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH2:24][Br:32])=[O:4]
Reactant: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Solvent: CCCCC
Product: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of 1-benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (0.42 g, 1.0 mmol) in 1,2-dichloroethane (9 mL) were added NBS (0.20 g, 1.1 mmol) and AIBN (30 mg, 0.2 mmol) and the reaction mixture was heated under reflux for 45 minutes. The reaction mixture was allowed to cool to ambient temperature and was diluted with pentane (4.0 mL), the solid was removed by filtration and the liquors were then concentrated in vacuo. The resultant residue was purified by chromatography (silica, 5 g cartridge, Si-SPE, 30-100% DCM in pentane) to afford the title compound as a white solid (0.46 g, 90%). LCMS (Method B): RT=4.55 min, M+H+=489.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([CH3:11])=[O:21])=[N:7][C:6]=2[CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2cc(F)ccc2s1
Solvent: ClCCl
Product: CS(=O)c1nc2cc(F)ccc2s1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
5-Fluoro-2-(methylthio)benzo[d]thiazole (example 40A, 0.178 g, 0.893 mmol) was dissolved in CH2Cl2 (5.96 mL). mCPBA (0.154 g, 0.893 mmol) was added in one portion and the reaction mixture was stirred at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate and diluted with dichloromethane. The aqueous layer was extracted with dichloromethane (2×). The combined organic were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. 5-Fluoro-2-(methylsulfinyl)benzo[d]thiazole (0.180 g, 94% yield) was isolated as a white solid and used without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C@H:10]2[O:30][C@H:29]([C@@H:31]([CH2:33][OH:34])[OH:32])[C@@H:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:11]2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CO>CN(C)C=O>[C:1]1([CH2:7][O:8][CH2:9][C@H:10]2[O:30][C@H:29]([C@@H:31]([CH2:33][O:34][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:32][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:11]2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@@H](O)[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: c1ccc(COC[C@@H](OCc2ccccc2)[C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
An 850 mg portion of 2,5-anhydro-1,3,4-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol was dissolved in dry dimethylformamide and added to a slurry of 218 mg of sodium hydride in dimethylformamide. After stirring 1 hour, 1.9 ml of benzyl bromide was added, the mixture stirred overnight, 5 ml to methanol added and the solvents evaporated. The residue was taken up in 50 ml of water and 50 ml of dichloromethane, the organic layer separated, washed with water and brine, dried and evaporated to an orange oil. This oil was flash chromatographed, eluting with hexane:ether (5:1). Evaporation of the fractions gave 1.06 g of the desired compound.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:28][CH:29]([CH3:36])[CH2:30]/[CH:31]=[CH:32]/B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1/[CH:32]=[CH:31]/[CH2:30][CH:29]([CH3:36])[CH3:28])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C/C=C/B(O)O
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
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
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(/C=C/CC(C)C)n2n1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A mixture of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (300 mg, 0.613 mmol), (E)-(4-methylpent-1-en-1-yl)boronic acid (94 mg, 0.736 mmol) and 2N Na2CO3 (0.613 mL, 1.226 mmol) in DMF (6 mL) was degassed for 15 min. Tetrakis(triphenylphosphine)palladium(0) (49.6 mg, 0.043 mmol) was then added and the degassing was continued for another 5 min. The mixture was then heated at 100° C. for 2 h. At this point LCMS indicated completion of reaction and presence of desired product. After cooling to room temperature, water was added (10 mL) and the mixture was extracted with ether (2×50 mL), washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. the crude was then purified by biotage (5-30% EtOAc/hexane) to afford (S,E)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (200 mg, 0.449 mmol, 73.2% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.09 (s, 1H), 7.07 (s, 0.6H), 7.04 (s, 1H), 5.57 (s, 1H), 4.49 (q, J=7.1 Hz, 2H), 4.33-4.20 (m, 2H), 2.70 (s, 3H), 2.40 (td, J=7.0, 1.3 Hz, 2H), 1.90 (dt, J=13.4, 6.7 Hz, 1H), 1.46 (t, J=7.1 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.17 (s, 9H), 1.06 (dd, J=6.6, 2.7 Hz, 6H). LCMS (M+H)=446.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:33])[NH:20][CH2:21][CH2:22][C:23]3[C:28]([O:29][CH3:30])=[CH:27][C:26]([Cl:31])=[CH:25][C:24]=3[Cl:32])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([O-:36])=[O:35].[OH-].[Na+].Cl.[Na].C[O-].[Na+]>O1CCCC1.C(O)C.CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:33])[NH:20][CH2:21][CH2:22][C:23]3[C:28]([O:29][CH3:30])=[CH:27][C:26]([Cl:31])=[CH:25][C:24]=3[Cl:32])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([OH:36])=[O:35]
Reactant: COc1cc(Cl)cc(Cl)c1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Cl)cc(Cl)c1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a stirred solution of 6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate (0.56 g; 0.97 mmol) in a mixture of 10 mL tetrahydrofuran and 5 mL ethanol at ambient temperature was added 3.9 mL of 1M aqueous sodium hydroxide. The resulting slightly cloudy mixture was vigorously stirred at ambient temperature the reaction mixture was poured into a separatory funnel containing 100 mL ethyl acetate and 50 mL 1M aqueous hydrochloric acid. After shaking, the organic layer was washed with 20 mL brine, then dried over sodium sulfate and evaporated to give 0.60 of light yellow oil. To convert to the sodium salt, the material was dissolved in 10 mL methanol, and 0.22 mL of 25% sodium methoxide in methanol was added. The solvent was evaporated, and the residue evaporated from ether to give 0.54 g of 6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid as an off-white glass. MS (apci, pos) m/z=550. MS (apci, neg) m/z=548.