Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:25][CH:26]=O)[CH2:10][N:11]([CH3:24])[C:12]([C:14]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:31])=[O:30]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:25][CH2:26][N:41]2[CH2:40][CH2:39][CH:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[S:29]([CH3:28])(=[O:31])=[O:30])[CH2:43][CH2:42]2)[CH2:10][N:11]([CH3:24])[C:12]([C:14]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(CC(CC=O)c1ccc(F)c(F)c1)C(=O)c1cccc2c1CCCC2
Reactant: CS(=O)(=O)c1ccccc1C1CCNCC1
Solvent: O
Product: CN(CC(CCN1CCC(c2ccccc2S(C)(=O)=O)CC1)c1ccc(F)c(F)c1)C(=O)c1cccc2c1CCCC2

Procedure:
Using standard reductive amination conditions N-[2-(3,4-difluorophenyl)-4-oxobutyl]-N-methyl-5,6,7,8-tetrahydro-1-naphthamide was reacted with 4-[2-methylsulfonylphenyl]piperidine and converted to the citrate salt. MS: m/z 595 (M+H). Analysis for C34H40F2N2O3S.C6H8O7.1.4 H2O: calculated: C, 59.16; H, 6.31; N, 3.45; found: C, 59.04; H, 6.10; N, 4.08.
Reaction SMILES: Br[CH:2]([CH2:14][O:15][CH3:16])[C:3]([NH:5][C:6]([CH3:13])([CH3:12])[C:7]#[C:8][CH2:9][O:10][CH3:11])=[O:4].[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([OH:24])[CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH:2]([CH2:14][O:15][CH3:16])[C:3]([NH:5][C:6]([CH3:13])([CH3:12])[C:7]#[C:8][CH2:9][O:10][CH3:11])=[O:4])[CH:21]=[N:20][CH:19]=1
Reactant: COCC#CC(C)(C)NC(=O)C(Br)COC
Reactant: Oc1cncc(Cl)c1
Product: COCC#CC(C)(C)NC(=O)C(COC)Oc1cncc(Cl)c1

Procedure:
2-Bromo-N-(1-methoxy-4-methylpent-2-yn-4-yl)-3-methoxypropionamide was reacted with 3-chloro-5-hydroxypyridine in a similar procedure to Example 10, Stage 2 to give the required product as a pale yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[C:10]([CH2:12][O:13][CH3:14])=[CH:9][N:8]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:3]1[OH:26].[CH2:27](O)[CH3:28]>>[OH:26][C@H:3]1[C@H:2]([O:1][CH2:27][CH3:28])[C:11]2[C:10]([CH2:12][O:13][CH3:14])=[CH:9][N:8]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COCc1cn2c(C)c(C)nc2c2c1[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N2
Reactant: CCO
Product: CCO[C@@H]1c2c(COC)cn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O

Procedure:
Analogously to Example 15, 350 mg of the title compound [Rf=0.45 (methylene chloride/methanol=13/1)] of melting point 184-6° C. (decomp.) are obtained by reaction of (7R,8R,9R)-7,8-dihydroxy-6-methoxymethyl-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine with ethanol and purification on silica gel (mobile phase: methylene chloride/methanol=100/3).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1B(O)O.C(N(CC)CC)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:16]1[CH:17]=[C:8]([C:6](=[O:7])[NH:5][CH2:4][CH2:3][N:2]([CH3:26])[CH3:1])[CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)NCCN(C)C)c1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)NCCN(C)C)cc(-c2cc(Cl)ccc2Cl)c1
Temperature: 100 °C

Procedure:
A mixture of methyl 3-((2-dimethylaminoethyl)carbamoyl]-5-(trifluoromethylsulfonyloxy)benzoate (2 g), 2,5-dichlorophenyl-dihydroxyborane 1.25 g), tetrakis(triphenylphosphine)palladium(0) (0.17 g) and triethylamine (1.52 g) in N,N-dimethylformamide (40 ml) was heated at 100° C. for 3 hours under nitrogen atmosphere. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate (100 ml) and water (100 ml). The organic layer was successively washed with 10% potassium carbonate aqueous solution, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (100 ml) eluting with a mixture of chloroform and methanol (20:1). The fractions containing the desired products were collected and evaporated in vacuo. The residue was crystallized from diisopropyl ether to afford methyl 5-(2,5-dichlorophenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoate.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:10]=[O:11])[CH2:2][CH:3]([CH3:5])[CH3:4].P([O-])(O)(O)=[O:22].[Na+].Cl([O-])=O.[Na+].Cl>C(#N)C.O.OO.C(Cl)(Cl)Cl>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]([OH:22])=[O:11])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O=P([O-])(O)O
Reactant: CC(C)CCOc1ccc(C=O)cc1OCCC(C)C
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC#N
Product: CC(C)CCOc1ccc(C(=O)O)cc1OCCC(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.6 %

Procedure:
In 30 ml of acetonitrile is dissolved 3.0 g of 3,4-diisopentyloxybenzaldehyde, to which are successively added at ambient temperature a solution of 4.5 g of sodium dihydrogenphosphate in 15 ml of water and 1.8 ml of 30% aqueous hydrogen peroxide. Then, a solution of 2.0 g of sodium chlorite in 30 ml of water is dropwise added thereto at 5-10° C., and the mixture thus obtained is stirred at ambient temperature for 3.5 hours. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 3.0 g of 3,4-diisopentyloxybenzoic acid is obtained as a white solid product.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:47]1[C:42](=[CH:43][C:44]([Cl:57])=[C:45]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=3)[CH:46]=1)[CH2:41][CH2:40]2)C1C=CC=CC=1>CO.[Pd]>[Cl:57][C:44]1[CH:43]=[C:42]2[C:47](=[CH:46][C:45]=1[CH2:48][C:49]1[CH:50]=[CH:51][C:52]([CH2:55][CH3:56])=[CH:53][CH:54]=1)[C@:10]1([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]1)[CH2:40][CH2:41]2
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CC[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Cc2cc3c(cc2Cl)CC[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To a solution of (1S,3′R,4′S,5′R,6′R)-3′,4′,5′-tris(benzyloxy)-6′-(benzyloxymethyl)-5-chloro-6-(4-ethylbenzyl)-2,3,3′,4′,5′,6′-hexahydrospiro[indene-1,2′-pyran] (120 mg, 0.15 mmol) in methanol (10 mL) was added Pd/C (40 mg, 30% wt). The mixture was stirred under hydrogen (1 atm) for 12 h at room temperature. It was filtered, and the filtrate was concentrated to give a residue, which was purified by preparative HPLC to provide 52 mg (81%) of product as a white solid. 1H NMR (CD3OD, 300 MHz): δ 7.25 (s, 1H), 7.23 (s, 1H), 7.09 (m, 4H), 4.05 (s, 2H), 3.80 (m, 1H), 3.64-3.34 (m, 5H), 2.93 (dd, J=7.8, 6.6 Hz, 2H), 2.58 (q, J=7.8 Hz, 2H), 2.53 (dt, J=13.2, 7.5 Hz, 1H), 2.11 (dt, J=13.2, 7.5 Hz, 1H), 1.19 (t, J=7.8 Hz, 3H); MS ESI (m/z) 419 (M+1)+, calc. 418.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH2:13].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C@@:5]3([CH2:11][CH2:12][NH:13][C@@H:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:6][NH:7][C:8]2=[CH:9][CH:10]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=Cc1ccccc1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1ccc2c(c1)[C@@]1(CCN[C@@H]1c1ccccc1)CN2
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of 2-(5-chloro-1H-indol-3-yl)ethanamine (1.67 g, 8.58 mmol) in DCM (43 mL) was added benzaldehyde (0.96 g, 9.0 mmol). The reaction mixture was stirred over molecular sieves 4 Å (4.1 g) overnight. The mixture was filtered through Celite. The filtrate was concentrated in vacuo. The crude product was dissolved in DCM (35 mL). A solution of (−)-Ipc2BCl (12.3 g, 38.2 mmol) in DCM (40 mL) was added to the reaction mixture. The resulting solution was stirred at about room temperature for about 3 days. Aqueous 15% NaOH solution (50 mL) was added and the mixture was stirred for about 15 min. The organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexane:EtOAc, 1:1) to give the less polar product (2′R,3S)-5-chloro-2′-phenylspiro[indoline-3,3′-pyrrolidine] (0.73 g, 35%). Further elution with EtOAc gave the other diastereomer (2′S,3S)-5-chloro-2′-phenylspiro[indoline-3,3′-pyrrolidine] (0.50 g, 24%). LCMS (APCI+) m/z 285, 287 [M+H]+; Rt=2.35 min.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][C:24]([F:32])=[C:25]([NH:30][CH3:31])[CH:26]=4)[C:21]3=[O:33])=[CH:16][CH:15]=2)=[O:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][C:24]([F:32])=[C:25]([NH:30][CH3:31])[C:26]=4[F:35])[C:21]3=[O:33])=[CH:18][CH:19]=2)=[O:12])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)cc1)CC2
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Product: CNc1c(F)cc2c(c1F)CCN(c1ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)cc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
To a solution of 1-(5-chlorothiophen-2-ylsulfonyl)-3-(4-(7-fluoro-6-(methylamino)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)urea (17 mg, 0.033 mmol) in DMF (2 mL) at room temperature, selectFluor (1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate), 32 mg, 0.090 mmol) was added. After being stirred at room temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by RP-HPLC to give the titled compound as a powder (1 mg). ES-MS (M+H)+=527, 529 (Cl pattern).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:27]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1)(=[O:29])[CH3:28]
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1

Procedure:
Using essentially the technique of Example 19, but starting from (5R)-3-(4-((3S)-3-aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one hydrochloride (250 mg, 0.65 mM), and replacing the methyl chloroformate with acetic anhydride gave the desired product (150 mg).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[C:4]([CH3:16])[CH:3]=1.N([O-])=O.[Na+].[I-:21].[K+]>Cl.O>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([I:21])=[CH:3][C:4]=2[CH3:16])=[CH:9][CH:10]=1)#[N:15]
Reactant: Cc1cc(N)ccc1-c1ccc(C#N)cc1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(I)ccc1-c1ccc(C#N)cc1
Reaction time: 0.33 h
Yield: 68.7 %

Procedure:
A suspension of 4-amino-1-(4-cyanophenyl)-2-methylbenzene (250 mg 1.2 mmol) in conc. hydrochloric acid (1.3 mL) and water (1.6 mL) at 0° C., was treated with a solution of sodium nitrite (183 mg, 2.65 mmol) in water (1 mL) over 10 mins. The mixture was stirred for 20 mins and then a solution of potassium iodide (840 mg, 5.06 mmol) in water (2 mL) was added, over 10 mins. The resultant mixture was heated at 90° C. for 2 h, then cooled. The residue was extracted with dichloromethane (3×30 mL) and the combined organic extracts were washed with 5% aqueous sodium metabisulphite (4×30 mL), to remove iodine. The organic solution was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane:ethyl acetate 20:1 to 10:1) to give 1-(4-cyanophenyl)-4-iodo-2-methylbenzene as a white solid (263 mg, 69%).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[NH:43]1[CH2:46][CH:45]([NH:47][C:48](=[O:50])[CH3:49])[CH2:44]1>>[CH3:41][C@@H:39]1[CH2:40][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:33][C:24]3[C:25]([C:28]([N:43]4[CH2:46][CH:45]([NH:47][C:48](=[O:50])[CH3:49])[CH2:44]4)=[O:29])=[N:26][O:27][C:23]=3[C:22]=2[F:34])[CH2:36][C@H:37]([CH3:42])[O:38]1
Reactant: CC(=O)NC1CNC1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: CC(=O)NC1CN(C(=O)c2noc3c(F)c(N4C[C@@H](C)O[C@@H](C)C4)c(CO)cc23)C1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and N-(azetidin-3-yl)acetamide
Reaction SMILES: [C:1]1([CH2:11][C:12]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.O>[C:1]1([CH2:11][C:12]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1sccc1NC(=O)Cc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1cccc2ccccc12)Nc1ccsc1C(=O)O
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Methyl 3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylate (210 mg, 0.645 mmol) was dissolved in THF/H2O (2.5 mL, 4/1, v/v). Sodium hydroxide (129 mg, 3.22 mmol) was added and the reaction mixture was stirred at 50° C. for 20 h. The resulting solution was acidified with 10% aqueous HCl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum to give 3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylic acid. Retention time=1.962 min, method [1], MS (ESI) 312.1 (M+H).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[Na].Cl[CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Cl>C(O)C.O>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][CH2:9][CH2:8][S:1][CH2:2][C:3]([OH:5])=[O:4])=[CH:12][CH:13]=1
Reactant: Oc1ccc(SCCCl)cc1
Reactant: O=C(O)CS
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(O)CSCCSc1ccc(O)cc1
Temperature: 25 °C

Procedure:
Mercaptoacetic acid (3.5 g, 0.039 mole) was added to ethyl alcohol (100 ml) containing sodium (1.8 g, 0.078 mole). The compound of Example 36 (7.3 g, 0.039 mole) in ethyl alcohol (20 ml) was added dropwise and the mixture refluxed 1 hour. The reaction mixture was cooled to room temperature, poured into water (250 ml) and acidified with 2N hydrochloric acid. The product was extracted into ethyl ether (2×150 ml) and the ethyl ether extracted with 1M sodium bicarbonate (3×80 ml). The combined basic washes were acidified with 2N hydrochloric acid and extracted with ethyl ether (3×150 ml). The combined ethyl ether extracts were washed with water (3×75 ml) and saturated sodium chloride (50 ml), dried over magnesium sulfate, filtered and concentrated to give a yellow solid. Recrystallization from ethyl ether/pentane gave the title compound, m.p. ca. 105° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:14]2[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C@H:15]2[CH2:28][OH:29])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>C1COCC1.C(=O)([O-])O.[Na+]>[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:14]2[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:16][C@H:15]2[CH2:28][O:29][S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CO)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COS(C)(=O)=O)C1
Yield: 96.4 %

Procedure:
Methanesulfonyl chloride (1.366 mL, 17.65 mmol) was added dropwise to a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (5.11 g, 13.58 mmol) and triethylamine (2.84 mL, 20.37 mmol) in THF (50 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (5.95 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:10]=[C:11]([S:14](O)(=[O:16])=[O:15])[S:12][CH:13]=2)=[O:8])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH4+:24].[OH-]>C(Cl)Cl.CC(C)=O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:10]=[C:11]([S:14]([NH2:24])(=[O:16])=[O:15])[S:12][CH:13]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2csc(S(=O)(=O)O)c2)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2csc(S(N)(=O)=O)c2)cc1

Procedure:
To 2.98 g (0.01 mol) of product from Step B suspended in 75 ml CH2Cl2 was added excess thionyl chloride and the resulting suspension was stirred, and heated at reflux for 1.5 hours to give a homogeneous solution. The thionyl chloride was evaporated and the residue was extracted with CHCl3 after ice had been added. The organic extract was washed with brine, dried and the solvent evaporated to give a yellow oil. This was taken up in acetone and treated with 5 ml of concentrated NH4OH dropwise. After stirring for 15 minutes, this was extracted with chloroform and the extract was dried. Filtration and evaporation of the solvent gave the desired product as a yellow solid, m.p. 173°-175° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12]P(=O)(OC)OC)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([N-]C(C)C)(C)C.[Li+].[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>C1COCC1>[O:33]1[CH2:38][CH2:37][C:36](=[CH:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[C:5]=3[N:11]=2)[CH2:35][CH2:34]1
Reactant: COP(=O)(Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1)OC
Reactant: O=C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2nc(C=C3CCOCC3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of dimethyl (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylphosphonate from Example 117 (0.45 g) in anhydrous THF (6 mL) at 0° C. was added 2.0 M of lithium diisopropylamide in tetrahydrofuran (1.5 eq). The resulting solution was allowed to warm to RT before adding a solution of dihydro-2H-pyran-4(3H)-one (1.5 eq) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 1 h, then partitioned between brine and Ethyl Acetate. The organic layer was isolated, dried (MgSO4), concentrated and recrystallized from methanol. The light yellow solid was filtered and collected to give 0.36 g of 4-(6-((2H-pyran-4(3H,5H,6H)-ylidene)methyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine as a light yellow solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:10]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[O:9][C:7](=[O:8])[C:5]=2[CH:6]=1.O.[OH-].[Na+]>C(O)C.[Zn]>[CH:2]1[CH:3]=[C:4]([CH:10]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[C:5]([C:7]([OH:9])=[O:8])=[CH:6][CH:1]=1
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a 3 L 3-necked flask containing 60 g of phenolphthalein (A), 450 ml of water and 525 ml of ethanol was added 450 mL of 50% sodium hydroxide solution in ethanol and 300 g of zinc powder. The contents were heated to reflux and maintained at that temperature for 12 hrs. The solution was cooled to room temperature, filtered and acidified until phenolphthalin precipitated as a white powder. This was collected by filtration and dried at 80° C. for 24 hrs at reduced pressure. Yield=95%. m.p.=234°-236° C.
Reaction SMILES: CSC(SC)=[N:4][C@H:5]([C:17]([OH:19])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1.C[N:23]1CCOCC1.ClC(OCC)=O>CN(C=O)C>[NH2:4][C@H:5]([C:17]([NH2:23])=[O:19])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1
Reactant: CSC(=N[C@@H](Cc1cccc(C(C)(C)C)c1)C(=O)O)SC
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(C[C@H](N)C(N)=O)c1
Reaction time: 0.5 h

Procedure:
To a solution of 492 mg (1.51 mmol) of N-[bis-(methyl-thio)methylene]-3-t-butylphenylalanine in 5 ml of DMF, 0.183 ml (1.66 mmol) of NMM and 0.159 ml (1.66 mmol) of ethyl chloroformate were added at −15° C. and the mixture was stirred for 30 minutes. The reaction mixture was stirred with bubbling of ammonia gas for another 30 minutes, left to stand at room temperature, diluted with ethyl acetate and washed first with water, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure; the resulting residue was dissolved in 3 ml of 1,4-dioxane and, after adding 1 ml of 2 N hydrochloric acid, the solution was stirred at room temperature for 3 days. Under cooling with ice, the solution was neutralized with saturated aqueous NaHCO3, extracted with chloroform, and washed first with water, then with saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol=10:1) to give Phe(3-tBu)-NH2 in the amount of 210 mg (63%).
Reaction SMILES: [Cl-].[CH:2]1([CH2:6][NH2+:7][CH2:8][CH2:9]Cl)[CH2:5][CH2:4][CH2:3]1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[S:21]>>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]=[C:20]1[N:7]([CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5]2)[CH2:8][CH2:9][S:21]1
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: ClCC[NH2+]CC1CCC1
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2CC2CCC2)c(Cl)c1

Procedure:
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-(cyclobutylmethyl)-1,3-thiazolidine.