Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C)C=O.Cl.[CH2:13]([N:16]([CH:20]=[C:21]1[CH:29]=[CH:28]C(C(O)=O)=[CH:23][CH2:22]1)[CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>ClCCl>[CH2:17]([N:16]([CH:20]=[C:21]1[CH:22]=[CH:23][C:1]([C:2]([Cl:4])=[O:3])=[CH:28][CH2:29]1)[CH2:13][CH2:14][CH3:15])[CH2:18][CH3:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCN(C=C1C=CC(C(=O)O)=CC1)CCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C=C1C=CC(C(=O)Cl)=CC1)CCC

Procedure:
0.283 cm3 of oxalyl chloride and then a drop of dimethylformamide are successively added, at a temperature close to 20° C., to a suspension of 0.748 g of 4-(N,N-di-n-propylaminomethylene)benzoic acid monohydrochloride in 20 cm3 of dichloromethane. The reaction medium is kept stirred at a temperature close to 20° C. until the gaseous emission ceases, and then concentrated to dryness under reduced pressure (about 0.5 kPa) at a temperature close to 35° C. The white solid thus obtained is used as a base for the preparation of 4,4′-O,O-di(4-(N,N-di-n-propylaminomethylene)benzoyl)-2-[(1R,2S,3R)(1,2,3,4-tetrahydroxybutyl)]-5-[(2′S, 3′R)(2′,3′,4′-trihydroxybutyl)]pyrazine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)([O-:3])=[O:2].[NH2:16][C@@H:17]([CH2:26][S:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][S:27][CH2:26][C@H:17]([NH:16][C:13]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][CH:6]=[CH:5][C:4]=3[N+:1]([O-:3])=[O:2])=[O:15])[CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:34][CH:33]=1
Reactant: COc1ccc(CSC[C@H](N)COC(=O)C(C)(C)C)cc1
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)c2cc3cccc([N+](=O)[O-])c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
7-Nitro-1H-indole-2-carboxylic acid (8.2 g, 22.7 mmol) prepared in Step A and 2,2-dimethyl-propionic acid (R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propyl ester (13.2 g, 27.2 mmol) prepared in Preparation 31 were dissolved in N,N-dimethylformamide (100 mL). EDC (6.6 g, 25.0 mmol) and HOBT (4.6 g, 25.0 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. Saturated aqueous sodium bicarbonate solution was added to the mixture to quench the reaction. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was purified by column chromatography to give the title compound (8.1 g, Yield 71%).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28]([O:30]C)=O)=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.Cl.[CH3:34][NH2:35]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28]([NH:35][CH3:34])=[O:30])=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1

Procedure:
In like manner to preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and methylamine hydrochloride gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.06 (s, 1H), 7.85 (d, 1H, J=3.3 Hz), 7.42 (d, 2H, J=1.2 Hz), 7.35 (s, 1H), 7.29 (d, 1H, J=2.4 Hz), 6.99 (dd, 1H, J=3.3 and 8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.24 (s, 4H), 2.94 (s, 3H); LCMS: ret. time: 18.05 min.; purity: 99%; MS (m/e): 436 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[CH:16][N:15]=3)[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1nc(Br)ccc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)c(C)c1
Yield: 50.8 %

Procedure:
Using 6-bromo-2-methylnicotinic acid (986 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (917 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (903 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1.[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1cnc(Cl)c(C(F)(F)F)c1

Procedure:
Heat a mixture of 2-chloro-5-nitro-3-trifluoromethyl-pyridine (2.27 g, 10 mmol), calcium chloride (1.1 g, 10 mmol) and iron powder (4.5 g) in ethanol (30 mL) and water (5 mL) at reflux for 1 hour. Cool the mixture and filter through Celite. Evaporate the filtrate, dissolve the residue in EtOAc (200 mL) and wash with saturated NaHCO3(aq) (100 mL) and brine (100 mL). Dry the organic extract over MgSO4 and remove the solvent under reduced pressure to yield the title compound.
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][CH:12]([CH3:20])[C:13](=O)[C:14](OCC)=[O:15]>C(O)C(F)(F)F>[CH:12]([C:13]1[C:14](=[O:15])[O:10][CH2:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)([CH3:20])[CH3:11]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CCOC(=O)C(=O)C(C)C
Solvent: OCC(F)(F)F
Product: CC(C)C1=N[C@H](c2ccccc2)COC1=O
Yield: 35.6 %

Procedure:
(R)-2-phenylglycinol (4) (2.00 g, 14.6 mmol, 1.0 equiv.) and ethyl 3-methyl-2-oxobutyrate (2.20 mL, 14.6 mmol. 1.0 equiv.) were refluxed in trifluoroethanol (30 mL) over activated 4 molecular sieves (7.0 g) for 24 hours. Filtration through a short pad of Celite® CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo generated the crude product which was purified by flash column chromatography on silica, eluting with petrol and diethyl ether (4:1) to furnish the title compound as a colourless oil (1.13 g, 36%); v(max)(film) 2965 (C—H), 1740 (C═O), 1638 (C═N) cm−1; δH (250 MHz, CDCl3) 7.45-7.32 (5H, m, Ph), 4.90-4.83 (1H, m, PhCH), 4.55 (1H, dd, J 4.4 Hz, T 11.5 Hz, 6β-H), 4.13 (1H, dd/10.9 Hz, T 11.4 Hz, 6α-H), 3.32 (1H, m, CH(CH3)2), 1.25 (3H, d, J 5.0 Hz, CH(CH3)2×3), 1.22 (3H, d, /5.0 Hz, CH(CH3)2×3); δc (62.5 MHz, CDCl3) 167.7, 155.7, 137.5, 129.3, 128.6, 127.4, 71.7, 59.7, 32.7, 20.7, 19.9: m/z (CL, NH3), 220 (100%), 218 (MH+, 17%), 217 (27%), and 216 (25%); HRMS for C13H16NO2 requires 218.1177 found 218.1181. [α]D20-207.5 (c 1.17 CHCl3).
Reaction SMILES: [NH2:1][CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[C:12](Cl)=[CH:13][C:14]=1[Cl:15]>O.C(O)C>[N+:17]([C:11]1[CH:10]=[C:9]([C:8]([F:7])([F:20])[F:21])[C:14]([Cl:15])=[CH:13][C:12]=1[NH:1][CH2:2][P:3]([OH:6])(=[O:4])[OH:5])([O-:19])=[O:18]
Reactant: NCP(=O)(O)O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1NCP(=O)(O)O
Temperature: 120 °C
Yield: 68.2 %

Procedure:
3.3 g (30 mmol) of aminomethanephosphonic acid in 120 ml of water and 120 ml of ethanol are introduced together with 3.37 g (31.8 mmol) of soda and mixed with 7.8 g (97%, 30 mmol) of 3-trifluoromethyl-4,6-dichloronitrobenzene, and it is refluxed for 4 hours at 120° C. bath temperature. After removing the ethanol in a rotary evaporator, it is extracted three times with 100 ml of ethyl acetate. The organic phase is washed with a little water. It contains starting material and is discarded. The collected aqueous phase is adjusted acidic with 4N hydrochloric acid to pH 1 and extracted three times with 100 ml of ethyl acetate each. The organic phase is washed with water, dried, filtered and concentrated by evaporation. 6.85 g (68% of theory) of N-(2-nitro-4-trifluoromethyl-5-chloro-phenyl)-aminomethanephosphonic acid of melting point 207.3° C. is obtained.
Reaction SMILES: [NH:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:18]([N:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:3]1)(=[O:21])[CH2:19][CH3:20]
Reactant: N=C1N[SH](=O)(c2ccccc2)c2ccccc21
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)N=C1N[SH](=O)(c2ccccc2)c2ccccc21

Procedure:
From 12 g. 3-imino-1-phenyl-3H-1,2-benzisothiazole-1-oxide, 5 g. propionyl chloride and 6.6 g. triethylamine in chloroform, there is obtained, after heating under reflux for 3 hours and then working up the reaction mixture in the usual manner, the desired 3-(propionyl-imino)-1-phenyl-3H-1,2-benzisothiazole-1-oxide which, after recrystallisation from ethyl acetate, melts at 170°C.
Reaction SMILES: C[N:2]([C@@:10]1([CH3:15])[CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=O)OC(C)(C)C.C(N(CC)CC)C.[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[O:33][C:29]=2[C:28](F)=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=2)[C:26]=1[CH3:47])#[N:24]>CS(C)=O>[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[O:33][C:29]=2[C:28]([N:12]2[CH2:13][CH2:14][C@:10]([CH3:15])([NH:2][CH3:3])[CH2:11]2)=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=2)[C:26]=1[CH3:47])#[N:24]
Reactant: CN(C(=O)OC(C)(C)C)[C@@]1(C)CCNC1
Reactant: Cc1c(-c2cccc(F)c2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN[C@@]1(C)CCN(c2c(-c3cccc(F)c3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 150 °C
Yield: 21 %

Procedure:
A dimethyl sulfoxide (0.5 ml) solution of the above-mentioned tert-butyl methyl[(3S)-3-methylpyrrolidin-3-yl]carbamate (I-348) and triethylamine (172 μl, 1.23 mmol) was added to a dimethyl sulfoxide (4.5 ml) solution of 4-cyano-7-fluoro-6-(3-fluorophenyl)-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-184) (300 mg, 0.878 mmol) stirred in an oil bath at 150° C., followed by stirring in an oil bath at 150° C. for 30 minutes. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1→1:2, v/v). The obtained yellow foamy substance was dissolved in dichloromethane (3 ml), and with cooling with ice, trifluoroacetic acid (6 ml) was added, followed by stirring at room temperature for 8 hours. The reaction liquid was concentrated under reduced pressure, then an aqueous saturated sodium hydrogencarbonate solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was purified in slurry with a mixed solvent of isopropyl ether and hexane to obtain the entitled compound (80.0 mg, 21%) as a pale yellow solid.
Reaction SMILES: [Cl-].[CH3:2][Mg]I.[C:5](=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:17])([CH3:7])[CH3:6].[Cl-].[NH4+]>O1CCCC1>[C:5]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:17])([CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)=C1Cc2ccccc2C1=O
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C1Cc2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To the cupurous chloride (0.258 g, 2.61 mmol) inside 250 mL round bottom flask was added 22 mL of methylmagnesium iodide (3.0 M solution in diethyl ether, 66 mmol) at 0° C. under nitrogen. Diethyl ether was removed in vacuo. Tetrahydrofuran (65 mL) was then introduced. To this resulting suspension was added a solution of 2-isopropylidene-1-indanone (5.00 g, 29 mmol) in Tetrahydrofuran (25 mL) through a dropping funnel dropwise at 0° C. The mixture was stirred at the same temperature for another 1 h and then at ambient temperature overnight (16 h). The slurry was poured into ice (32 g) containing ammonium chloride (6.44 g). The solution was extracted with diethyl ether (5*80 mL). All ethereal layers were combined, washed with water (20 mL), dried over anhydrous magnesium sulfate and concentrated to yield 5.29 g (97%) of 2-t-butyl-1-indanone. H-NMR (CDCL3) δ 0.95 (s, 9H), 2.38 (dd, J=4.3, 8.0 Hz, 1 H), 2.90 (dd, J=4.3, 17.4 Hz, 1H), 3.08 (dd, J=8.0, 17.4 Hz, 1H) 7.23 (br t, J=7.4 Hz, 1H), 7.35 (br d, J=7.6 Hz, 1H), 7.46 (br t, J=7.6 Hz, 1H), 7.61 (br d, J=7.4 Hz, 1H):
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:15])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Yield: 104.3 %

Procedure:
10 g of p-acetyloxybenzoic acid was added to 45 ml of benzene, and 11.8 g of PCl5 was added little by little under stirring at room temperature. After 8.5 hours of heat-refluxing thereafter, the solvent was distilled off to obtain 11.5 g of p-acetyloxybenzoic acid chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:16]2[C:17](=[O:26])[C:18]([CH3:25])=[C:19]([CH3:24])[C:20](=[O:23])[C:21]=2[CH3:22])=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:2]=1>C(O)(=O)C.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:16]2[C:17](=[O:26])[C:18]([CH3:25])=[C:19]([CH3:24])[C:20](=[O:23])[C:21]=2[CH3:22])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:2]=1
Reactant: CC1=C(C)C(=O)C(C(=CCCCCC(=O)O)c2cccnc2)=C(C)C1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2cccnc2)=C(C)C1=O
Reaction time: 2 h
Yield: 83.5 %

Procedure:
7-(3-pyridyl)-7-(3,5,6-trimethyl-1,4-benzoquinon- 2-yl)-6-heptenoic acid (2.5 g) was hydrogenated in the presence of 5% palladium-carbon (0.5 g) in acetic acid (20 ml) (the reaction completed in about 2 hours). The catalyst was removed, the solvent was concentrated, and water (10 ml) and methanol (40 ml) were added. This solution was neutralized by addition of a saturated solution of sodium hydrogen carbonate, and the hydroquinone derivative was oxidized by aeration. After completion of oxidation, the mixture was concentrated under reduced pressure and the product was extracted with chloroform. The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and purified with silica gel column chromatography [ethyl acetate-ethanol(9:1)] and recrystallized from a mixture of ethyl acetate-isopropyl ether, to give 7-(3-pyridyl)-7-(3,5,6-trimethyl-1,4-benzoquinon- 2-yl)heptanoic acid (2.1 g).
Reaction SMILES: [OH:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH2:26]([O:25][C:23]([CH2:22][O:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4])=[O:24])[CH3:27]
Reactant: COc1ccccc1OC(c1ccccc1)C(O)C#N
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)COC(C#N)C(Oc1ccccc1OC)c1ccccc1
Temperature: 50 °C
Yield: 100 %

Procedure:
2.69 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile in 25 ml of anhydrous DMA was stirred with 6.68 g of ethyl bromoacetate in the presence of 2.76 g of anhydrous potassium carbonate. The mixture was heated at 50° C. for 16 hours, poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and concentrated to dryness, to obtain 3.55 g of 2-ethoxycarbonylmethyloxy-3-phenyl-3-(2-methoxyphenoxy)-propionitrile (oil) (Yield 100%), which was used as such for the reaction described in the previous example.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9](N(OC)C)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][CH2:24][Mg+].[Br-]>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[C:9](=[O:10])[CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-cyclohexyl-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (5.23 g, 16.66 mmol) in anhydrous toluene (80 mL) at −20° C. was added EtMgBr (3 M in Et2O, 16.7 mL, 49.97 mmol) slowly. The reaction was allowed to warm to 0° C., and stirred at this temperature for 2 h. The reaction was quenched with 1 M HCl at 0° C. and extracted with EtOAc. The organic phase was washed with sat. aq. NaHCO3, brine, concentrated to give (S)-tert-butyl 1-cyclohexyl-3-oxopentan-2-ylcarbamate. The product was used in the next step without further purification. MS ESI +ve m/z 306 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.Cl>C1COCC1.O.[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(C3CCC4(CC3)OCCO4)ccc(N)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-amino-4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (1.64 g, 5.42 mmol) in THF (60 mL) was added aqueous 3.0 M HCl (1.81 mL), the resulting mixture was stirred at rt overnight. The mixture to 0° C., diluted with water and basified to pH ˜10 with 1M NaOH. The aqueous mixture was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J=8.34 Hz, 1H), 6.53 (d, J=8.34 Hz, 1H), 5.88 (s, 2H), 4.41 (s, 2H), 3.00 (s, 3H), 2.56 (dt, J=6.06, 14.15 Hz, 2H), 2.21-2.30 (m, 2H), 1.96-2.04 (m, 2H), 1.78-1.91 (m, 2H); MS (ES+): m/z: 260.1517 [MH+]. HPLC: tR=1.06 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([N:11]2[C:16](=[O:17])[CH2:15][CH:14]([C:18]([F:21])([F:20])[F:19])[CH2:13][C:12]2=[O:22])=[C:6]([F:23])[CH:5]=1.[C:24]1([S:30][CH2:31]Cl)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Cl:3][C:4]1[C:9]([O:10][CH2:31][S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:7]([N:11]2[C:16](=[O:17])[CH2:15][CH:14]([C:18]([F:20])([F:19])[F:21])[CH2:13][C:12]2=[O:22])=[C:6]([F:23])[CH:5]=1
Reactant: ClCSc1ccccc1
Reactant: O=C1CC(C(F)(F)F)CC(=O)N1c1cc(O)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(C(F)(F)F)CC(=O)N1c1cc(OCSc2ccccc2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
While kept under N2, 0.15 g (3.7 mmol, 60% dispersion in oil) sodium hydride was washed with pentanes (2×0.5 ml), then suspended in 2 ml of dry THF (fleshly distilled from sodium/benzophenone). To the suspension, cooled in an ice bath, were added 1.1 g (3.4 mmol) of N-(4'-chloro-2'-fluoro-5'-hydroxyphenyl)-3-(trifluoromethyl)glutarimide (Compound 19) dissolved in 3.5 ml of dry THF (freshly distilled from sodium/benzophenone) and two 1 ml rinses of dry THF. The reaction was then allowed to warm to room temperature and stirred for 15 minutes. The flask was again cooled in an ice bath while a solution of chloromethyl phenyl sulfide (0.46 ml, 0.54 g, 3.4 mmol) in 3 ml dry THF was added dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred for about 24 hours, then warmed to 50° C. for 54 hours. The THF was evaporated in vacuo (2-10 Torr) and the reaction mixture was taken up in 12 ml anhydrous dimethylformamide. The reaction was heated to 100° C. for 8 hours then cooled to room temperature. The reaction mixture was suction filtered through a short pad of neutral alumina and rinsed with 30 ml EtOAc. The filtrate was evaporated in vacuo and the residue was dried in the vacuum oven for 12 hours (20-50 Torr, 50° C.). The resulting oil was vacuum distilled (2-10 Torr, 70° C.). The residue was chromatographed (silica gel, 1:1 hexanes/methylene chloride) to yield 350 mg (23% yield) of the desired product as a white solid, m.p. 108°-109.5° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C(C)=CC=CC=1.CCCCCC>[C:1]([O:9][CH2:10][CH3:11])(=[S:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: CCOC(=S)c1ccccc1
Yield: 175.3 %

Procedure:
70 ml (0.487 mol) of ethyl benzoate were heated to reflux for 12 hours with 100 g (0.247 mol) of Lawesson reagent in 350 ml of xylene. After cooling to 20° the reaction mixture was diluted with 500 ml of hexane and filtered. The filtrate was flash-chromatographed on 1 kg of silica gel. Elution was carried out with hexane. The fractions which were pure according to the thin-layer chromatogram (eluent: toluene) were combined and evaporated under reduced pressure. There were obtained 72 g (89%) of O-ethyl thiobenzoate as a dark yellow evil-smelling oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([CH2:20][CH2:21][NH:22][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCCN1CCOCC1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-morpholin-4-ylethylamine. The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([O:29][CH3:28])[CH:35]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: COc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.66 min, m/z=461.