Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([Br:23])=[C:19]([CH:22]=1)[CH:20]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1.C1COCC1>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([Br:23])=[C:19]([CH:20]=[CH2:1])[CH:22]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1Br
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(OCc2ccccc2)ccc1Br
Reaction time: 5 h
Yield: 86.5 %

Procedure:
Methyltriphenylphosphonium bromide (12.4 g, 0.0347 mol) and 18-crown-6 (90 mg, 0.41 mmol) were added to THF (100 mL). The mixture was cooled in a ice-water bath. Potassium tert-butoxide (34.7 mL of 1.0M in THF, 0.0347 mol) was added via cannula to the stirred solution. 5-(Benzyloxy)-2-bromobenzaldehyde (9.2 g, 0.0316 mol) was added in one portion which resulted in a slight exotherm. After 30 minutes the cooling bath was removed and stirring was continued at 22° C. for 5 hours. The mixture was concentrated and the residue was purified by flash column chromatography on SiO2 (75 g) with hexanes/ethyl acetate (95:5) to provide 4-(benzyloxy)-1-bromo-2-vinylbenzene as a clear oil (7.9 g, 86% yield). 1H NMR (300 MHz, CDCl3) 5.03 (s, 2H), 5.32 (d, J=10.98 Hz, 2H,) 5.63 (d, J=17.20 Hz, 2H), 6.74 (dd, J=8.78, 2.93 Hz, 2H), 6.98 (dd, J=17.57, 10.98 Hz, 2H), 7.13 (d, J=2.93 Hz, 2H), 7.33 (m, 6H).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[Cl:55][C:56]1[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([NH2:63])[CH:57]=1>[Cl-].[Na+].O.CN(C=O)C>[CH:10]1[C:11]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:62][C:59]3[CH:60]=[CH:61][C:56]([Cl:55])=[CH:57][C:58]=3[NH2:63])=[O:24])=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(Cl)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ccc1NC(=O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.7 %

Procedure:
6-(2-(9H-fluoren-9-ylidene)acetamido)hexanoic acid (335 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-chloro-o-phenylenediamine (171 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (353 mg, 77% yield) as a brown solid. 1H NMR (DMSO-d6) δ1.38 (m, 2H, CH2), 1.59 (m, 2H, CH2), 1.63 (m, 2H, CH2), 2.34 (t, J=8.0 Hz, 2H, CH2CO), 3.26 (m, 2H, NCH2), 5.18 (s, 2H, benzene-NH2), 6.49 (d, J=8.0 Hz, 1H, Ar—H), 6.72 (s, 1H, Ar—H), 7.10 (s, 1H, ═CH—CO), 7.19 (d, J=8.0 Hz, 1H, Ar—H), 7.33 (m, 2H, Ar—H), 7.40 (m, 2H, Ar—H), 7.76 (d, J=8.0 Hz, 1H, Ar—H), 7.82 (m, 2H, Ar—H), 8.57 (t, J=4.0 Hz, 1H, CONH), 8.71 (d, J=8.0 Hz, 1H, Ar—H), 9.17 (s, 1H, benzene-NH). LC-MS (m/z) 459 (M+1).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[CH3:32][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[O:29]([C:27]([C@:18]1([CH3:32])[CH2:17][CH2:16][C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:14][CH:13]=2)[N:19]1[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])=[O:28])[CH3:30]
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 78.1 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-{4-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D6, 1.52 g, 3.7 mmol) in dry THF (27 ml) at −78° C. was added LiHMDS (4.0 ml, 4.0 mmol, 1M solution in THF). The mixture was allowed to warm to −20° C. and was stirred for 40 min at that temperature. Then the mixture was again cooled to −78° C. and methyl iodide (3.15 g, 22.1 mmol) was added. The mixture was left stirring for another 30 min at the same temperature. After standard work up, the organic layer was evaporated. The crude material was purified by chromatography on silica gel using cyclohexanes and ethyl acetate (1:0 to 9:1) affording the title compound (1.23 g, 78%); Rt (HPLC): 6.76 min; MS: (ES/+) m/z: 448 [M+Na+]; C25H31NO5 requires 425; 1H NMR (400 MHz, CDCl3) δ(ppm): 7.45-7.38 (m, 4H); 7.35 (t, 2H); 7.29 (t, 1H); 6.90 (d, 2H); 5.04 and 5.01 (s, s, 2H); 4.98 and 4.79 (d, d, 1H); 3.79 (s, 3H); 2.50-2.35 (m, 1H); 2.34-2.22 (m, 1H); 1.87-1.73 (m, 2H); 1.58 and 1.55 (s, s, 3H); 1.37 and 1.09 (s, s, 9H). NOE between the methyl group and the proton at C5 could be observed.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:3]1(C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].N12CCCN=C1CCCCC2>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]=[C:6]([Cl:7])[Cl:8])[CH:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C=C(Cl)Cl)C1(C)C
Solvent: Cc1ccccc1C
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Yield: 34.1 %

Procedure:
13 g of diethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1,1-dicarboxylate were dissolved in 50 g of xylene (technical grade) and 30 g of 1,8-diaza-bicyclo[5.4.0]undec-7-ene were added. The mixture was then heated to the boil for 8 hours. After cooling, ice-cold dilute hydrochloric acid was added so that a neutral or weakly acid pH value resulted. The organic phase was separated off and dried with Na2SO4 and the xylene was distilled off in vacuo. The residue weighed 12.2 g. Fractional distillation gave 3.4 g of ethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1-carboxylate and also 8.0 g of recovered starting material. The yield was thus 87%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+].[Cl-].C([NH+](CC)CC)C.Cl>CN1CCCC1=O>[CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]2[NH:13][N:12]=[N:11][N:8]=2)=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CNc1ccc(C#N)cc1
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: CNc1ccc(-c2nnn[nH]2)cc1
Temperature: 150 °C
Yield: 79 %

Procedure:
A mixture of the compound (450 mg) obtained in Step 1, 90% sodium azide (664 mg), triethylammonium chloride (703 mg) and anhydrous 1-methyl-2-pirrolidone (12 mL) was stirred at 140 to 160° C. for ten hours under nitrogen atmosphere. The reaction mixture was poured into ice-water, and the residue was adjusted to pH 3 with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was crystallized from tert-butyl methyl ether, collected by filtration and dried to obtain the titled compound (471 mg) as crystals.
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:4][N:5]2[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=12.[F:20][C:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[C:2]([C:25]3[CH:24]=[CH:23][N:22]=[C:21]([F:20])[CH:26]=3)=[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]3[N:4]=2)=[CH:14][CH:15]=1
Reactant: COc1cccc2c(Br)c(-c3ccc(F)cc3)nn12
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c(-c3ccnc(F)c3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
A solution of 3-bromo-2-(4-fluorophenyl)-7-methoxypyrazolo[1,5-a]pyridine (from Example 27,180 mg, 0.560 mmol), 2-fluoropyridin-4-ylboronic acid (from Example 33, 112 mg, 0.800 mmol) and dichlorobis(triphenylphosphine)palladium (40.0 mg, 0.056 mmol) in N,N-dimethylformamide (6.00 mL) was placed in a pre-heated oil bath at 110° C. To the reaction was added, in a dropwise manner, 2M sodium carbonate (0.840 mL, 1.68 mmol). The reaction was allowed to stir for three hours before cooling to room temperature and filtering through a Celite 545 pad. The Celite filter was washed with ethyl acetate and the filtrate was concentrated to dryness at 50° C. under vacuum. The residue was dissolved in methylene chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated and purified by silica gel chromatography to yield the title compound (110 mg, 0.326 mmol, 58%). 1H NMR (CDCl3): δ 8.14(d, 1H, J=5.5 Hz), 7.53(dd, 2H, J=6.0, 8.0 Hz), 7.24–7.32(m, 2H), 7.00–7.10(m, 3H), 6.89(s, 1H), 6.23(dd, 1H, J=2.0, 6.0 Hz), 4.2(s, 3H). MS (ES+ve): 338.1 (40, M+), 323.1 (100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][C:3]=1[CH2:14][O:15][Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([CH2:14][OH:15])=[C:2]([CH3:1])[CH:7]=1)#[CH:9]
Reactant: Cc1cc(C#C[Si](C)(C)C)ccc1CO[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(CO)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Using General Procedure E; 2-methyl-4-trimethylsilanylethynyl-1-trimethylsilananyloxymethyl-benzene (Intermediate 135, 380.0 mg, 1.30 mmols) in methanol (10 mL) was treated with potassium carbonate (180.0 mg, 1.3 mmol) and stirred overnight at ambient temperature. The crude alkyne was purified by column chromatography (5-20% EtOAc-hexanes) to give 100.0 mg (34%) of the title compound.
Reaction SMILES: N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][C:23]1([CH3:37])[C@@H:25](/[CH:26]=[C:27](\[F:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@H:24]1[C:34]([OH:36])=[O:35].[C:38]([C@@H:40](O)[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:42]=1)#[N:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:37][C:23]1([CH3:22])[C@@H:25](/[CH:26]=[C:27](\[F:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@H:24]1[C:34]([O:36][C@H:40]([C:38]#[N:39])[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:42]=1)=[O:35]
Reactant: CCOC(=O)/C(F)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)/C(F)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 0 °C
Yield: 72.3 %

Procedure:
1.9 ml of pyridine and 4.8 g of dicyclohexylcarbodiimide were added to a solution of 4.9 g of (1R,cis) 2,2-dimethyl-3(Z)-[2-fluoro-2-ethoxycarbonyl-ethenyl]-cyclopropane-1-carboxylic acid in 39 ml of methylene chloride and a solution of 5.3 g of (S)α-cyano-3-phenoxy-benzyl alcohol in 9.8 ml of methylene chloride was added with stirring to the mixture. After stirring the mixture for 2 hours, 30 mg of 4-dimethylamino-pyridine were added thereto and the mixture was stirred for 2 hours. The mixture was cooled to 0° C. and was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was successively eluted with a 9-1 cyclohexane-ethyl acetate mixture and with a 6-4 methylene chloride-petroleum ether (b.p.=35°-70° C.) mixture to obtain 6.73 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-fluoro-2-ethoxycarbonyl-ethenyl]-cyclopropane-1-carboxylate with the same characteristics of the compound of Example 2.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:29])=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccc(Br)cc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccc(Br)cc2)CC1)c1ccc(Cl)cc1
Yield: 81.5 %

Procedure:
0.27 g (0.001 mol) of 1-(4-bromo-benzyl)-piperidin-4-ol and 0.359 ml (0.0025 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.16 ml (0.00125 mol) of 4-chlorobenzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.333 g (81.5%) of 1-(4-bromo-benzyl)-piperidin-4-yl 4-chloro-benzoate was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][C@@H:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[OH:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH2:13][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC[C@H](O)C1CCCCC1)c1ccc(Br)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CCOS(=O)(=O)c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of (S)-3-cyclohexyl-3-hydroxypropyl 4-bromobenzenesulfonate (J. A. Werner et al, J. Org. Chem., 1996, 61, 587), (40 mg, 0.106 mmol) in dichloromethane (3 ml) was added silica (50 mg) and pyridinium chlorochromate (20 mg, 0.09 mmol), and the reaction mixture was left to stir at room temperature for 16 h. The reaction mixture was subjected to direct silica (5 g) column chromatography eluting with dichloromethane:hexane (4:1) to afford the title compound as a yellow solid (38 mg, 96%).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]([O-:10])=O)[C:4]([O:6]C)=[O:5].[NH3:11]>C(Cl)Cl>[CH3:1][O:2][CH:3]([C:8]([NH2:11])=[O:10])[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: COC(=O)C(OC)C(=O)[O-]
Solvent: ClCCl
Product: COC(C(N)=O)C(=O)O

Procedure:
A solution of 10.4 g of monomethyl methoxymalonate in 70 ml of methylene chloride was added dropwise at -10° C. to 26 ml of 25 percent aqueous ammonia. After stirring the mixture was evaporated and the residue was dissolved in water and chromatographed on a cation exchanger with water. The eluate was concentrated and the residue was triturated with diethyl ether and filtered off. The precipitate was washed with water and dried. There were obtained 8.9 g of methoxymalonamic acid, m.p. 128°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[C:29]([O:33][C:34](=[O:38])[C@@H:35]([CH3:37])[NH2:36])([CH3:32])([CH3:31])[CH3:30]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][NH:36][C@H:35]([CH3:37])[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:38]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: C[C@@H](NCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (101.1 mg, 0.270 mmol) and D-alanine tert-butyl ester hydrochloride (49.1 mg, 0.270 mmol) according to Reference R and the general procedure for reductive amination to give (R)-tert-butyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzylamino)propanoate as a yellow-orange solid. MS (ESI) m/z: Calculated: 503.2; Observed: 503.8 (M++1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B.CSC.[ClH:18]>O1CCCC1.CO>[ClH:18].[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:13])[CH2:11][NH2:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(C)C#N)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CC(C)c1ccc(C(C)CN)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
In a 100 ml flask, fitted with a condenser, 2-(4-isopropylphenyl) propionitrile 1.90 g (11.0 mmol) was dissolved in tetrahydrofuran (70 ml) under a nitrogen atmosphere. Borane-methyl sulfide complex (10.0-10.2 M in tetrahydrofuran, 1.20 ml, 12.1 mmol) was added to the solution and the mixture heated to reflux for 3 hours. The solution was cooled to ambient temperature and a saturated solution of hydrochloric acid in methanol added slowly until a white precipitate formed. The solvent was removed in vacuo and the resulting white solid triturated (×4) with diethyl ether. Drying under vacuo gave 1.76 g (73%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].C(N(CC)CC)C.[CH2:19]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To 2-amino-benzoic acid methyl ester (0.51 mL) and triethylamine (0.69 mL) in dichloromethane (31 mL) at −50° C. was slowly added a solution of 4-benzyloxy-benzoyl chloride [1486-50-6] (1 g) in 31 mL of dichloromethane. The reaction mixture was then allowed to warm up to room temperature and stirred for an additional hour. After such time, the reaction mixture was washed with water. The aqueous phase was further extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (heptane-ethyl acetate: 0-50%) to yield 2-(4-benzyloxy-benzoylamino)-benzoic acid methyl ester (400 mg). MS (m/e): 362.5 (M+H+, 100%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[N:2]1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([S:11]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[N:2]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccon2)s1
Reactant: Nc1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(NS(=O)(=O)c2ccc(-c3ccon3)s2)c1
Yield: 55 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 5-isoxazol-3-ylthiophene-2-sulfonyl chloride (13.7 mg, 0.055 mmol) and 3-aminobenzoic acid (6.9 mg, 0.050 mmol). The title compound was obtained in 55% yield (9.6 mg). MS (ESI+) calcd mass for C14H10N2O5S2 350.003113, found 350.002783.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH2:10][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[C:13]1([C@H:11]2[CH2:10][O:9][C:8]([C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[O:1][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:12]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(C2=N[C@@H](c3ccccc3)CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(C2=N[C@@H](c3ccccc3)CO2)c1
Reaction time: 12 h
Yield: 100.2 %

Procedure:
To a vigorously stirred mixture of 4,5-dihydro-2-(3-hydroxyphenyl)-4(S)-phenyloxazole (2.04 g, 8.5 mmol) and potassium carbonate (2.36 g, 17 mmol) in DMF (40 ml) was added dropwise over 5 min. a solution of ethyl bromoacetate (1.71 g, 10.2 mmol) in DMF (5 ml) at ambient temperature. The reaction mixture was stirred for 12 h and then poured into water (100 ml). The mixture was extracted with diethyl ether (3×50 ml), and the combined extracts were washed with brine (50 ml), dried (MgSO4) and concentrated under reduced pressure to afford title compound (2.77 g, quant.) as a pale yellow liquid.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:8]=[C:9]([N:13]2[Si](C)(C)CC[Si]2(C)C)[CH:10]=[CH:11][CH:12]=1.[C:22]1([CH:28]([N:35]2[CH2:38][C:37](=[O:39])[CH2:36]2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1CCCCC1.C1COCC1>[NH2:13][C:9]1[CH:10]=[CH:11][C:12]([C:37]2([OH:39])[CH2:38][N:35]([CH:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:36]2)=[C:7]([F:6])[CH:8]=1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Nc1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1
Reaction time: 2 h

Procedure:
Sec. butyllithium (22.5 mL) of a 1.3M solution in cyclohexane, 29.5 mmol) was added dropwise to a stirred solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (Example 20, Step 1) (6.0 g, 23.7 mmol) at −78° C. under nitrogen in dry THF (75 mL). After 2 hr a solution of 1-(1,1-diphenylmethyl)azetidine-3one (5.6 g, 23.6 mmol) in dry THF (60 mL) was added dropwise and stirring continued at −78° for 2 hr, when the cooling bath was removed. After reaching room temperature, a solution of saturated ammonium chloride (75 mL) was added followed by water (200 mL). The mixture was extracted with ether (500 mL), washed with brine (100 mL), dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in methanol (150 mL) and anhydrous potassium carbonate (6.0 g, 43.5 mmol) added and then stirred overnight. The suspension was filtered and the filtrate evaporated. The residue was partitioned between ether (500 mL) and water (200 mL). The water was extracted with additional ether (200 mL) and the combined ether extracts washed with brine (100 mL), dried over magnesium sulfate, filtered and evaporated to afford an orange foam. Chromatography over silica gel (150 g, 40-60 μm) eluting with 25-50% ethyl acetate-hexane gave the title compound as a pale yellow foam. 1H NMR δ (CDCl3): 2.62, 3.53, 3.78, 4.41, 6.36, 6.41, 7.03, 7.14-7.30, 7.39-7.47.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:27](O)=[O:28])[NH:24][C:25]=1[CH3:26].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:20][C:21]1[N:22]=[C:23]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:28])[NH:24][C:25]=1[CH3:26]
Reactant: CCOC(=O)c1cnc(N2CC[C@H](N)[C@H](OC)C2)s1
Reactant: Cc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(C)[nH]3)[C@H](OC)C2)s1
Yield: 19.7 %

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (5d) (0.21 g, 0.73 mmol), 4-chloro-5-methyl-1H-imidazole-2-carboxylic acid obtained in Example (5c) (0.10 g, 0.64 mmol), WSC hydrochloride (0.27 g, 1.41 mmol) and DMAP (10 mg, 0.083 mmol), to obtain 54 mg of the title compound as a pale yellow solid (20%).