Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][S:7](Cl)(=[O:9])=[O:8])(=[O:4])=[O:3].[CH3:11][NH2:12]>C(Cl)(Cl)Cl.O>[CH3:11][NH:12][S:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:9])=[O:8]
Reactant: CN
Reactant: CS(=O)(=O)CCS(=O)(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)CCS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a stirred mixture of 2-(methylsulfonyl)ethanesulfonyl chloride in 50 ml chloroform, 15.5 g (0.2 mole) 40% methylamine in water were added slowly. The reaction mixture was stirred one hour and then filtered. The filtrate was washed with water. The organic phase was separated and then stripped. Cold ether was added to the residue; the resulting mixture was stirred. Filtration of the ether mixture gave 11.0 g of the above-identified product as a white solid, mp. 116°-117° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH3:31])[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1N1CCc2c(ncnc2Nc2ccc(C(F)(F)F)cc2)C1
Reaction time: 6 h
Yield: 4.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added o-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (6.0 mg, 5%).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:14][O:15][C:16]([C:18]12[CH2:23][CH:22]1[CH:21]([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:19]2=[O:29])=[O:17]>>[CH3:14][O:15][C:16]([CH:18]1[CH:22]([CH2:23][S:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:21]([O:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[CH2:20][C:19]1=[O:29])=[O:17]
Reactant: COC(=O)C12CC1C(O[Si](C)(C)C)CC2=O
Reactant: Sc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)C1C(=O)CC(O[Si](C)(C)C)C1CSc1ccccc1
Yield: 66.7 %

Procedure:
In accordance with the process of Preparation 3, potassium t-butoxide (246 mg; 2.2 mmol), thiophenol (220 mg; 2 mmol) and 2-oxo-4-trimethylsilyloxy-bicyclo[3.1.0] hexane-1-carboxylic acid methyl ester (484 mg; 2 mmol) were used to obtain 470 mg of 2-oxo-5-phenylthiomethyl-4-trimethylsilyloxy-cyclopentanecarboxylic acid methyl ester as a viscous oil.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:8][C@@H:7]([N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][C:12]([Cl:33])=[N:13][C:14]=3[NH:18][CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:6]([OH:34])[C@@H:5]1[OH:35].[C:36]([O:39][CH2:40][C:41](Cl)=[O:42])(=[O:38])[CH3:37]>C1COCC1>[Cl:33][C:12]1[N:11]=[C:10]2[C:15]([N:16]=[CH:17][N:9]2[C@@H:7]2[CH2:8][C@H:4]([NH:3][C:41]([CH2:40][O:39][C:36](=[O:38])[CH3:37])=[O:42])[C@@H:5]([OH:35])[C@H:6]2[OH:34])=[C:14]([NH:18][CH2:19][CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol dihydrochloride (Intermediate JJ3) (250 mg, 0.46 mmol) in dry THF (10 ml) is treated with TEA (0.188 g, 1.86 mmol) followed by acetoxyacetylchloride (0.064 g, 0.46 mmol) and then stirred at room temperature for 30 minutes. The solvent is removed in vacuo and the solvent is partitioned between DCM and 0.1M HCl. The organic portion is separated and washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title product.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].C[O:10][P:11]1[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]1>>[CH:6]([O:5][C:3]([CH2:2][P:11]1(=[O:10])[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]1)=[O:4])([CH3:8])[CH3:7]
Reactant: CC(C)OC(=O)CBr
Reactant: COP1OC(C)C(C)O1
Product: CC(C)OC(=O)CP1(=O)OC(C)C(C)O1
Yield: 94.8 %

Procedure:
Using the procedure of Step A of Example 1, 2.03 g of isopropyl bromoacetate and 1.3 g of 2-methoxy-4,5-dimethyl-1,3,2-dioxaphospholane were reacted to obtain 1.94 g of raw 2-isopropoxycarbonylmethyl-4,5-dimethyl-2-oxo-1,3,2-dioxaphospholane used as is for the next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: c1coc(C2CCCN2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1ccco1

Procedure:
The title compound, white solid, m.p. 69° C. and MS: m/e=295 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-furan-2-yl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[N:11]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([NH:7][NH2:11])[CH:8]=1
Reactant: COc1ccc(Cl)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(Cl)cc1NN
Yield: 115.4 %

Procedure:
To a stirred suspension of 5-chloro-2-methoxyaniline (20.0 g, 126.98 mmol, 1.0 eq) in conc. HCl (250 mL) was added a solution NaNO2 (10.5 g, 152.38 mmol, 1.2 eq) in water (40 mL) dropwise at −5-0° C. until reaction mixture formed a clear solution. The reaction mixture was added dropwise to a stirred solution of SnCl2 (52.90 g, 279.36 mmol, 2.2 eq) in conc. HCl (250 mL) at −5° C. for 30 min. The solid precipitate obtained was filtered out and washed with excess of ice cold water to get (5-chloro-2-methoxyphenyl)hydrazine (25.3 g, 92%, off-white solid; TLC system: EtOAc/PE (3:7) Rf: 0.6).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.Cl>CN(C=O)C.CCOCC>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: Fc1ccccc1CBr
Reactant: Oc1ccc2cc(O)ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Oc1ccc2cc(OCc3ccccc3F)ccc2c1
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A stirred solution of 15.0 g (94.0 mM) of 2,6-dihydroxynaphthalene in 60 mL of DMF was treated with 3.21 g (80.0 mM) of NaH under nitrogen. The resulting dark solution was treated dropwise with a solution of 5.94 g (31.0 mM) of 2-fluorobenzyl bromide in 20 mL of Et2O over 0.75 h. The mixture was stirred an additional 2 h then treated cautiously with 200 mL 1N HCl. The mixture was stirred 8 to 16 hours then filtered. The solid was washed thoroughly with water and dried. Flash chromatography produced a solid which was recrystallized from i-PrOH to afford 4.51 g (56%) of product as gray crystals mp 143-144° C.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1N=C[N:12](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CCOC(C)=O>[CH:1]1([C:7]([NH2:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1CCCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 111.8 %

Procedure:
A solution of cyclohexanecarboxylic acid (1.00 g, 7.80 mmol) in EtOAc (10 mL) was treated with CDI (1.581 g, 9.75 mmol), stirred at RT for 20 minutes, treated with ammonium hydroxide (5.00 mL, 70.0 mmol) and stirred for 20 minutes. The mixture was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford cyclohexanecarboxamide (1.109 g, 112%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 5.61 (s, 2H), 2.13 (m, 1H), 1.89 (m, 2H), 1.78 (m, 2H), 1.66 (m, 1H), 1.42 (m, 2H), 1.24 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[C:21]([CH3:30])([CH3:29])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:34]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:34])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[C:21]([CH3:30])([CH3:29])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(Cl)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a cooled solution of (2R,5R)-4-[2-(6-chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.22 mmol) in DMF (1.1 mL) at 0° C. (ice bath) was added sodium hydride (60%, 10 mg, 0.24 mmol). After stirring for 1 h, methyl iodide (15 μL, 0.24 mmol) was added and the reaction stirred for 30 mins. Reaction was allowed to warm gently to ambient temperature over 18 h. The solvent was removed in vacuo and residue was purified by column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), to give the title compound (20 mg, 19%) as a colourless oil. 1H NMR (Me-d3-OD): 8.14 (1H, s), 7.27-7.13 (1H, m), 7.09 (1H, dd), 4.19 (1H, dd), 4.13-3.84 (3H, m), 3.78-3.44 (3H, m), 3.44-3.38 (1H, m), 3.36 (3H, s), 3.29 (1H, d), 3.07-2.94 (1H, m), 2.94-2.81 (1H, m), 2.66 (1H, dd), 1.48 (9H, s), 1.37 (6H, s), 1.34-1.20 (3H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:10]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[O:4].[C:27](=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:2][C:3]([C@H:5]1[C@H:10]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:6]1)=[O:4])[CH3:27]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Yield: 22.6 %

Procedure:
In a dry flask (3S,4R)-4-[(R)-1-phenyl-ethylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (13.78 g, 38.0 mmol) was dissolved in ethanol (400 mL) along with 3 Å molecular sieves (1.04 g). The mixture was heated to reflux over 2.5 hours. Potassium carbonate (26.3 g) was added and refluxing continued for 4 additional hours. The reaction mixture was cooled, filtered through a bed of celite, and concentrated in vacuo to give a crude oil (16.05 g). Purification by flash column chromatography (20-50% ethyl acetate/hexanes) provided a colorless oil (3.24 g, 23%). Unepimerized ethyl ester was also isolated (7.55 g, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:51])([CH3:50])[C:29]([F:49])([F:48])[C@:30]([C:33]3[CH:38]=[C:37](B4OCC(C)(C)CO4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br[C:53]1[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=1>>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:50])([CH3:51])[C:29]([F:48])([F:49])[C@:30]([C:33]3[CH:38]=[C:37]([C:53]4[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(B4OCC(C)(C)CO4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccc(Br)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4ccc(C#N)cc4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 78.2 %

Procedure:
Reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (intermediate B10.1) (199 mg, 254 μmol) with 4-bromobenzonitrile (61.3 mg, 330 μmol) yielded the 3′-((R)-3-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4′-fluoro-biphenyl-4-carbonitrile (137 mg, 78% yield) as a white foam. MS (ISP): m/z=690.4 [M+H]+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][N:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[C:1]1([C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][N:21]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)c1ccnc(-c2ccccc2)c1

Procedure:
Phenylboronic acid (147 mg) and ethyl 2-chloroisonicotinate (200 mg) were treated in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [NH:1]([C:29]([CH3:31])=[O:30])[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([OH:28])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O[N:33]1[C:38](=[O:39])[CH2:37][CH2:36][C:34]1=[O:35].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:29]([CH3:31])=[O:30])[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([O:28][N:33]1[C:38](=[O:39])[CH2:37][CH2:36][C:34]1=[O:35])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:10])[CH2:3][O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)ON1C(=O)CCC1=O
Reaction time: 5 h

Procedure:
A solution of Ac-Ser(tBu)-Asp(OtBu)-Ala-OH (24.7 g, 55.4 mmol) in dry THF (526 mL) was treated with HOSu (9.55 g, 83.1 mmol, 1.5 eq.) and cooled to 0°. To the cold stirring (mechanical) solution DCC (17.14 g, 83.1 mmol, 1.5 eq.) was added portionwise and stirring proceeded at 0° for 30 min at 25° for 5 h. The reaction mixture was filtered and the filtrate evaporated to dryness and crystallized from isopropanol (250 mL). Yield: 23.2 g (77.2%); mp 155°-157°; [α]D25 -41.48° (c 1, MeOH); Rf 0.54 (CHCl3 :MeOH:AcOH; 80-5-1). Anal. calc. for C24H38N4O10 (542.58): C, 53.13; H, 7.06; N, 10.33. Found: C, 53.21; H, 6.85; N, 10.29.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6](=O)[CH:7](Br)[CH2:8][CH3:9])[CH3:2].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[S:20])=[CH:17][CH:16]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:21]=[C:19]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:25])=[CH:23][CH:22]=2)[S:20][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(Br)CC
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CCOC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC
Temperature: 25 °C
Yield: 70.6 %

Procedure:
4-Bromo-3-oxo-hexanoic acid ethyl ester (4.68 g, 20.98 mmol) is dissolved into denatured ethanol (100 mL) and para-trifluoromethyl thiobenzamide (4.31 g, 21 mmol) is added in one portion. The reaction is purged of air and flushed with nitrogen then heated to reflux. The reaction is monitored by TLC and HPLC and when complete, the reaction is allowed to cool to room temperature. The solvent is removed and the reaction is diluted with ethyl acetate (200 mL), followed by ishes with saturated sodium bicarbonate solution, water, and brine. The ethyl acetate solution is dried over anhydrous sodium sulfate, then concentrated and further purified using flash column chromatography (10% EtOAc/Hexanes) to yield pure [5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid ethyl ester (5.09 g, 14.82 mmol) or 71% yield.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[CH3:35][N:36]1[CH2:40][CH:39]([C:2]2[C:10]3[C:9]([N:11]4[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:3]=2)[CH:38]=[N:37]1
Reactant: O=C(NC1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1)c1ccccc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CC(c2cn(S(=O)(=O)c3ccccc3)c3ncnc(N4CCC(NC(=O)c5ccccc5)CC4)c23)C=N1
Temperature: 25 °C

Procedure:
N-{1-[5-bromo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D6 (400 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (185 mg, 0.89 mmol, commercially available from Maybridge, Sigma-Aldrich and Fluorochem), potassium phosphate trihydrate (590 mg, 2.22 mmol), palladium tetrakis (26 mg, 0.022 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml) and stirred under nitrogen at 90° C. overnight. Cooled to room temperature and the solvent removed in vacuo. Water (30 ml) was added and extracted with EtOAc (3×30 ml). The combined extracts were washed with brine and dried over MgSO4, concentrated to give crude product which was purified by silica gel column eluting with EtOAc to give 160 mg of desired product D27. LCMS [MH+] 542.2@1.56 min (5 min run)
Reaction SMILES: [C:1](Cl)(C)=O.[CH3:5][C:6]1[N:10]2[C:11]3[CH:17]=[CH:16][NH:15][C:12]=3[N:13]=[CH:14][C:9]2=[C:8]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][C:24]([OH:26])=[O:25])[CH:22]=2)[N:7]=1>CO>[CH3:5][C:6]1[N:10]2[C:11]3[CH:17]=[CH:16][NH:15][C:12]=3[N:13]=[CH:14][C:9]2=[C:8]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][C:24]([O:26][CH3:1])=[O:25])[CH:22]=2)[N:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1nc(-c2cnn(CC(=O)O)c2)c2cnc3[nH]ccc3n12
Solvent: CO
Product: COC(=O)Cn1cc(-c2nc(C)n3c2cnc2[nH]ccc23)cn1
Yield: 40 %

Procedure:
AcCl (20 mL) was added slowly with stirring to MeOH (100 mL) that was cooled in an ice bath. After about 1 h the solution was transferred to the 2-(4-(1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)-1H-pyrazol-1-yl)acetic acid. The solvents were removed under reduced pressure and saturated Na2CO3 (25 mL) was added. The product was extracted with DCM (5×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40 g silica gel) and eluted with a gradient of 2-9% MeOH in DCM to give methyl 2-(4-(1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)-1H-pyrazol-1-yl)acetate (0.109 g, 40%): LCMS (Table 2, Method b) Rt=1.46 min.; MS m/z: 311 (M+H)+. Syk IC50=B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][OH:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a stirred solution of [5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol (7.2 g, 0.021 mol) in THF (125 mL) and triethylamine (TEA) (4.6 mL, 0.033 mol) was added methanesulfonyl chloride (2.5 mL, 0.031 mol). The reaction mixture was stirred at 45° C. for 4 h. The reaction mixture was cooled to rt, quenched with H2O (75 mL) then washed with EtOAc (3×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to oil. This crude pyrazole mesylate was used in the next step without further purification. HPLC: Rt=10.03 (Method E). MS (ES+): mass calculated for C18H18Cl2N2O4S, 427.30; m/z found 428.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH3:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.C(N(CC)CC)C.[CH3:62][S:63](Cl)(=[O:65])=[O:64]>ClCCl>[CH3:62][S:63]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH3:12])[CH:6]=[C:7]([CH2:9][O:10][S:63]([CH3:62])(=[O:65])=[O:64])[CH:8]=1)(=[O:65])=[O:64]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN(C)c1cc(CO)cc(CO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN(C)c1cc(COS(C)(=O)=O)cc(COS(C)(=O)=O)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 2-(3,5-bis(hydroxymethyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate (265d) (71 mg, 0.091 mmol) in anhydrous dichloromethane (1.4 mL) was added triethylamine (0.038 mL, 0.272 mmol). The mixture was cooled to −5° C. and methanesulfonyl chloride (0.018 mL, 0.227 mmol) was added slowly. After stirring for one hour at −5° C. the reaction was quenched with cold water and extracted with cold ethyl acetate. The organic extracts were washed with cold water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 2-(3,5-bis((methylsulfonyloxy)methyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate. MS (m/z). found 960.2 (M+Na)+. To a mixture of methyl 2-(3,5-bis((methylsulfonyloxy)methyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate (69 mg, 0.074 mmol) and compound 8 (54.1 mg, 0.184 mmol) in anhydrous DMF (0.8 mL) was added potassium carbonate (50.8 mg, 0.368 mmol). The reaction was allowed to stir for 18 hours at room temperature. The reaction was quenched with water and extracted twice with dichloromethane. The remaining aqueous layer was extracted twice with 50% MeOH/CH2Cl2. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash silica gel chromatography (5% MeOH/CH2Cl2) followed by preparative reverse phase HPLC (C18 column, eluted with CH3CN/H2O) gave compound 265e (23 mg, 23%). MS (m/z). found 1375.4 (M+Na+H2O)+, 1393.4 (M+Na+2H2O)+.