Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]([C:7]([N-:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8])[CH3:6])[CH:2]=[CH2:3].N[C@H](C([N-]CCCC1C=CC=CC=1)=O)C.[C:34]([NH:41][C@H:42]([C:53](O)=[O:54])[CH2:43][C:44]1[C:49]([CH3:50])=[CH:48][C:47]([OH:51])=[CH:46][C:45]=1[CH3:52])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(OC(Cl)=O)C(C)C>C(Cl)Cl.CN(C)C=O>[CH3:40][C:37]([CH3:38])([O:36][C:34]([NH:41][C@H:42]([C:53]([N:4]([CH2:1][CH:2]=[CH2:3])[C@@H:5]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:8])[CH3:6])=[O:54])[CH2:43][C:44]1[C:49]([CH3:50])=[CH:48][C:47]([OH:51])=[CH:46][C:45]=1[CH3:52])=[O:35])[CH3:39]
Reactant: C=CCN[C@H](C)C(=O)[N-]CCCc1ccccc1
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: C[C@H](N)C(=O)[N-]CCCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCN(C(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C)[C@H](C)C(=O)NCCCc1ccccc1

Procedure:
N-Allyl-(D)-alanylphenylpropylamide (5.00 g, 20.3 mmol) replaced (D) alanyl-phenylpropylamide in the mixed anhydride synthesis described in Example 2. It was reacted using Boc-2,6-dimethyl-tyrosine (6.28 g, 20.3 mmol) N-methyl morpholine (2.05 g, 20.3 mmol) and isobutylchloroformate (2.77 g, 20.3 mmol). Dimethylformamide replaced CH2Cl2 as the solvent. The reaction mixture was worked up as in Example 2 and the resultant oil (10.62 g) was purified by column chromatography on Woelm silica eluting with 3 to 5% methanol-methylene chloride and the diasteromers were separated:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19].C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C1COCC1>[C:36]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CN(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1(CCCN)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCCC1(c2ccccc2)C=C(c2cc(Cl)ccc2F)CN1C(=O)N(C)C
Reaction time: 8 h

Procedure:
To 20 mg (0.05 mmol) of amine 20-2 in THF was added 21 μL (0.15 mmol) of triethylamine and 7 μL (0.10 mmol) of acetyl chloride. After stirring overnight the reaction was partitioned between EtOAc and 10% KHSO4, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 20-3 as a white solid. Data for 20-3: 1HNMR (500 MHz, d6-DMSO) δ 7.8 (m, 1H), 7.6 (m, 1H), 7.4-7.2 (m, 7H), 6.2 (s, 1H), 4.9 (m, 1H), 4.7 (m, 1H), 3.05 (m, 2H), 2.7 (s, 6H), 2.05 (m, 1H), 1.8 (s, 3H), 1.2-1.1 (m, 3H) ppm. HRMS (ES) calc'd M+H for C24H27ClFN3O2: 444.1849. Found: 444.1847.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([Cl:31])=[C:7]([NH:21][C:22](=[O:30])[C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])[CH:8]=[CH:9][C:10]=1[S:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=[O:3])[CH3:2].[CH2:32]([CH2:34][NH2:35])[OH:33]>C(#N)C>[C:1]([NH:4][C:5]1[C:6]([Cl:31])=[C:7]([NH:21][C:22](=[O:30])[C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:25])[F:26])[CH:8]=[CH:9][C:10]=1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:35][CH2:34][CH2:32][OH:33])=[CH:16][CH:15]=1)(=[O:12])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(S(=O)(=O)c2ccc(F)cc2)ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c1Cl
Reactant: NCCO
Solvent: CC#N
Product: CC(=O)Nc1c(S(=O)(=O)c2ccc(NCCO)cc2)ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c1Cl
Temperature: 85 °C
Yield: 33.3 %

Procedure:
(R)-N-[3-Acetamido-2-chloro-4-(4-fluorophenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (683 mg) (Example 10), ethanolamine (177 mg, 2 eq) and acetonitrile (6 ml) were stirred and heated (85° C.) under argon for 24 hours. The solvent was removed and the residual gum was redissolved in MeOH (10 ml) and poured onto deactivated silica (5 g). This was concentrated to give a free flowing powder which was transferred to the top of an ISOLUTE column (50 g silica). This was chromatographed, eluting with MeOH/DCM to give the title compound (247 mg) as a brown solid. NMR (400 MHz): 1.59 (s, 3H), 1.95 (s, 3H), 3.08-3.19 (m, 2H), 3.53 (q, 2H), 4.66-4.73 (t, 1H), 6.62 (d, 2H), 6.67 (t, 1H), 7.0 (brs, 1H), 7.44 (d, 2H), 8.06 (d, 1H), 8.29 (d, 1H), 9.61 (brs, 1H), 9.82 (brs, 1H); m/z 524 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Cl[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[N:14]=1.C1(O)C=CC=CC=1.[H-].[Na+]>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:15]2[N:16]=[C:17]([CH3:19])[CH:18]=[C:13]([O:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:10])([F:11])[F:1])[N:14]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: Oc1ccccc1
Product: COc1cc(Nc2nc(C)cc(Oc3ccccc3C(F)(F)F)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogous manners as described in example 9 from 2-trifluoromethyl-phenol and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The reaction was heated for 3.5 h to 200° C. in a microwave oven. Several times the phenol (overall 4.4 equivalents) and additional sodium hydride had to be added in order to obtain complete conversion. The title compound was obtained, after purification by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent, as a white solid in 15% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:29]([C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)(=[O:31])=[O:30])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Clc1nc(N2CCOCC2)c2cc(CN3CCNCC3)sc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccs1)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C

Procedure:
To 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[2,3-d]pyrimidine (150 mg) in anhydrous DCM (4 ml) and triethylamine (90 ul) was added 2-thiophenesulfonyl chloride (101 ul) at 0° C. The reaction mixture was allowed to warm up to room temperature over 4 hours. Aqueous work-up and purification on silica gave 2-chloro-4-morpholin-4-yl-6-[4-(thiophene-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[2,3-d]pyrimidine (208 mg).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1>C(O)C>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([N:13]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:15][CH:16]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: CC(=O)c1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 104.3 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g, 2.94 mmol) and 1-(4-aminophenyl) ethanone (1.19 g, 1.19 mmol) in ethanol (3 mL). 1-(4-acetylphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.307 g (42%) was obtained as a bright yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:6][CH:7]=1
Reactant: Nc1cc(C2=C(c3ccc(F)cc3)CCCC2)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc([C@@H]2CCCC[C@@H]2c2ccc(F)cc2)ccn1
Reaction time: 48 h
Yield: 54.1 %

Procedure:
A solution of 4-[2-(4-Fluoro-phenyl)-cyclohex-1-enyl]-pyridin-2-ylamine (220 mg, 0.82 mmol, synthesis described in example 56) in methanol (10 mL) is passed through H-Cube® Continuous-flow Hydrogenation Reactor at 60° C. and under 60 psi hydrogen pressure. The 10% Pd/C cartridge is used and the reaction is run for 48 hours. The solvent is removed to give 120 mg of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:11].[C:12]1(B(O)O)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=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>[C:12]1([C:2]2[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=2[NH2:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: OB(O)C1=CCCCC1
Reactant: CC(C)c1ccc(N)c(Br)c1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(N)c(C2=CCCCC2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a mixture of 2-bromo-4-isopropyl-phenylamine (214 mg, 1.00 mmol), cyclohexane-1-enyl boronic acid (139 mg, 1.10 mmol) and Pd(PPh3)4 (116 mg, 0.100 mmol) in 5 mL of 1,4-dioxane was added 2.0 M aqueous Na2CO3 solution (4.0 mL, 8.0 mmol). The resulting mixture was stirred at 80° C. for 8 h under Ar, and then cooled to RT. The reaction was treated with EtOAc (20 mL) and washed with H2O (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (DCM) to give 205 mg (95%) of the title compound as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C15H21N, 216.2 (M+H), found 216.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][C:13]([C:15]3[CH:35]=[CH:34][C:18]([O:19][C:20]4[CH:29]=[C:28]5[C:23]([CH:24]([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][O:27]5)=[CH:22][C:21]=4[Cl:33])=[CH:17][CH:16]=3)=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.O1CCCC1CO.C[O-].[Na+:45]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][C:13]([C:15]3[CH:35]=[CH:34][C:18]([O:19][C:20]4[CH:29]=[C:28]5[C:23]([CH:24]([C:30]([O-:32])=[O:31])[CH2:25][CH2:26][O:27]5)=[CH:22][C:21]=4[Cl:33])=[CH:17][CH:16]=3)=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[Na+:45]
Reactant: O=C(NCCc1ccc2c(c1)OCO2)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: OCC1CCCO1
Product: O=C(NCCc1ccc2c(c1)OCO2)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.25 h
Yield: 100 %

Procedure:
7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid (60 mg, 0.12 mmol), 0.1 molar in 4:1 tetrahydrofuran-methanol, was treated with sodium methanolate (242 μl, 0.12 mmol) at ambient temperature. After 15 minutes, the solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate and concentrated in vacuo. The solid was then taken up in 4:1 dichloromethane-hexanes and concentrated in vacuo and dried under high vacuum to provide sodium 7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (63 mg, 0.12 mmol, 101% yield) as a solid. MS (apci) m/z=495.9 (M+2H—Na).
Reaction SMILES: [F:1][C:2]1[C:3]([O:37][CH3:38])=[C:4]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:5][CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:9][N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[C:7]1=O.Cl>C1COCC1>[F:1][C:2]1[C:3]([O:37][CH3:38])=[C:4]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:5][CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:9][N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[CH2:7]1
Reactant: COc1ccc(CN2CC(c3ccc(OC)c(OC)c3)C(Cc3cc(F)cc(F)c3OC)C2=O)cc1OC
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(Cc3cc(F)cc(F)c3OC)C(c3ccc(OC)c(OC)c3)C2)cc1OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
200 ml of a solution of 17.78 g (33.8 mmol) of 3-(3,5-difluoro-2-methoxybenzyl)-N-(3,4-dimethoxybenzyl)-4-(3,4-dimethoxyphenyl)pyrrolidone in THF was dropwise added at 0° C. in a nitrogen atmosphere to 150 ml of a 1M solution of a borane/THF complex in THF. The mixture was heated under reflux for 2 hr and cooled, and 50 ml of a 6N hydrochloric acid solution was added thereto. The mixture was heated to 60° C. After stirring for 2 hr, THF was concentrated in vacuo and extracted twice with methylene chloride. The obtained organic phase was washed with a saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled off in vacuo. The residue was subjected to silica gel column chromatography (ethyl acetate:n-hexane=4:1) to prepare 12.46 g (yield: 72%) of the intended product.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[S:8][CH:6]1[OH:7])(=[O:3])[CH3:2].[BH3:25].[CH2:26]([C:28]1[CH:41]=[CH:40][C:31]([CH2:32][C:33]2[CH:38]=[CH:37][NH+:36]=[CH:35][C:34]=2O)=[CH:30][CH:29]=1)[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[BH3:25].[CH2:26]([C:28]1[CH:41]=[CH:40][C:31]([CH2:32][C:33]2[CH:34]=[CH:35][NH+:36]=[CH:37][C:38]=2[O:7][C@@H:6]2[S:8][C@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:5]2[O:4][C:1](=[O:3])[CH3:2])=[CH:30][CH:29]=1)[CH3:27]
Reactant: CCc1ccc(Cc2cc[nH+]cc2O)cc1
Reactant: CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: B
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc[nH+]cc2O[C@@H]2S[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.9 %

Procedure:
To a solution of 2, 3, 4, 6-tetra-O-acetyl-5-thio-D-glucopyranose (481 mg, 1.32 mmol), 4-(4-ethylbenzyl)-3-hydroxypyridinium borane (200 mg, 0.881 mmol) and triphenylphosphine (230 mg, 1.32 mmol) in tetrahydrofuran (2.5 mL), diisopropyl azodicarboxylate (40% in toluene, 0.781 mL, 1.32 mmol) was added dropwise at 0° C. After stirring at room temperature for 2.5 hours, the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give a crude product of 4-(4-ethylbenzyl)-3-(2, 3, 4, 6-tetra-O-acetyl-5-thio-β-D-glucopyranosyloxy)pyridinium borane (440 mg) as a colorless oil. To this crude product, triethylamine:methanol:water (2:1:1, 3 mL) was added and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and the resulting residue was mixed, without purification, with methanol (1.8 mL) and 2M HCl (1.8 mL), followed by stirring at room temperature for 30 minutes. After addition of saturated sodium bicarbonate solution under ice cooling, the reaction mixture was extracted with chloroform (5 mL×4). The organic layers were concentrated and the resulting residue was purified by silica gel column chromatography (chloroform:methanol 7:1) to give the titled compound (30 mg, 9%).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[O:23]1[CH2:24][CH2:25][N:20]([CH2:1][C@@H:3]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][N:4]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:21][CH2:22]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1CN1CCOCC1
Yield: 89.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (Aubry, S. et al., Tetrahedron Lett., 47:1319-1323 (2006)) (71 mg, 0.27 mmol) and morpholine (28 μL, 0.33 mmol) were converted to the title compound (80 mg, 89%). 1H NMR (CDCl3, mixture of rotamers) δ 7.24-7.20 (m, 4H), 4.85-4.66 (m, 1H), 4.54-4.42 (m, 1H), 4.30-4.17 (m, 1H), 3.67 (br s, 4H), 3.13-2.96 (m, 1H), 2.93-2.69 (m, 1H), 2.62-2.29 (m, 5H), 2.18-2.01 (m, 1H), 1.51 (s, 9H); MS(ESI+) m/z 333.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]([Sn](CCCC)(CCCC)CCCC)=[CH:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:16])[CH3:15].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:12]([F:11])=[CH:13][C:14]([CH3:15])([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[CH3:16])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: CCCC[Sn](CCCC)(CCCC)C(F)=CC(C)(C)c1ccc(Cl)cc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1C(F)=CC(C)(C)c1ccc(Cl)cc1

Procedure:
This compound is prepared in a manner analogous to that of Step E of Example 4, using 1.2 grams (0.0048 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine, 2.3 grams (0.0048 mole) of 1-fluoro-3-(4-chlorophenyl)-3-methyl-1-tributylstannyl-1-butene, 0.04 gram of tri-2-furylphosphine, 0.04 gram of tris(dibenzylidineacetone)dipalladium(0) in about 30 mL of N,N-dimethylformamide, yielding 2,4-diamino-6-methyl-5-[1-fluoro-3-methyl-3-(4-chlorophenyl)-1-butenyl]pyrimidine.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32]C)=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[Br:39]C1C=CC(CC(=O)C(OC)=O)=CC=1.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH3:32])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][C:25]([Br:39])=[CH:24][CH:23]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC(=O)C(=O)Cc1ccc(Br)cc1
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: COC(=O)/C(=C/c1ccc(Br)cc1)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 11 %

Procedure:
The title compound was prepared as described for C4 using methyl 3-(4-bromophenyl)-2-oxopropanoate B18 (100 mg, 0.389 mmol), sodium hydride (10.27 mg, 0.428 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-galactose bromide (160 mg, 0.389 mmol). The resulting compound was isolated in the form of white solid in 11% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](B2OC(C)(C)C(C)(C)O2)=[N:23]1>>[NH:22]1[C:30]2[C:25](=[C:26]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][CH2:13][CH2:14][O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: Cn1ncc2c(NCCOc3ccccc3)nc(Cl)nc21
Product: Cn1ncc2c(NCCOc3ccccc3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-phenoxy-ethyl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification by preparative HPLC yielded 143. NMR (CDCl3) 4.19 (s, 3H, CH3), 4.27 (m, 2H, CH2), 4.36 (m, 2H, CH3), 5.83 (sbr, H, NH), 7.00 (m, 3H, 3×ArH), 7.32 (m, 2H, 2×ArH), 7.55 (m, H, ArH), 7.64 (m, H, ArH), 7.96 (s, H, ArH), 8.45 (d, H, ArH, J=7.23 Hz0, 9.18 (s, H, ArH), 10.16 (sbr, H, NH). MS: (ESI+) MEI+=386.19
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.BrC1C=C(O)C=CC=1.[C:19]1([CH:25]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:26]2[C:34]3[CH:33]=[C:32]4[O:35][CH2:36][CH2:37][O:38][C:31]4=[CH:30][C:29]=3[C:28](=[O:39])[C:27]2=[O:40])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[C:41]1([CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]2[C:34]3[CH:33]=[C:32]4[O:35][CH2:36][CH2:37][O:38][C:31]4=[CH:30][C:29]=3[C:28]([OH:39])([C:8]3[C:7]([OH:10])=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=3)[C:27]2=[O:40])[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cc3c(cc21)OCCO3
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cc3c(cc2C1(O)c1cc2c(cc1O)OCC2)OCCO3

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,3-dihydrobenzofuran-6-ol to replace 3-bromophenol, and 6-(diphenylmethyl)-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 6-(diphenylmethyl)-8-hydroxy-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one was obtained (94%) as a colorless solid: MS (ES−) m/z 506.1 (M−1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:12][C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])=[CH2:2]>C(O)C.[C].[Pd]>[CH:1]([C:4]1[CH:5]=[C:6]([CH2:12][C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(CC#N)ccc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CC#N)cc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
(3-Isopropenyl-4-methoxyphenyl)acetonitrile (4.42 g, 23.61 mmol) obtained in Example (109-1) was dissolved in ethanol (50 ml) and 10% palladium-carbon (1 g) was added thereto, and the mixture was stirred at room temperature under a hydrogen atmosphere for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1) to give (3-isopropyl-4-methoxyphenyl)acetonitrile (4.08 g, yield: 91%).
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][C:37]=1[CH3:38])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]2)=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=1)=[O:17]>>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:36]2[CH:35]=[C:15]([CH:14]=[CH:13][C:37]=2[CH3:38])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([C:31]([F:32])([F:33])[F:34])[CH:20]=2)=[O:17])[N:7]2[C:6]=1[CH:11]=[CH:10][CH:9]=[N:8]2
Reactant: C#Cc1cnc2cccnn12
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(I)c3)cc2C(F)(F)F)cn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(C#Cc4cnc5cccnn45)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 3-iodo-4-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)-3(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The title compound was obtained as a light yellow solid. Mp: 124-126° C.; 1H NMR (300 MHz, CDCl3) δ: 9.00 (1H, s), 8.48 (1H, d, J=4.8 Hz), 8.17 (1H, s), 8.09 (3H, m), 7.93-7.95 (1H, d, J=8.7 Hz), 7.86-7.89 (1H, d, J=8.1 Hz), 7.55 (1H, s), 7.39-7.42 (1H, d, J=8.1 Hz), 7.34-7.36 (1H, d, J=8.4 Hz), 7.11-7.16 (1H, dd, J=4.2 and 8.4 Hz), 6.82 (1H, s), 2.64 (3H, s), 2.29 (3H, s). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C27H20F3N6O: 501.1645. found: 501.1626.