Azzindani/Open_Reaction_Data huggingface dataset:
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])[CH2:8][O:7][CH:6]1[N:19]=[C:20]=[S:21])(=[O:3])[CH3:2].[NH2:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>C1(C)C(C)=CC=CC=1>[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])[CH2:8][O:7][C@@H:6]1[NH:19][C:20]([NH:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)=[S:21])(=[O:3])[CH3:2]
Reactant: Nc1nc2ccccc2s1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)C(N=C=S)OC[C@H]1OC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](NC(=S)Nc2nc3ccccc3s2)OC[C@H]1OC(C)=O

Procedure:
To 15 ml of anhydrous xylene were added 320 mg (1 mmol) of 2,3,4-tri-O-acetyl-D-arabinopyranosyl isothiocyanate and 150 mg (1 mmol) of 2-aminobenzothiazole (MW 150) and the mixture was treated in the same manner as that used in Example 4, yielding a syrup. The syrup was purified by column chromatography on silica-gel using benzene-acetone as eluent to give the tilted compound from the fraction of benzene-acetone (9:1). Yield: 110 mg (24%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](/[CH:14]=[C:15]1/[C:16](=[O:36])[N:17]([C@@H:20]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]4[O:30][C:31](=[O:35])[O:32][C:33]=4[CH3:34])=[O:26])[CH2:21]3)[CH2:18][CH2:19]/1)=[C:7]2[C:11]([OH:13])=[O:12].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Cl.[C:50]([O:69][N:70]=[C:71]([C:75]1[N:79]=[C:78]([NH2:80])[S:77][N:76]=1)[C:72](Cl)=[O:73])([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.O>ClCCl.CO>[NH2:80][C:78]1[S:77][N:76]=[C:75](/[C:71](=[N:70]/[O:69][C:50]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)/[C:72]([NH:1][C@@H:2]2[C:9](=[O:10])[N:8]3[C@@H:3]2[S:4][CH2:5][C:6](/[CH:14]=[C:15]2/[C:16](=[O:36])[N:17]([C@@H:20]4[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]5[O:30][C:31](=[O:35])[O:32][C:33]=5[CH3:34])=[O:26])[CH2:21]4)[CH2:18][CH2:19]/2)=[C:7]3[C:11]([OH:13])=[O:12])=[O:73])[N:79]=1
Reactant: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](N)[C@H]4SC3)C2=O)C1
Reactant: Nc1nc(C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)Cl)ns1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(c5ccccc5)(c5ccccc5)c5ccccc5)c5nsc(N)n5)[C@H]4SC3)C2=O)C1

Procedure:
0.5 g of (6R, 7R)-7-amino-3[E-(R)-1′-(5-methyl-2-oxo-[1,3]-dioxol-4-ylmethoxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid were dissolved in 20 ml of dichloromethane at 0°. 0.7ml of bis(trimethylsilyl)acetamide were then added and 0.46 g of 2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetic acid chloride hydrochloride (J. Antibiotics 37:557-571, 1984) were metered in portions. The mixture was poured onto 15 ml of water/15 ml of MeOH and the phases were separated. The water phase was washed once again with 15 ml of dichloromethane and the combined organic phases were dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.CO[CH:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Br:24])[CH:22]=2)[C:17](=[O:25])[NH:16][C:15]1=[O:26]>CN(C)C=O>[Br:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:25])[NH:16][C:15](=[O:26])[C:14]2=[CH:13][NH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCc1cc(=O)c(O)co1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNCc1cc(=O)c(O)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-aminomethyl-5-hydroxy-pyran-4-one (106 mg, 0.75 mmole), 4 mL of N,N-dimethylformamide and 4-methoxymethylene-6-bromo-4H-isoquinoline-1,3-dione (212 mg, 0.75 mmole) is stirred for one hour at ambient temperature. The reaction mixture is evaporated to dryness, dissolved in 7.5% methanol in chloroform passed through Florisil eluting with 7.5% methanol in chloroform. The eluate is evaporated, treated with acetonitrile, the resulting solid filtered and dried to give an off white solid, 220 mg, (75%), mp 293-7° C. dec; MS (ES+): m/z 391 (M+H).
Reaction SMILES: Br[C:2]1[C:12]([OH:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:14][CH2:15][CH3:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH2:15]([O:14][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=[C:12]([OH:13])[C:2]=1[C:29]1[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=1)[CH3:16]
Reactant: CCOC(=O)c1cc(O)c(Br)c(OCC)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(O)c(-c2ccc(F)cc2)c(OCC)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
Palladium acetate (344 mg) was added to a mixture of ethyl 4-bromo-3-ethoxy-5-hydroxybenzoate (8.87 g), tripotassium phosphate (19.5 g), (4-fluorophenyl)boronic acid (10.7 g), tricyclohexylphosphine (20% toluene solution, 5.45 mL), toluene (80 mL), and water (40 mL), and the resultant mixture was stirred overnight at 90° C. in an argon atmosphere. The reaction mixture was allowed to cool to room temperature, then diluted with ethyl acetate, and washed with water and saturated saline in this order. The organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (9.34 g).
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[OH:17][C:18]([C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)([CH3:20])[CH3:19].[Cl-].[NH4+]>CN(C)C=O>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[C:18]([O:17][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([CH3:19])[CH3:20]
Reactant: CC(C)(O)c1nc2ccccc2s1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(Oc1ccc([N+](=O)[O-])cc1)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
108.9 mg of potassium t-butoxide and 134.1 mg of 4-chloronitrobenzene were added to a solution of 156.6 mg of 2-(1-hydroxy-1-methylethyl)benzothiazole [prepared as described in step (a) above] in 3.1 ml of dimethylformamide at room temperature. The resulting mixture was stirred at room temperature for 3 hours, and then it was stirred at 60° C. for a further 4 hours. The temperature of the reaction mixture was then raised to 90° C. and the mixture stirred at this temperature for a further 5 hours, after which it was cooled to room temperature. A saturated aqueous ammonium chloride solution was then added to the reaction mixture and the mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 197.1 mg (yield 70%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][N:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH:17]([CH2:30][CH3:31])[S:16][C:15]2=[O:32])=[CH:11][CH:10]=1>ClCCl.C(N(CC)CC)C>[F:1][C:2]([F:7])([F:6])[C:3]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH:17]([CH2:30][CH3:31])[S:16][C:15]2=[O:32])=[CH:33][CH:34]=1)=[O:4]
Reactant: O=C(Cl)C(F)(F)F
Reactant: CCC1SC(=O)N(Cc2ccc(N)cc2)N=C1c1ccc(OC)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1SC(=O)N(Cc2ccc(NC(=O)C(F)(F)F)cc2)N=C1c1ccc(OC)c(OC)c1

Procedure:
0.8 ml of trifluoroacetyl chloride is added with stirring and ice cooling to a solution of 1.4 g of 3-(4-aminobenzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one ("D") in 60 ml of dichloromethane and 1 ml of triethylamine, and the mixture is subsequently stirred for 3 hours. The solvent is removed and the residue is worked up in the conventional manner. Recrystallization from isopropanol/petroleum ether gives 1.9 g of 3-(4-trifluoroacetamidobenzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 124°.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:19]1[C:23]2([CH2:28][CH2:27][CH:26]([C:29]3[CH:38]=[CH:37][C:32]([C:33](OC)=[O:34])=[CH:31][N:30]=3)[CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1>O1CCCC1>[O:19]1[C:23]2([CH2:24][CH2:25][CH:26]([C:29]3[N:30]=[CH:31][C:32]([C:33](=[O:34])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])=[CH:37][CH:38]=3)[CH2:27][CH2:28]2)[O:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(C2CCC3(CC2)OCCO3)nc1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1ccc(C2CCC3(CC2)OCCO3)nc1
Temperature: 25 °C

Procedure:
Tert-butyl acetate (2.40 mL, 17.82 mmol) was added to a stirred and cooled (−78° C.) solution of lithium hexamethyldisilazide (17.8 mL, 1 M in tetrahydrofuran) in dry tetrahydrofuran (10 mL). After 30 minutes of stirring at −78° C., a solution of Example 93B (2.47 g, 8.9 mmol) in tetrahydrofuran was added dropwise into the solution. The resulting mixture was stirred for another hour before it was quenched with ammonium chloride and allowed to warm to room temperature. The mixture was partitioned with ether and water and the phases were separated. The organic phase was washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography using 30% ethyl acetate in hexanes to provide the title compound as a yellow oil.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+].CO.O>CCOC(C)=O>[CH3:26][O:27][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: C[C@@H](NCc1ccc(OCc2ccc(F)nc2)nc1)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc(COc2ccc(CN[C@H](C)c3ccccc3)cn2)cn1

Procedure:
(1R)—N-((6-((6-Fluoro-3-pyridinyl)methoxy)-3-pyridinyl)methyl)-1-phenylethanamine (0.500 g, 1.48 mmol) was added to a microwave tube with NaOMe (0.400 g, 7.40 mmol) and MeOH (1.0 mL). The vial was sealed and irradiated for 7 min at 130° C. After the allotted time, the reaction was worked up by adding water (1.0 mL) and EtOAc (1.0 mL). The layers were separated and the aqueous layer was washed with EtOAc (3×1.0 mL). The combined organic layers were then washed with 1M sodium phosphate buffer (pH 5.5) (2×3.0 mL), dried over MgSO4, filtered, and concentrated to leave an oil. This was then purified by silica gel chromatography (1:1 hexane-EtOAc) to afford (1R)—N-((6-((6-methoxy-3-pyridinyl)methoxy)-3-pyridinyl)methyl)-1-phenylethanamine 2. MS m/z: 350 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.C[O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41]2[CH:49]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH:47]=[C:46]3[C:42]=2[CH:43]=[CH:44][NH:45]3)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:48]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][NH:45]3)=[C:41]([NH:40][S:37]([C:34]3[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH:49]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cc3[nH]ccc23)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(NS(=O)(=O)c4ccc(O)cc4)c4cc[nH]c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.18 mmol) were added 4-methoxy-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-4-yl)benzenesulfonamide (137 mg, 0.27 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (14 mg, 0.02 mmol) and 182 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified using SP1® Purification System (50% to 100%, hexane-ethyl acetate) to obtain 27 mg (21% yield, 95% purity) and 98 mg (72% yield, 88% purity) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[N:12][C:11]=2[C:22](OCC)=[O:23])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[BH4-].[Na+].C(OCC)(=O)C.O>C(O)C.O1CCCC1>[OH:23][CH2:22][C:11]1[N:12]=[N:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:15][C:10]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(-c2cc(-c3ccccc3)nnc2CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
To a solution of ethyl 4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxylate (1 g) in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml) was added sodium borohydride (0.22 g) and the mixture was stirred for 3 hours at ambient temperature. Then the reaction mixture was poured into a mixture of ethyl acetate (100 ml) and water (50 ml) The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (50 g) and eluted with a mixture of benzene and ethyl acetate (5 1 V/V). The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethanol and chloroform to give 3-hydroxymethyl-4-(3-nitrophenyl)-6-phenylpyridazine (0.19 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][CH2:13][CH2:14][N:15]([CH3:42])[C:16]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([O:26][C:27](=[O:41])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:22][CH2:21]2)=[O:17])=[O:11])=[CH:5][CH:4]=1)=O.C(O)(=O)C.[NH2:47][CH2:48][C@@H:49]([C:58]1[CH:67]=[CH:66][C:65]([OH:68])=[C:64]2[C:59]=1[CH:60]=[CH:61][C:62](=[O:69])[NH:63]2)[O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52].CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[C:54]([Si:51]([CH3:53])([CH3:52])[O:50][C@H:49]([C:58]1[CH:67]=[CH:66][C:65]([OH:68])=[C:64]2[C:59]=1[CH:60]=[CH:61][C:62](=[O:69])[NH:63]2)[CH2:48][NH:47][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH2:12][CH2:13][CH2:14][N:15]([CH3:42])[C:16]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([O:26][C:27](=[O:41])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:24][CH2:25]2)=[O:17])=[O:11])=[CH:7][CH:8]=1)([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CN(CCCC(=O)Nc1ccc(C=O)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCCC(=O)Nc1ccc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c3[nH]c(=O)ccc23)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of biphenyl-2-ylcarbamic acid 1-(2-{[3-(4-formyl-phenylcarbamoyl)propyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (91 mg, 0.16 mmol) in DCM (2 mL) was added 5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-hydroxy-1H-quinolin-2-one acetic acid salt (101 mg, 0.256 mmol) (see, e.g., U.S. Patent Publication No. 2006/0035931 A1, published Feb. 16, 2006) followed by MeOH (1 mL). The resulting yellow solution was stirred at room temperature for 10 min and then sodium triacetoxyborohydride (89 mg, 0.40 mmol) was added and this mixture was stirred overnight. LC-MS (Method 2-90) showed product was present (Rt 3.25 min; m/z 889.8 [M+H]+). Water and DCM were added and the layers were separated. The organic layer was washed with water (2×) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[C:13]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C(O)(C(F)(F)F)=O.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)c1ccc(CNc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
4-Formylbenzoic acid methyl ester (10.6 g, 64 mmol) was dissolved in methanol (200 mL). 4-tert-Butylaniline (9.61 g, 64 mmol) was added and the resulting suspension was refluxed for 15 min. After cooling to room temperature, TFA (5.18 mL, 68 mmol) was added followed by portion wise addition of sodium cyanoborohydride (3.26 g, 52 mmol). The resulting mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was partitioned between ethyl acetate (200 mL) and 1 N aqueous sodium hydroxide (150 and 100 mL). The organic phase was dried (magnesium sulphate) and evaporated in vacuo to afford 19.0 g (99%) of 4-[(4-tert-butylphenylamino)methyl]benzoic acid methyl ester as a solid.
Reaction SMILES: C(O[K])(C)(C)C.[N:7]1([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:11]=[CH:10][N:9]=[CH:8]1.N1C=CNC1=S.F[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.[Na]>CS(C)=O.O>[N:7]1([N:12]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=2)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: FC(F)(F)c1ccc(Nn2ccnc2)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: CC(C)(C)O[K]
Agent: S=c1[nH]cc[nH]1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N(c2ccc(C(F)(F)F)cc2)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a cold solution (10-15° C.) of tBuOK (1.06 g, 0.00895 mol) in DMSO (18 ml) was added portionwise N-(1H-imidazol-1-yl)-4-trifluoromethylaniline (1.85 g, 0.00814 mol) (prepared by desulfurization from the corresponding 2,3-dihydro-1H-imidazol-2-thione, J. G. Schantl, Heterocycles, 37(3), 1873, 1994). The reaction mixture was stirred at room temperature for 1 h, then 4-fluorobenzonitrile (0.936 g, 0.00773 mol) in DMSO (18 ml) was added, the reaction mixture was stirred for 2 h and pourred into water and concentrated sodium hydroxyde solution. The precipitate was collected and dried under vacuum. Flash chromatography on silica gel (toluene/dioxane: 7/3) and crystallization from diisopropyl ether yielded a solid (1.6 g, 60%), mp 104° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].Cl>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][C:21]([NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:27]([Cl:26])[CH:28]=4)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(c2ccc(-c3ccc(Cl)nn3)cc2)CC1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CC1CCC(c2ccc(-c3ccc(Nc4cccc(Cl)c4)nn3)cc2)CC1
Temperature: 100 °C

Procedure:
To a suspension of {4-[4-(6-chloro-pyridazin-3-yl)-phenyl]-cyclohexyl}-acetic acid ethyl ester (2.0 g, 5.6 mmol, 1.0 equiv) in 40 Ml dioxane was added 3-chloroaniline (0.70 Ml, 6.7 mmol, 1.2 equiv) followed by 2 Ml 4 N HCl in dioxane. The mixture was then heated to 100° C. overnight. The reaction was partitioned between EtOAc and saturated bicarbonate solution, and the organic extracts were then washed with brine and dried. Removal of solvent in vacuo afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07-1.17 (m, 2 H) 1.21 (t, J=7.20 Hz, 3 H) 1.42-1.53 (m, 2 H) 1.86 (t, J=10.99 Hz, 4 H) 1.78-1.90 (m, 1 H) 2.18 (d, J=6.57 Hz, 2H) 2.47 (td, J=12.00, 3.03 Hz, 1 H) 4.08 (q, J=7.24 Hz, 2 H) 7.03 (d, J=7.58 Hz, 1 H) 7.26 (d, J=8.08 Hz, 3 H) 7.20-7.28 (m, 2 H) 7.45 (s, 1 H) 7.68 (d, J=9.35 Hz, 1 H) 7.84 (d, J=8.34 Hz, 2 H); (M+H)+ 450.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:27]3[CH2:28][CH2:29][CH:24]([N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH3:30])[CH2:25][CH2:26]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: COCCN(C)C1CCNCC1
Product: COCCN(C)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carboxaldehyde was reacted with (2-methoxy-ethyl)-methyl-piperidin-4-yl-amine using standard reductive amination conditions to give [1-(2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-(2-methoxy-ethyl)-methyl amine as a solid, which was reacted with methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester according to General Procedure A. The resulting solid was triturated with diethyl ether to give 367 as an off white solid (35% yield). NMR (DMSO, 400 MHz), 1.38-1.50 (2H, m), 1.60-1.66 (2H, m), 1.97-2.03 (2H, m), 2.09 (2H, s), 2.19 (3H, s), 2.24-2.33 (1H, m), 2.55 (2H, dd, J=7.8 and 6.2), 2.84 (3H, d, J=4.8), 2.88-2.94 (2H, m), 3.31-3.36 (2H, m), 3.71 (2H, s), 3.75-3.79 (4H, m), 3.86-3.89 (4H, m), 6.50 (1H, d, J=8.8), 6.90-6.94 (1H, m), 7.43 (1H, s), 8.26 (1H, dd, J=8.8 and 2.3), 9.00 (1H, d, J=2.1). MS: (ESI+): MH+=512