Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[SH:27][CH:28]([CH2:31][CH3:32])[CH2:29][OH:30]>CN(C)C=O>[Br:1][C:2]1[C:3]([S:27][CH:28]([CH2:29][OH:30])[CH2:31][CH3:32])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CCC(S)CO
Reactant: CS(=N)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(CO)Sc1nc(Nc2ccc(S(C)(=N)=O)cc2)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.1 %

Procedure:
362 mg of (RS)-S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide is dissolved in 1.5 ml of dimethylformamide, mixed with 0.5 ml of triethylamine and 320 mg of (RS)-2-mercapto-butan-1-ol and stirred for 18 hours at room temperature. The mixture is evaporated to the dry state in a vacuum and purified by flash chromatography (dichloromethane/ethanol). 255 mg of the product with a melting point of 175-180° C. is obtained.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:22]=[C:23]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)[CH:24]=[CH:25][CH:26]=1.CO>O1CCCC1>[CH3:1][O:20][C:21]1[CH:22]=[C:23]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3cccc(O)c3)nc2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCOc1ccc(-c2cnc(-c3cccc(OC)c3)nc2)cc1
Yield: 80 %

Procedure:
1.50 g (5.76 mmol) of triphenylphosphine and 0.90 ml (5.76 mmol) of diethyl azodicarboxylste in 40 ml of tetrahydrofuran are stirred at 0° C. for 30 minutes. 1.50 g (3.84 mmol) of 2-(3-hydroxyphenyl)-5-(4-octyloxyphenyl)pyrimidine and 0.23 ml (5.76 mmol) of methanol are subsequently added, and the resultant solution is stirred at room temperature overnight. Evaporation to dryness, chromatographic purification (silica gel/dichloromethane:ethyl acetate=95:5) and recrystallization from acetonitrile give 1.20 g of 2-(3-methoxyphenyl)-5-(4-octyloxyphenyl)pyrimidine. ##STR16##
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14]>C(OCC)C>[CH3:6][C:7]1[N:8]=[C:9]([Si:13]([CH3:15])([CH3:14])[CH3:12])[S:10][CH:11]=1
Reactant: Cc1cscn1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1csc([Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexane, 1.1 equivalents) was added dropwise to a solution of 4-methylthiazole (1.0 equivalent) in dry diethyl ether at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, trimethylsilylchloride (1.0 equivalent) was added dropwise. The mixture was allowed to warm to room temperature and was then quenched by the addition of saturated aqueous sodium hydrogen carbonate. Work-up in the normal fashion and vacuum distillation then gave the title compound. B.p. 42° C. at 1 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:11])[CH:3]=1.F[B-](F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[NH:8])[O:7][CH2:17][CH3:18])=[C:4]([F:11])[CH:3]=1
Reactant: NC(=O)c1ccc(Cl)cc1F
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Product: CCOC(=N)c1ccc(Cl)cc1F

Procedure:
starting from 4-chloro-2-fluorobenzamide and triethyloxonium tetrafluoroborate there is obtained ethyl 4-chloro-2-fluorobenzimidate as an oil; mass spectrum: 202 (3.5), 201 (1), 200 (10), 182 (2), 173 (27), 157 (100), 156 (75);
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1)([CH3:3])[CH3:2].[I:22]N1C(=O)CCC1=O.O>C(#N)C>[I:22][C:15]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:16]([CH3:18])[CH3:17])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)[Si](OCc1cn2ccccc2n1)(C(C)C)C(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC#N
Product: CC(C)[Si](OCc1nc2ccccn2c1I)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
1.85 g (6.08 mmol) of 2-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine were solubilised in 25 ml of acetonitrile with magnetic stirring, to this solution were added 1.409 g (6.08 mmol) of N-iodosuccinimide. The mixture was stirred at r.t. for 16 h before being treated with 100 ml of water. The aqueous phase was extracted with 3×50 ml of dichloromethane. The combined organic phases were washed with 100 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. 2.29 g (yield=83%) of 3-iodo-2-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine were obtained as a pale yellow solid. LC-MS: m/z=431 (MH+); UV purity at 254 nm=95%.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:20]O>>[CH3:20][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1
Reactant: N#Cc1ccc(C(N)CC(=O)O)cc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1ccc(C#N)c(F)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
436 mg (2.09 mmol) 3-amino-3-(4-cyano-3-fluorophenyl)propionic acid were suspended in 8.5 ml methanol and the mixture cooled to 0° C. 0.23 ml (3.14 mmol) thionyl chloride were slowly added. The mixture was stirred at room temperature for 20 hours and concentrated. The residue was treated with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic part was dried with sodium sulfate and concentrated. Chromatography over silica gel (dichloromethane/ethanol 100/0-97/3-94/6) gave 245 mg (47%) 3-amino-3-(4-cyano-3-fluoro-phenyl)-propionic acid methyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1.[CH2:23]([NH2:25])[CH3:24]>>[CH2:23]([NH:25][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH2:12][C:11]2[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][O:9][CH:10]=2)=[N:15][CH:16]=1)[CH3:24]
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Reactant: CCN
Product: CCNC(=O)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 81 %

Procedure:
As described for example 358 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted using ethylamine (2 M solution in THF) instead of 4-aminotetrahydropyran to the title compound (88 mg, 81%) which was obtained as a white solid. MS: m/e=325.3 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[N:41]1([CH2:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][N:20]4[C:28]([C:31]([NH:33][CH2:34][C:35]5[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=5)=[O:32])=[CH:29][CH:30]=[C:19]4[CH2:18]3)=[O:16])=[CH:13][CH:14]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: C1COCCN1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3CN3CCOCC3)cc1)C2

Procedure:
The title compound was prepared from 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56, Step B, and morpholine in the manner of Example 42, m.p. 191-194° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[C:4]([C:7]#[N:8])[S:5][CH:6]=1.[CH:10]([B-](F)(F)F)=[CH2:11].[K+]>CCO>[CH:10]([C:2]1[C:3]([CH3:9])=[C:4]([C:7]#[N:8])[S:5][CH:6]=1)=[CH2:11]
Reactant: C=C[B-](F)(F)F
Reactant: Cc1c(Br)csc1C#N
Agent: [K+]
Solvent: CCO
Product: C=Cc1csc(C#N)c1C

Procedure:
A mixture of 4-bromo-3-methylthiophene-2-carbonitrile (3.00 g, 14.8 mmol), potassium vinyltrifluoroborate (2.40 g, 17.8 mmol) and Pd (dppf)2Cl2 (0.5 g) in 30 mL of EtOH and 30 mL of TEA was refluxed under Ar for 4 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography (petrol ether:EtOAc=50:1) to afford 4-ethenyl-3-methylthiophene-2-carbonitrile.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[CH2:15]1[CH:19]2[CH2:20][C:21](=[O:22])[CH:17]([CH2:18]2)[CH2:16]1.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CCOCC>[O:29]=[C:23]([CH:20]1[C:21](=[O:22])[CH:17]2[CH2:18][CH:19]1[CH2:15][CH2:16]2)[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C1CC2CCC1C2
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)C1C(=O)C2CCC1C2

Procedure:
The title product was prepared by a procedure similar to that described in step 1 of intermediate 1, from hexamethyldisilazane (4.2 ml, 20.0 mmol), ether (91 ml), nBuLi (2.3M in hexane, 11.63 ml, 27.3 mmol), norcamphor (2.0 g, 18.2 mmol) and diethyl oxalate (2.96 ml, 21.82 mmol) the title product was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[CH2:22]([O:21][C:19]([C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:20])[CH3:23]
Reactant: Cc1cccnc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ncccc1C)C(=O)OCC
Temperature: 135 °C
Yield: 74.1 %

Procedure:
A mixture of 2-amino-3-methylpyridine (5.5 g) and 2-ethoxy-1,1-bis(ethoxycarbonyl)ethene (10.8 g) was heated in a heating bath at 135° C. for 30 minutes. It was then cooled and triturated with light petroleum ether (b.p. 40°-60° C.). The resulting crude solid was recrystallised from light petroleum ether (b.p. 40°-60° C.), to give 1,1-bis(ethoxycarbonyl)-2-(3-methylpyrid-2-ylamino)ethene (10.3 g), m.p. 65°-67° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:16]=[C:15]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)[CH:14]=[CH:13][C:12]=1[OH:22].[CH3:23][O:24][CH:25](Cl)Cl>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[C:15]([CH:17]2[O:18][CH2:19][CH2:20][O:21]2)[CH:14]=[CH:13][C:12]=1[O:22][CH2:23][O:24][CH3:25]
Reactant: Oc1ccc(C2OCCO2)cc1Br
Reactant: COC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc(C2OCCO2)cc1Br
Reaction time: 1 h
Yield: 93.4 %

Procedure:
(iPr)2NEt (6.0 mL, 35.0 mmol) was added dropwise to a stirred and cooled (0° C.) solution of alcohol 3a (4.0 g, 16.3 mmol) in CH2Cl2 (50 mL). After 15 min methoxymethylene chloride (MOMCl) (1.6 mL, 28 mmol) was added dropwise over a period of 5 min, and stirring was continued for 1 h. The cold bath was removed, and stirring was continued for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography using hexanes-ethyl acetate mixture (5:1) as eluent to give compound 4a (4.4 g, 94%) as a colorless liquid. Rf=0.48 (25% EtOAc-hexanes); IR (neat) 2956, 2889, 1606, 1497, 1246, 1100, 1043 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J=1.8 Hz, 1H), 7.31 (dd, J=8.7, 2.1 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 5.70 (s, 1H), 5.21 (s, 2H), 4.02 (m, 4H), 3.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.2, 132.8, 131.4, 126.7, 115.5, 112.6, 102.5, 94.8, 65.1, 56.2; EIMS (m/z, rel intensity) 290 (M++2, 54), 288 (M+, 58), 259 (23), 257 (23), 209 (56), 73 (100).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:37])[C:34]=1[O:35][CH3:36])[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:2]([O:4][C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7][C@H:8]([NH:22][C:29](=[O:30])[C:28]1[CH:32]=[C:33]([F:37])[C:34]([O:35][CH3:36])=[C:26]([F:25])[CH:27]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH3:3]
Reactant: COc1c(F)cc(C(=O)O)cc1F
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(F)c(OC)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride salt (200 mg, 0.58 mmol) in CH2Cl2 (2 mL) and DMF (2 mL) at rt is added 3,5difluoro-4-methoxy benzoic acid (108 mg, 0.58 mmol) followed by an addition of TEA (0.32 mL, 2.3 mmol) and HATU (262 mg, 0.69 mmol). The mixture is stirred at rt for 4 hours and quenched with saturated NaHCO3 and diluted in ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained material is purified by preparative silica gel thin-layer chromatography plates (eluent:EtOAc/hepane=3/2) to give 265 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-methoxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester.
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:8][CH:9]2[N:12]([CH:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])Cl)[C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]1([P:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C>[C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:8][CH:9]2[N:12]([C:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])=[P:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)C(Cl)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C(N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of 4-(triphenylmethylthio)-1-(benzyloxycarbonylchloromethyl)azetidin-2-one (850 mg), triphenylphosphine (640 mg) and 2,6-butidine (210 μl) in DMF (50 ml) was heated at 80° C. under nitrogen for 24 hours. The reaction was then cooled, diluted with ice water and extracted with ethyl acetate (2×100 ml). The ethyl acetate extracts were washed with water and brine, dried (Na2SO4) and evaporated. The residue was flash chromatographed with a solvent gradient of 15 to 60% ethyl acetate/hexane to afford recovered starting material (500 mg) and then 4-(triphenylmethylthio)-1-[(benzyloxycarbonyl)triphenylphosphoranylidenemethyl]azetidin-2-one (650 mg) as a white foam, Rf =0.20 (30% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[C:4]([CH2:21][CH2:22][C:23](OCC)=[O:24])[C:5]2[O:9][CH2:8][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)[C:6]=2[C:19]=1[CH3:20].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[NH2:1][C:2]1[C:3]([CH3:28])=[C:4]([CH2:21][CH2:22][CH2:23][OH:24])[C:5]2[O:9][CH2:8][CH:7]([C:10]3[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=3)[C:6]=2[C:19]=1[CH3:20]
Reactant: CCOC(=O)CCc1c(C)c(N)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N)c(C)c2c(c1CCCO)OCC2c1ccc(C(C)C)cc1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a suspension of ethyl 3-(5-amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)propanoate synthesized in Reference Example 321 (1.28 g, 3.36 mmol) in THF, was added Lithium aluminum hydride (255 mg, 6.72 mmol) at 0° C., and the mixture was stirred at the same temperature for 30 minutes and heated under reflux for 30 minutes. To the reaction solution was added water, and the product was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 750 mg (yield 66%) of the title compound. Melting point: 110-111° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[C:17](=O)[O:16][CH2:15][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:19]([NH2:21])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][NH:21][CH2:19][CH3:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:15][OH:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1OCC2CCCCC12c1ccc(Cl)c(Cl)c1
Reactant: CCN
Product: CCNCC1(c2ccc(Cl)c(Cl)c2)CCCCC1CO

Procedure:
The title compound was prepared from racemic 7a-(3,4-dichlorophenyl)hexahydroisobenzofuran-1(3H)-one and ethylamine according to General Procedures AA, followed by General Procedure E. The racemic aminol was separated using a chiral column (Chiracel OD column; 95:5:0.1 hexanes:IPA:DEA, λ=254 nm, 1 mL/min) to give the fast moving enantiomer 169 E1 (Rt=7.5 min) and the slow moving enantiomer 169 E2 (Rt=9.7 min). LCMS Rt=7.88 min, m/z=316 (M+1). 1H NMR (CDCl3, δ): 7.4 (m, 2H), 7.17 (dd, J=2.4, 8.5 Hz, 1H), 3.7 (m, 2H), 3.10 (d, J=12.3 Hz, 1H), 2.71 (d, J=12.3 Hz, 1H), 2.6 (m, 2H), 2.3 (m, 1H), 1.9-1.3 (m, 8H), 1.04 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3, δ, mult): 146.5(0), 133.1(0), 130.8(1), 130.0(0), 128.5(1), 125.7(1), 63.2(2), 53.6(br, 2), 45.4(0), 43.9(2), 41.9(1), 39.8(br, 2), 26.1(2), 24.8(2), 22.0(2), 14.5(3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:13]1([NH2:20])[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1>C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:19][C@H:16]3[CH2:17][CH2:18][C@@H:13]([NH2:20])[CH2:14][CH2:15]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: NC1CCC(N)CC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCO
Product: N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Temperature: 250 °C

Procedure:
A mixture of 4,7-dichloroquinoline(2 g, 10.2 mmol) and 1,4-cyclohexanediamine (2.5 g, 21.9 mmol) was heated at 250° C. for 15 hours, cooled to room temperature, diluted with ethanol, and filtered. The residue was extracted with chloroform from 50%NaOH solution. The extract was dried with Na2SO4 and MgSO4, filtered and concentrated to give the desired compound. MS (ESI(+)Q1MS m/z 276 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl.[N:35]1[CH:40]=[CH:39][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[CH:37][N:36]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[CH:39]=[CH:40][N:35]=[N:36][CH:37]=3)[CH2:43][CH2:42]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: NC1(c2ccnnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccnnc5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.080 g, 0.177 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamine HCl (0.024 g, 0.177 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.090 g, 0.89 mmol, 5.0 eq) and BOP reagent (0.117 g, 0.264 mmol, 1.5 eq). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as eluent. Yield: 0.060 g (60.0%). 1H NMR (400 MHz, CD3OD): δ 9.08 (m, 1H), 9.05 (d, J=1.0, 5.8 Hz, 1H), 7.97-7.93 (m, 2H), 7.72 (s., 1H), 7.54 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 4.10 (s, 3H), 2.95 (s, 3H), 2.30 (s, 3H), 1.63 (s, 4H). 19F NMR (376.57 MHz, CD3OD): δ −112.33, −122.75. LCMS: (ES+) m/z=569.2 (M+H)+
Reaction SMILES: I[C:2]([F:11])([F:10])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])I.I[C:13]1[CH:14]=[C:15]([C:21]#[N:22])[C:16](=[CH:19][CH:20]=1)[C:17]#[N:18].CS(C)=O>[Cu].O>[C:21]([C:15]1[CH:14]=[C:13]([C:2]([F:11])([F:10])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]#[N:22])[CH:14]=2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])#[N:22]
Reactant: FC(F)(I)C(F)(F)C(F)(F)I
Reactant: N#Cc1ccc(I)cc1C#N
Agent: [Cu]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(C(F)(F)C(F)(F)C(F)(F)c2ccc(C#N)c(C#N)c2)cc1C#N
Yield: 54.4 %

Procedure:
1,3-Diiodoperfluoropropane (2.0 g, 5 mmol), 1.8 g (30 meq) of activated copper, 2.5 g (10 mmol) of 4-iodophthalonitrile and 6 ml of dry dimethyl sulfoxide were purged for 15 minutes with argon and the mixture was then heated at 115°-120° C. for 4 hours. After cooling, the content was poured into 100 ml of water and extracted with four 50 ml portions of ether. The combined ethereal extract was washed with water, charcoaled, dried over anhydrous sodium sulfate and concentrated at reduced pressure to afford 1.1 g (52%) of product, m.p 133°-135° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=2)[C:12]([OH:27])=[C:11]([C:28](OCC)=[O:29])[C:10]1=[O:33].[CH2:35]([CH2:37][NH2:38])[OH:36]>>[O:34]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=2)[C:12]([OH:27])=[C:11]([C:28]([NH:38][CH2:37][CH2:35][OH:36])=[O:29])[C:10]1=[O:33]
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCS2(=O)=O)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCS2(=O)=O)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(1,1-dioxido-2-isothiazolidinyl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as an white solid. 1H NMR (400 MHz, CDCl3) δ 10.37 (t, J=5.3 Hz, 1 H), 8.59 (s, 1 H), 7.87 (s, 1 H), 7.24 (m, 2 H), 7.02 (t, J=8.6 Hz, 2 H), 4.42 (t, J=7.0 Hz, 2 H), 4.13 (s, 2 H), 3.87 (t, J=5.2 Hz, 2 H), 3.65 (m, 2 H), 3.36 (t, J=7.0 Hz, 2 H), 3.26 (t, J=6.5 Hz, 2 H), 3.08 (t, J=7.5 Hz, 2 H), 2.25 (m, 2 H); HRMS C23H25FN4O6S (M+H)+ calcd 505.1479, found 505.1558.