Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH2:2]([N:9]1[CH2:12][CH2:11][CH:10]1[C:13]([O:15]CC)=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(CC(C)C)=O>C(O)C>[CH2:2]([N:9]1[CH2:12][CH2:11][C@H:10]1[C:13]([OH:15])=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CCN1Cc1ccccc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)CC(C)C
Product: O=C(O)[C@@H]1CCN1Cc1ccccc1
Temperature: 10 °C
Reaction time: 10 h
Yield: 105.8 %

Procedure:
To 77 g of water were added 0.5 g of the immobilized enzyme produced in Example 1 above and 65 g of ethyl N-benzylazetidine-2-carboxylate, followed by stirring at 10° C. for 10 hours. To the reaction mixture, were added 65 g of methylisobutyl ketone and 36 g of ethanol, and further stirring was conducted for 30 minutes. The reaction mixture was thereafter filtrated, and the filtrate was subjected to separation. To the aqueous layer were added 65 g of methylisobutyl ketone and 6.5 g of ethanol followed by stirring for 30 minutes and the separation. This operation was repeated twice. Thus resulting aqueous layer was concentrated under a reduced pressure (10 kPa or lower) to give 60 g of crude (S)-N-benzylazetidine-2-carboxylic acid (43 weight %).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:30]=[CH:29][C:24]([CH:25]=[CH:26][CH2:27]Br)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:30]=[CH:29][C:24](/[CH:25]=[CH:26]/[CH2:27][N:17]2[CH2:18][CH2:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:9][CH:10]=3)[CH2:15][CH2:16]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(C=CCBr)cc1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: Fc1ccc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 4-fluorocinnamyl bromide to produce the above.
Reaction SMILES: C([O-])(=O)C.[Na+:5].C(O)C.[CH3:9][S:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[CH:22]([NH:23][C:24](=[O:34])[C:25]([C:28]3[N:29]=[C:30]([NH2:33])[S:31][CH:32]=3)=[N:26][OH:27])[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19]>CN(C)C=O>[CH3:9][S:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[CH:22]([NH:23][C:24](=[O:34])[C:25]([C:28]3[N:29]=[C:30]([NH2:33])[S:31][CH:32]=3)=[N:26][OH:27])[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([O-:20])=[O:19].[Na+:5]
Reactant: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CSCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1

Procedure:
3.5 ml of a methanolic solution of sodium acetate and 30 ml of ethanol were added to a solution of 1 g of the syn isomer of 3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylic acid in 2 ml of dimethylformamide and the mixture was vacuum filtered. The product was rinsed with ethanol and then with ether to obtain 0.804 g of syn isomer of sodium 3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20](C(C)C)[C@H:21]([C:23](O)=O)[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C(F)=C(C=CC=1)NC1C2C(=CC(OC)=C(C=O)C=2)N=CN=1.C(N)(C)C>>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C(C)C)[C@@H](C)C(=O)O
Agent: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Solvent: CC(C)N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC(C)C

Procedure:
The N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-isopropyl-L-alanine used as starting material was prepared as follows: 4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with isopropylamine using an analogous method to that described for the equivalent step in Example 1 to give N-(3-chloro-2-fluorophenyl)-6-[(isopropylamino)methyl]-7-methoxyquinazolin-4-amine; 1H NMR Spectrum: (DMSO-d6) 1.07 (d, 6H); 1.90 (brs, 1H); 2.80 (m, 1H); 3.83 (s, 2H); 3.97 (s, 3H); 7.20 (s, 1H); 7.28 (t, 1H); 7.50 (m, 2H); 8.32 (s, 1H); 8.43 (s, 1H); 9.76 (s, 1H); Mass Spectrum: (M+H)+ 375.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][O:13][C@@H:14]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@@H:15]1[OH:16])C1C=CC=CC=1>O.[Pd]>[O:13]([CH2:12][CH2:11][NH2:10])[C@@H:14]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@@H:15]1[OH:16]
Reactant: O=C(NCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: NCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of benzyl[2-(β-D-mannopyranosyloxy)ethyl]carbamate (133 mg, 0.372 mmol), and Pd/C (20 mg, 0.019 mmol) in water (5 mL) was allowed to stir under a balloon of H2 at rt for 4 hr. The catalyst was filtered off and washed with H2O (3×5 mL). The fitrate was concentrated to give the title compound. 1H NMR (CD3OD) δ 4.53-4.52 (1H, m), 3.93-3.85 (3H, m), 3.72-3.64 (2H, m), 3.53-3.49 (1H, m), 3.44-3.42 (1H, m), 3.22-3.18 (1H, m), 2.92-2.85 (2H, m).
Reaction SMILES: [OH-].[Na+:2].[C:3]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([N:11]=[C:12]2[N:16]([CH3:17])[C:15]([CH3:18])=[C:14]([C:19]([O:21]CC)=[O:20])[S:13]2)=[O:10])=[CH:7][CH:6]=1)#[N:4].C(Cl)Cl>CO>[C:3]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([N:11]=[C:12]2[N:16]([CH3:17])[C:15]([CH3:18])=[C:14]([C:19]([O-:21])=[O:20])[S:13]2)=[O:10])=[CH:7][CH:6]=1)#[N:4].[Na+:2]
Reactant: CCOC(=O)c1sc(=NC(=O)c2ccc(C#N)cc2)n(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C(=O)[O-])sc(=NC(=O)c2ccc(C#N)cc2)n1C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
10% Aqueous sodium hydroxide solution (48 ml) was added to a mixture of ethyl 2-(4-cyanobenzoylimino)-3,4-dimethylthiazoline-5-carboxylate (9.88 g), methylene chloride (250 ml) and methanol (250 ml), followed by stirring at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give sodium 2-(4-cyanobenzoylimino)-3,4-dimethylthiazoline-5-carboxylate (10.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][NH2:16])[O:8][CH2:7][CH2:6]2.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC=CC=1>[CH2:17]([NH:16][CH2:15][CH:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:7][O:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc2c(cc1OC)C(CN)OCC2
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(CNCc1ccccc1)OCC2
Reaction time: 8 h

Procedure:
A mixture of 6,7 -dimethoxy-1-isochromanmethylamine (18.0 g), benzaldehyde (9.7 g) and dry benzene (400 ml) is heated under reflux (Dean-Stark) for 18 hr. The solvent is removed under reduced pressure and the residue (27.0 g) is dissolved in ethanol 400 ml), sodium borohydride (17.0 g) is added portionwise to the stirred solution. When the addition is complete the mixture is stirred and heated under reflux for 1.5 hr. and then left at room temperature overnight. The mixture is concentrated, diluted with water and extracted with ether. The ether extract are in turn extracted with 10% HCl and these extracts are made alkaline and re-extracted with ether. These extracts are washed with brine, dried and evaporated to give the title compound, λmaxEtOH 285 nm (3750) and 281 nm (4000).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:21][C:2]([F:20])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(C)c(C(F)(F)F)nc(C(F)(F)F)c1C(=O)OCC
Yield: 69.1 %

Procedure:
A mixture of 5.0 g (0.016 mol) of product of Example 35, 3.95 g (0.024 mol) of ethyl bromoacetate, 2.18 g (0.016 mol) of K2CO3 and 75 ml of acetone was held at reflux for 18 hours and filtered. The filtrate was concentrated. The residue was stirred with toluene and filtered. The toluene filtrate was concentrated to give 4.46 g (70.2%) of product as a solid; mp 42°-44° C.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[C:4](=[O:5])[O:3]1.[CH2:15](O)[CH3:16]>[Pd].S([O-])([O-])(=O)=O.[Ba+2]>[C:6]1([C:15]2[CH:16]=[N:12][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:11]=3[CH:2]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1OC(O)c2c1cccc2[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: O=C(O)c1cccc2ncc(-c3ccccc3)cc12
Reaction time: 4 h

Procedure:
50 g (0.256 mol) of 3-hydroxy-4-nitro-phthalide are hydrogenated at 20° C. and at 3 bar using 5 g of Pd/barium sulphate (5%) in 380 ml of ethanol. The mixture is filtered with suction, and 0.308 mol=38.7 ml of phenylacetaldehyde solution are added to the filtrate. The mixture is boiled for 4 hours, the quinolinecarboxylic acid precipitating. It is cooled, filtered with suction and washed with ethanol 28.3 g (44.3% of theory) of a colorless compound of melting point>290° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:9]([C:11]3[CH:20]=[C:19]4[C:14]([CH2:15][CH2:16][N:17]([CH3:21])[CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:32]1[C:33]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:50])[N:47]([CH3:49])[CH3:48])=[CH:41][CH:40]=2)=[N:34][N:35]([CH2:37][CH3:38])[CH:36]=1>>[CH2:37]([N:35]1[CH:36]=[C:32]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:23])=[O:24])[C:9]([C:11]4[CH:20]=[C:19]5[C:14]([CH2:15][CH2:16][N:17]([CH3:21])[CH2:18]5)=[CH:13][CH:12]=4)=[CH:10][C:3]=23)[C:33]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:50])[N:47]([CH3:49])[CH3:48])=[CH:41][CH:40]=2)=[N:34]1)[CH3:38]
Reactant: CN1CCc2ccc(-c3cc4c(Br)ccnc4n3S(=O)(=O)c3ccccc3)cc2C1
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc4c(c2)CN(C)CC4)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reaction time: 4.5 h

Procedure:
Following the procedure described for Intermediate 32 with 7-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-methyl-1,2,3,4-tetrahydroisoquinoline. Using this product crude and following the procedure described for Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea and stirring for 4.5 hours provided the title compound. ESMS [M+H]+: 660.6.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][NH:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[N-:26]=[C:27]=[O:28]>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][N:18]([C:27]([NH:26][CH2:3][C:4]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:5]=2)=[O:28])[CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1
Reactant: [N-]=C=O
Reactant: CSc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Product: CSc1ccc(C(OC2CN(C(=O)NCc3ccccc3)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 3-[2-trifluoromethyl-4′-(methylthio)benzhydryloxy]azetidine hydrochloride (118) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:59]=[CH:58][C:6]([CH2:7][O:8][C:9](=[O:57])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:56])[N:25]([CH2:31][C:32]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:35]=[C:34]([O:47][CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH:33]=2)[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(O[N:82]1[C:87](=[O:88])[CH2:86][CH2:85][C:83]1=[O:84])=[N+](C)C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:57])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:56])[N:25]([CH2:31][C:32]2[CH:33]=[C:34]([O:47][CH2:48][C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH:35]=[C:36]([O:38][CH2:39][C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH:37]=2)[CH2:26][CH2:27][C:28]([O:30][N:82]2[C:87](=[O:88])[CH2:86][CH2:85][C:83]2=[O:84])=[O:29])=[CH:58][CH:59]=1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)O)Cc2cc(OCC(=O)OC(C)(C)C)cc(OCC(=O)OC(C)(C)C)c2)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)ON2C(=O)CCC2=O)Cc2cc(OCC(=O)OC(C)(C)C)cc(OCC(=O)OC(C)(C)C)c2)cc1
Temperature: 0 °C
Yield: 76.6 %

Procedure:
15-[(3,5-Bis-tert-butoxycarbonylmethoxybenzyl)-(2-carboxyethyl)carbamoyl]pentadecanoic acid 4-methoxybenzyl ester (190 mg, 0.23 mmol) was dissolved in THF (5 mL). The mixture was cooled with an ice bath. Diisopropylethylamin (0.047 mL, 0.28 mmol) and O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (83 mg, 0.28 mmol) was added. The mixture was stirred under nitrogen at 0° C. After 30 minutes the ice cooling was removed and the mixture was stirred for an additional 3 hours. Solvent removed in vacuo. The crude product was dissolved in ethyl acetate (50 mL), washed with aqueous phosphate buffer (pH=5.5) (3×25 mL). The organic phase was dried (Na2SO4), solvent removed in vacuo to yield the title compound (163 mg) which was used in subsequent step.
Reaction SMILES: [C:1]([C@@H:3]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:4][C:5]([O-:7])=[O:6])#[N:2].[K+].O.[OH-].[K+].[H][H]>[Ni].C(O)(C)C>[NH2:2][CH2:1][C@@H:3]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: CC(C)C[C@H](C#N)CC(=O)[O-]
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of potassium (S)-3-cyano-5-methylhexanoate (20 g, 103.5 mmol), water (50 mL), 45% KOH (12 g), isopropanol (12 g), and Raney Nickel were shaken overnight in a Parr Shaker under 50 psi of hydrogen. The mixture was filtered, heated to approximately 50° C., treated with acetic acid (6.5 mL) and stirred overnight at room temperature. The mixture was then adjusted to slightly above pH 7 with 45% KOH and concentrated under vacuum to remove most of the isopropanol. Isopropanol (20 mL) was added to the mixture, which was then acidified with acetic acid, stirred overnight at room temperature, and filtered to give 4.3 g of (S)-3-aminomethyl-5-methylhexanoic acid as a white crystalline solid. The enantiomeric purity was determined to be 100% e.e. by preparing a derivative of (S)-3-aminomethyl-5-methylhexanoic acid using Marfey's reagent (Nα-(2,4-dinitro-5-fluorophenyl)-L-alaninamide) and analyzing by HPLC on a BDS Hypersil C18 column (250×4.6 mm, 5μ) eluted with acetonitrile:1% triethylamine (pH 3) (38:62, v/v).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:44][O:45][C:46](=[O:52])[C@H:47]([C@@H:49]([CH3:51])[OH:50])[NH2:48]>CN(C=O)C>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:48][C@H:47]([C:46]([O:45][CH3:44])=[O:52])[C@@H:49]([CH3:51])[OH:50])=[O:17])=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(O)c1ccc(Cn2cnc3ccccc32)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)[C@@H](NC(=O)c1ccc(Cn2cnc3ccccc32)cc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of 4-[(1H-benzoimidazol-1-yl)methyl]benzoic acid (0.37 g, 1.47 mmol) in dry DMF was treated sequentially with EDC (0.34 g, 1.76 mmol) and HOBt (0.25 g, 1.62 mmol), stirred at room temperature for 30 min, treated sequentially with DIPEA (0.62 mL, 3.6 mmol) and a solution of threonine methyl ester hydrochloride (0.27 g, 1.62 mmol), stirred for 3 h and concentrated under reduced pressure. The resultant residue was partitioned between CH2Cl2 and water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica, CH2Cl2:CH3OH 95:5) to afford the title product in 64% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 368 (MH+).
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C.[CH:13]1C=CC=CC=1>[Rh].C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>[CH:5]([C:6]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH2:13])=[O:4]
Reactant: CC(=O)OCC=CCOC(C)=O
Reactant: c1ccccc1
Agent: [Rh]
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: C=C(C=O)CCOC(C)=O
Temperature: 85 °C
Yield: 90 %

Procedure:
A mixture of 1,4-diacetoxy-2-butene (170 g.), triphenylphosphite (0.51 g.), 5% rhodium on charcoal (1.12 g.) and benzene (340 g.) was loaded into a 1 liter stainless steel autoclave and heated with stirring to 85° C. The autoclave was then pressured to 2000 psig with synthesis gas. When gas uptake had ceased (approximately 3 hours), the autoclave was cooled to room temperature and vented. The reaction mixture was filtered and heated under vacuum until all the benzene had been removed. After the addition of p-toluenesulphonic acid (0.5 g.), the reaction product was heated in an oil bath at 105°-110° C. under a vacuum of 5 mm Hg. and the distillate so produced was collected and then fractionally distilled to give 2-formyl-4-acetoxybutene (126.3 g., 90% yield, b.p. 67°-72° C./ 6 mm Hg.).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:8]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]3[CH2:26][C@H:25]([CH3:27])[C@@H:24]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@H:23]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:22]3)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.[CH3:69][N:70]1[CH2:75][CH:74]=[C:73](B2OC(C)(C)C(C)(C)O2)[CH2:72][CH2:71]1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.O>[C:40]([O:39][C:37]([NH:36][C@H:23]1[C@H:24]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@@H:25]([CH3:27])[CH2:26][N:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[NH:14][C:12]([C:8]2[C:7]([NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[CH:6][C:5]3[C:10](=[CH:11][C:2]([C:73]4[CH2:72][CH2:71][N:70]([CH3:69])[CH2:75][CH:74]=4)=[CH:3][CH:4]=3)[N:9]=2)=[O:13])[CH2:22]1)=[O:38])([CH3:41])([CH3:42])[CH3:43]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4=CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 90 °C
Yield: 36.2 %

Procedure:
A pressure vial was charged with benzyl [7-bromo-2-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)pyridin-3-yl]amino}carbonyl)quinolin-3-yl]carbamate (0.035 g, 0.043 mmol), K3PO4 (0.0181 g, 0.0852 mmol), 1,4-dioxane (0.55 mL), water (0.092 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.014 g, 0.063 mmol). The mixture was deoxygenated with nitrogen for 10 min. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.0022 g, 0.0028 mmol) was added. The mixture was sealed with screw cap, then heated at 90° C. for 1.5 h. The mixture was quenched with water, extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by flash chromatography on 20 g silica gel, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.013 g, 36%). LCMS calc. for C46H62N7O6Si [M+H]+: m/z=836.5. found: 836.6.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([OH:38])[CH2:35][C:36]#[CH:37].[C:39]1(=O)[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12>C1(C)C=CC=CC=1>[CH2:39]([N:43]1[C:34](=[O:38])[C:35]2[C:41](=[CH:45][CH:46]=[CH:37][CH:36]=2)[C:42]1=[O:44])[CH2:40][C:48]#[CH:47]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C#CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C#CCCN1C(=O)c2ccccc2C1=O
Temperature: -5 °C
Reaction time: 0.83 h
Yield: 80.5 %

Procedure:
Diisopropyl azodicarboxylate (316 g, 1.56 mol) was added to a solution of triphenylphosphine (PPh3) (393 g, 1.50 mol), 3-butyn-1-ol (105 g, 1.50 mol) and phthalimide (200 g, 1.36 mol) in toluene (1600 mL) which was pre-cooled with a −5° C. cooling bath at such a rate that temperature of the reaction mixture was kept between 15-25° C. The addition time was 50 min. The cooling bath was removed after the addition was finished. The reaction mixture was allowed to warm to 15-25° C. and stirred for 1 h. Then methanol (800 mL) was added. The mixture was stirred for 30 min and then filtered. The crude product was washed with methanol and dried to give a white solid (218 g) in 80% yield 99.8% purity by area. 1H NMR (DMSO-d6): δ 7.88 (m, 4 H), 3.72 (t, 2 H, J=7.0 Hz), 2.83 (t, 1 H, J=2.7 Hz), 2.55 (m, 2 H).
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:31]1[N:36]=[C:35]([C:37]([O:39][CH3:40])=[O:38])[CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C.C(Cl)Cl.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>[N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:31]5[N:36]=[C:35]([C:37]([O:39][CH3:40])=[O:38])[CH:34]=[CH:33][CH:32]=5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)OC1(C)C
Reactant: COC(=O)c1cccc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COC(=O)c1cccc(-c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)n1
Temperature: 80 °C

Procedure:
A vial containing (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (Example 64A, 30 mg, 0.072 mmol), methyl 6-bromo-2-pyridinecarboxylate (16 mg, 0.072 mmol), K2CO3 (30 mg, 0.22 mmol) and bis(triphenylphosphine)palladium(II) chloride (5 mg, 7 μmol) in tert-butanol (0.5 mL) was heated to 80° C. for 1 hour and cooled. The mixture was diluted with CH2Cl2 (5 mL), filtered, and concentrated. The residue was purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm) as described in Example 65. The title compound was obtained as the bis trifluoroacetate salt. 1H NMR (300 MHz, CD3OD) δ ppm 1.52-1.65 (m, 1H), 1.74-1.93 (m, 3H), 1.96-2.09 (m, 2H), 2.34-2.48 (m, 1H), 2.63-2.76 (m, 1H), 3.04-3.20 (m, 2H), 3.52-3.77 (m, 3H), 3.81-3.95 (m, 2H), 4.01 (s, 3H), 4.08-4.21 (m, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.98-8.07 (m, 2H), 8.08-8.15 (m, 2H), 8.57 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 423 (M+H)+.