Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[C@H:24]([CH3:25])[C@H:23](O)[CH2:22][C@H:21]([C:27]([O:29][CH3:30])=[O:28])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1C(O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O.O>[C:27]([C@@H:21]1[CH2:20][C@H:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:24]([CH3:25])=[CH:23][CH2:22]1)([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H]1C[C@@H](O)[C@@H](C)[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C(O)c1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC=C(C)[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 88.8 %

Procedure:
To a solution of 2.2.c (R=Me, P=TBDPS, A=COOCH3) (167 mg, 0.392 mmol), picolinic acid (257 mg, 2.092 mmol) and triphenylphosphine (548 mg, 2.092 mmol) in THF at −38° C. was added dropwise DIAD (diisopropyl azodicarboxylate; 412 μL, 2.092 mmol) over 4 min. The reaction solution was stirred for 4.5 h and warmed to room temperature overnight. The mixture was poured into water and EtOAc (50 ml:50 ml). The organic phase was separated, the aqueous layer was extracted with EtOAc (3×50 ml) and dried over MgSO4. The residue was separated by HPLC (isooctane/EtOAc 98:2), affording (4S,6S)-4-carbomethoxy-6-t-butyldiphenylsilyloxy-1-methylcyclohexene (142 mg, 88.8%) as a colorless oil.
Reaction SMILES: [C:1]([NH:5][CH:6]([OH:10])[C:7]([OH:9])=[O:8])(=[O:4])[CH:2]=[CH2:3].S(=O)(=O)(O)O.COC.[C:19]1([CH:26]=[CH:25][C:23](O)=CC=1)O>O.C1(C)C=CC=CC=1.C(O)CCC>[CH2:23]([O:10][CH:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:7]([O:9][CH2:19][CH2:26][CH2:25][CH3:23])=[O:8])[CH2:25][CH2:26][CH3:19]
Reactant: C=CC(=O)NC(O)C(=O)O
Reactant: Oc1ccc(O)cc1
Agent: COC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: C=CC(=O)NC(OCCCC)C(=O)OCCCC

Procedure:
One hundred parts of acrylamidoglycolic acid (AGA); 517 parts butanol, 1 part concentrated sulfuric acid and 0.1 part monomethyl ether of hydroquinone were mixed in a flask equipped with a Dean Stark water trap and a stirrer. The mixture was heated until homogeneous. After 5-10 minutes 100 ml of toluene was added and the mixture was brought to reflux and held 5 hours until the theoretical amount of water was collected by azeotrope.
Reaction SMILES: [C:1]([NH2:4])(=O)[CH3:2].O=P(Cl)(Cl)Cl.[BH4-].[Na+].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:18]1[C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:1][NH:4]1
Reactant: CC(N)=O
Reactant: Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)CCNC2
Yield: 51 %

Procedure:
Primary amine from example 1 (200 mg) was reacted with acetyl chloride (1.3 eq.) in dry ethylamine (3 eq.) and dry dichloromethane (5 ml) at 0° C. for 1 hour, then 25° C. for 14 hours and gave the acetamide in 88% yield. The acetamide (103 mg, 0.263 mmol) was refluxed for 3 hours with POCl3 (7.5 eq.) in dry toluene (10 ml) at 110° C. for 14 hours followed by NaBH4 reduction (11 eq.) in dry ethanol gave the corresponding 1,2,3,4-tetrahydroisoquinoline (50 mg, 51%). Demethylation as in example 1 gave the expected product as the hydrobromide salt (50 mg, 87%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13])=[C:2]=[O:3].[Cl:14][CH2:15][CH2:16][CH2:17][OH:18]>C1(C)C=CC=CC=1>[CH3:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[NH:1][C:2](=[O:3])[O:18][CH2:17][CH2:16][CH2:15][Cl:14]
Reactant: OCCCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)OCCCCl

Procedure:
Prepared analogously to Example 51b from 4-isocyanato-3-methyl-1-nitro-benzene and 3-chloro-propan-1-ol in toluene.
Reaction SMILES: [P:1]([O:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:28]([C@H:35]([NH:60][C:61](=[O:73])[C@@H:62]([N:66]1[CH2:71][CH2:70][CH2:69][NH:68][C:67]1=[O:72])[CH:63]([CH3:65])[CH3:64])[CH2:36][C@H:37]([OH:59])[C@@H:38]([NH:46][C:47](=[O:58])[CH2:48][O:49][C:50]1[C:55]([CH3:56])=[CH:54][CH:53]=[CH:52][C:51]=1[CH3:57])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:4]([O:3][P:1]([O:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([O:59][C@H:37]([C@@H:38]([NH:46][C:47](=[O:58])[CH2:48][O:49][C:50]1[C:55]([CH3:56])=[CH:54][CH:53]=[CH:52][C:51]=1[CH3:57])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:36][C@@H:35]([NH:60][C:61](=[O:73])[C@@H:62]([N:66]1[CH2:71][CH2:70][CH2:69][NH:68][C:67]1=[O:72])[CH:63]([CH3:64])[CH3:65])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(CCOP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)Cl
Reactant: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O)OC(=O)C(C)(C)CCOP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
To a solution containing the product from Example 11C (0.538 mmol) dissolved in dichloromethane (1.0 mL) at 0° C., were added the product of Example 3 (0.085 g, 0.134 mmol) and 4-(dimethylamino)pyridine (0.066 g) and the reaction was allowed to warm to room temperature and was stirred for 16 hours. The reaction was diluted with dichloromethane, and the organic layer was washed with 10% citric acid, water and brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with dichloromethane and ending with 5% methanol in ethyl acetate, to give the title compound (0.075 g, 56%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:25][CH2:24]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(CCCCn2cnc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 2-methoxyphenyl piperazine (5.77 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 7.7 g compound (I-4) with a yield of 70.6%. ESI-MS [M+H]+: m/z 365.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=3[F:20])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.BrC1C=C2C(C([C:33]3[CH:38]=[CH:37][CH:36]=[C:35](O)[C:34]=3C)=O)=CNC2=NC=1.C1(B(O)O)C=CC=CC=1.B(O)O>>[F:20][C:14]1[C:15]([OH:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:3]=2)[NH:8][CH:9]=1)=[O:12]
Reactant: O=C(c1cccc(O)c1F)c1c[nH]c2ncc(Br)cc12
Reactant: Cc1c(O)cccc1C(=O)c1c[nH]c2ncc(Br)cc12
Agent: OB(O)c1ccccc1
Agent: OBO
Product: O=C(c1cccc(O)c1F)c1c[nH]c2ncc(-c3ccccc3)cc12

Procedure:
Additional compounds were prepared following the protocol of Scheme 11, optionally replacing (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-hydroxy-phenyl)-methanone P-0067 with (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-hydroxy-2-methyl-phenyl)-methanone P-0055 (prepared as described in Example 56, Scheme 22) in Step 1 and optionally replacing phenylboronic acid with an appropriate boronic acid in Step 2. The following compounds were made following this procedure:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:32])[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:32])[C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][C:2]5=[O:1])=[CH:16][CH:15]=4)=[O:14])[CH2:30][CH2:31]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(CN2CCCC2=O)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3CCCC3=O)cc2)CC1
Yield: 36.1 %

Procedure:
Using 4-(2-oxopyrrolidin-1-ylmethyl)benzoic acid (132 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (156 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (91 mg) was obtained.
Reaction SMILES: C1C2CCCCC=2C=CC=1CC1C=C(C(O)=O)C(CC2C=CC3CCCCC=3C=2)=CC=1C(O)=O.C1C2CCCCC=2C=CC=1CC1C=C(CC2C=CC3CCCCC=3C=2)C(C(O)=O)=CC=1C(O)=O.FC(F)(F)S(O)(=O)=O.[CH2:77]1[C:106]2[C:81](=[CH:82][C:83]3[C:84](=O)[C:85]4[C:102]([CH2:103][C:104]=3[CH:105]=2)=[CH:101][C:100]2[C:99](=O)[C:98]3[C:89](=[CH:90][C:91]5[CH2:92][CH2:93][CH2:94][CH2:95][C:96]=5[CH:97]=3)[CH2:88][C:87]=2[CH:86]=4)[CH2:80][CH2:79][CH2:78]1.C1C2C(=CC3C(=O)C4C(CC=3C=2)=CC2CC3C(=CC5CCCCC=5C=3)C(=O)C=2C=4)CCC1>>[CH2:92]1[C:91]2[C:96](=[CH:97][C:98]3[C:89]([CH:90]=2)=[CH:88][C:87]2[C:100](=[CH:101][C:102]4[C:85]([CH:86]=2)=[CH:84][C:83]2[C:104](=[CH:105][C:106]5[CH2:77][CH2:78][CH2:79][CH2:80][C:81]=5[CH:82]=2)[CH:103]=4)[CH:99]=3)[CH2:95][CH2:94][CH2:93]1
Reactant: O=C1c2cc3c(cc2Cc2cc4c(cc21)Cc1cc2c(cc1C4=O)CCCC2)CCCC3
Agent: O=C(O)c1cc(C(=O)O)c(Cc2ccc3c(c2)CCCC3)cc1Cc1ccc2c(c1)CCCC2
Agent: O=C(O)c1cc(Cc2ccc3c(c2)CCCC3)c(C(=O)O)cc1Cc1ccc2c(c1)CCCC2
Agent: O=C1c2cc3c(cc2Cc2cc4c(cc21)C(=O)c1cc2c(cc1C4)CCCC2)CCCC3
Product: c1c2c(cc3cc4cc5cc6cc7c(cc6cc5cc4cc13)CCCC7)CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 35.3 grams of 2,5-bis(5,6,7,8-tetrahydronaphthalen-2-ylmethyl)terephthalic acid and 4,6-bis(5,6,7,8-tetrahydronaphthalen-2-ylmethyl)isophthalic acid was added 120 grams of trifluoromethanesulfonic acid. The resulting mixture was stirred at room temperature for one hour followed by heating to 60° C. for six hours. The mixture was poured over 500 grams of ice. The resulting solid was isolated by filtration and washed with 500 mL of saturated aqueous sodium bicarbonate solution and then 4 L of water until the filtrate was neutral to pH paper. The solid was dried to give a mixture of 1,2,3,4,8,10,11,12,13,17-decahydroheptacen-6,15-dione and 1,2,3,4,10,11,12,13-octahydroheptacen-6,8(15H,17H)-dione
Reaction SMILES: C([Li])CCC.[CH:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[S:19][CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10]1)([CH3:8])[CH3:7].C(Br)(Br)(Br)[Br:21]>C1COCC1>[Br:21][C:18]1[S:19][C:15]([N:12]2[CH2:11][CH2:10][N:9]([CH:6]([CH3:8])[CH3:7])[CH2:14][CH2:13]2)=[CH:16][N:17]=1
Reactant: CC(C)N1CCN(c2cncs2)CC1
Reactant: BrC(Br)(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2cnc(Br)s2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
At −78° C., n-butyl lithium (2.5 N in hexane, 0.27 mL, 2 eq.) was added to 5-(4-isopropylpiperazin-1-yl)thiazole (28 mg, 0.132 mmol) in 1 mL THF. CBr4 (22 mg, 0.5 eq.) was added after 30 minutes. The reaction was stirred at −78° C. for 2 hours. The reaction was quenched by adding water. The reaction crude was extracted using EtOAc. The organic layers were concentrated and purified via Combiflash (0-20% MeOH in EtOAc) to give desired product. LCMS-ESI+: calc'd for C10H17BrN3S: 290.0 (M+H+); Found: 290.1 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([OH:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2.[C:34](=O)([O:37]C)[O:35][CH3:36]>COCCOC.C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([OH:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][O:33][C:34]([O:35][CH3:36])=[O:37])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: Cc1cc(O)c(C(=O)CCc2ccc3occc3c2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Reactant: COC(=O)OC
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: COC(=O)OC[C@H]1O[C@@H](Oc2cc(C)cc(O)c2C(=O)CCc2ccc3occc3c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 24 h

Procedure:
3-(5-Benzo[b]furanyl)-2'-(β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone (10 g) is dissolved in ethyleneglycol dimethyl ether (30 ml), and thereto are added dimethyl carbonate (100 ml), Novozyme 435 (2 g, manufactured by Novo Nordisk A/S, Denmark) and molecular sieves 4A powder (8 g), and the mixture is stirred at 40° C. for 24 hours, and stirred at room temperature for 14 hours. The reaction mixture is diluted with chloroform, and the insoluble materials are removed by filtration. The filtrate is concentrated to dryness, and the residue is dissolved in ethyl acetate. The mixture is washed successively with 10% aqueous hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. The residue is recrystallized three times from ether-isopropyl ether-water to give 3-(5-benzo[b]-furanyl)-2'-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone (7.9 g). The physicochemical properties of the compound are the same as those of the compound obtained in Example 18.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>CC#N>[N+:19]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)([O-:21])=[O:20]
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnccc1-n1cccn1
Reaction time: 0.33 h

Procedure:
A suspension of pyrazole (150 mg, 2.2 mmol) and Cs2CO3(526 mg, 1.6 mmol) in anhydrous MeCN (3.5 mL) was stirred for 20 min under an inert atmosphere. 4-chloro-3-nitro-pyridine (233 mg, 1.47 mmol) was then added and stirred overnight at 75° C. The insoluble was filtered off and the filtrate was concentrated under reduced pressure yielding 3-nitro-4-(1H-pyrazol-1-yl)pyridine that was used without further purification. (410 mg, 98%). MS (ES+) 191.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:35]1[S:39][C:38]([C:40]2([OH:44])[CH2:43][CH2:42][CH2:41]2)=[N:37][CH:36]=1>CN(C=O)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[C:35]1[S:39][C:38]([C:40]2([OH:44])[CH2:43][CH2:42][CH2:41]2)=[N:37][CH:36]=1
Reactant: OC1(c2ncc(Br)s2)CCC1
Reactant: CC1(C)OB(c2cc(Nc3nccc(C(F)(F)F)n3)ccc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OC1(c2ncc(-c3cc(Nc4nccc(C(F)(F)F)n4)ccc3F)s2)CCC1
Temperature: 85 °C
Yield: 24.9 %

Procedure:
To a solution of the product of Step 2 (383 mg, 1.0 mmol) in DMF (2 mL) and aqueous sodium carbonate (2 M, 1.5 mL, 3.0 mmol) in a microwave vial was added Intermediate 1 (234 mg, 1.0 mmol), and PdCl2(dppf)-dichloromethane adduct (82 mg, 0.1 mmol) under dry nitrogen. The vial was sealed and the reaction was heated in a microwave at 85° C. for 2 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, then brine and was dried over sodium sulfate. The organic was concentrated after filtration and was purified by flash chromatography (25:75 ethyl acetate:hexanes) to afford 1-[5-(2-fluoro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanol as an off-white foamy solid (102 mg, 0.249 mmol, 24.9%). 1H NMR (500 MHz, CDCl3): δ 8.66 (d, J=4.9 Hz, 1H); 8.07 (s, 1H); 8.03 (d, J=6.1 Hz, 1H); 7.82 (s, 1H); 7.50 (dt, J=8.8, 3.4 Hz, 1H); 7.16 (t, J=9.6 Hz, 1H); 7.07 (d, J=4.9 Hz, 1H); 4.07 (s, 1H); 2.77-2.70 (m, 2H); 2.59-2.49 (m, 2H); 2.13-1.98 (m, 2H). rhSYK activity=++
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[CH3:11][S:12]([NH:15][CH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[CH2:16][NH:15][S:12]([CH3:11])(=[O:14])=[O:13])=[N:3]2)=[N:7][CH:8]=1
Reactant: CS(=O)(=O)NCc1cccc(B(O)O)c1
Reactant: Brc1nn2c(I)cnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)NCc1cccc(-c2nn3c(I)cnc3s2)c1
Temperature: 115 °C
Yield: 23.4 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.25 g, 0.757 mmol, 1 eq), (3-methanesulfonylaminomethylphenyl)boronic acid (0.208 g, 0.908 mmol, 1.2 eq), cesium carbonate (0.493 g, 1.514 mmol, 2 eq), Pd(PPh3)2Cl2 (0.053 g, 0.075 mmol, 0.1 eq), 1,4-dioxane (6 mL) and water (6 mL) was heated in a pressure tube at 115° C. for 4 h. Solvents were removed and the slurry obtained was partitioned between water and 10% MeOH in DCM. The organic layer was dried, filtered and evaporated. The residue was purified in an Isolute Flash Si II column (EtOAc) to give the desired product (77 mg, 23%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.04 min, [M+H]+ m/z 435.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:10](=[O:28])[N:9]([CH2:29][C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[O:38][CH3:39])[C:8]=3[C:6]=2[CH:7]=1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:40]1([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[C:12]([C:15]5[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=5)=[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:10](=[O:28])[N:9]([CH2:29][C:30]5[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=5[O:38][CH3:39])[C:8]=4[C:6]=3[CH:7]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c2oc3ccc(Br)cc3c2n(Cc2cc(OC)ccc2OC)c1=O
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c2oc3ccc(-c4ccccc4)cc3c2n(Cc2cc(OC)ccc2OC)c1=O

Procedure:
Ethyl 8-bromo-1-(2,5-dimethoxybenzyl)-4-(4-methoxyphenyl)-1,2-dihydro-2-oxobenzofuro[3,2-b]pyridine-3-carboxylate is reacted analogously to Example 3 with phenylboronic acid to give ethyl 8-phenyl-1-(2,5-dimethoxybenzyl)-4-(4-methoxyphenyl)-1,2-dihydro-2-oxobenzofuro[3,2-b]pyridine-3-carboxylate, m.p. 216°. By ester hydrolysis thereof the 8-phenyl-1-(2,5-dimethoxybenzyl)-4-(4-methoxyphenyl)-1,2-dihydro-2-oxobenzofuro[3,2-b]pyridine-3-carboxylic acid is obtained, m.p. 270°.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:16][NH:17][C:18](=[O:30])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[NH2:20].C(N(CC)CC)C>ClCCl.O.CN(C)C=O>[CH3:16][NH:17][C:18](=[O:30])[C@H:19]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[NH:20][C:5](=[O:7])[C:4](=[O:8])[CH2:3][CH:2]([CH3:1])[CH3:9]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CC(C)CC(=O)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(=O)CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
4-Methyl-2-oxopentanoic acid (31.3 g., 0.24 mol.) was dissolved in dry dichloromethane (50 mls.) and the resultant solution was cooled to 0° C. To the solution was added dropwise oxalyl chloride (23.2 mls., 0.265 mol.), followed by dimethylformamide (0.5 ml.). The resultant mixture was stirred at 0° C. for 1 hour, and then heated under reflux for 5 minutes and then allowed to cool. O-Methyl-L-tyrosine N-methylamide (50.0 g., 0.24 mol.) and triethylamine (37.1 mls., 0.265 mol.) were dissolved in dichloromethane (120 mls.) and the resultant solution added dropwise to the cooled reaction mixture. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into water (50 mls.) and the organic layer was removed. The aqueous layer was extracted with dichloromethane (30 mls.), the combined extracts were dried over anhydrous sodium sulfate and the solvent removed by evaporation in vacuo to yield a crude product as a yellow solid (85.1 g). The crude product was recrystallized from tertiary butyl ethyl ether to yield N-(4-methyl-2-oxopentanoyl)-O-methyl-L-tyrosine N-methylamide (55.6 g) (m.p. 152°-8° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH2:20])[CH2:8][C@@H:7]1[CH3:21])=[O:5])[CH3:2].C(O)(=O)C.[F:26][C:27]([F:41])([F:40])[C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH:31]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)C.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH:20][CH2:31][C:30]2[CH:33]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:35]=[C:28]([C:27]([F:26])([F:40])[F:41])[CH:29]=2)[CH2:8][C@@H:7]1[CH3:21])=[O:5])[CH3:2]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N)C[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 70.8 %

Procedure:
A solution of cis-4-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (527 mg, 1.8 mmol) in dichloroethane (12 mL) was treated sequentially with acetic acid (0.1 mL, 1.8 mmol) and 3,5-bis-trifluoromethyl-benzaldehyde (0.30 mL, 1.8 mmol). After stirring 35 minutes at room temperature, sodium triacetoxyborohydride (570 mg, 2.7 mmol) was added to the mixture. After 3 days, 20 mL of water was added and the mixture made basic (pH 10) with potassium carbonate. The mixture was extracted with ethyl acetate (3×35 mL), the combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-20% ethyl acetate in hexanes to provide the title compound (663 mg). 1H NMR (CDCl3) δ 1.22 (d, 3H), 1.3 (t, 3H), 1.5 (m, 1H), 2.6 (m, 1H), 3.55 (dd, 1H), 3.87 (s, 3H), 3.89 (s, 3H), 4.1-4.6 (m, 5H), 7.06 (s, 1H), 7.08 (s, 1H), 7.8 (s, 1H), 7.95 (s, 2H).