Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34](O)=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]=[C:37]2[C@@H:33]([NH:32][C:30]([O:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:31])[CH3:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.4 %

Procedure:
A mixture of (R)-3-(2-aminophenylamino)piperidine-1-carboxylic acid tertbutyl ester (2.25 g, 7.72 mmol), (S)-2-benzyloxycarbonylaminopropionic acid (1.9 g, 8.49 mmol), HOAt (1.16 g, 8.49 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.63 g, 8.49 mmol) and 4-methylmorpholine (1.87 mL, 16.98 mmol) in anhydrous DCM (50 mL) was stirred at RT for 1.5 h. The reaction mixture was diluted with DCM (200 mL) and washed with a 10% citric acid solution, followed by a saturated solution of NaHCO3 and then brine. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (20 mL) and heated at 70° C. for 20 h and then at 80° C. for 2 h. After cooling to RT, volatiles were then removed in vacuo and the residue was dissolved in EtOAc (200 mL) and washed with a saturated solution of NaHCO3 (100 mL×2). The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) affording (R)-3-[2-((S)-1-Benzyloxycarbonylaminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester as a white foam (2.75 g, 74%). LCMS: RT 3.16 min [M+H]+ 479.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36](O)=[O:37])=[CH:33][CH:34]=2)[NH:29][CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:36]([C:32]2[CH:31]=[C:30]3[C:35]([C:27]([Cl:26])=[CH:28][NH:29]3)=[CH:34][CH:33]=2)=[O:37])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccc2Cl)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2Cl)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-chlorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (7.5 g, 20 mmol) and 3-chloroindole-6-carboxylic acid (3.9 g, 20 mmol) afforded, after purification (SiO2: 33% to 50% EtOAc in hexane), 8 g (73%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH2:16][N:17]([CH2:24][CH2:25][CH3:26])[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])=[CH:4][C:3]=1[Br:27].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44]([O-:46])=[O:45].[Na+]>>[NH2:1][C:2]1[C:15]([CH2:16][N:17]([CH2:24][CH2:25][CH3:26])[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:45][C:44](=[O:46])[CH2:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[NH:36][C:30]2[C:29]([Cl:28])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:35])=[O:7])=[CH:4][C:3]=1[Br:27]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CCCN(Cc1cc(C(=O)OCCCCCl)cc(Br)c1N)C1CCCCC1
Agent: [Na+]
Product: CCCN(Cc1cc(C(=O)OCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from 4-[4-amino-3-bromo-5-(N-cyclohexyl-n-propylaminomethyl)-benzoyloxy]-n-butyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8. Oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14](O)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Solvent: C1CCOC1
Product: OCC1(c2ccc(F)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 109.1 %

Procedure:
A 1 M solution of borane-THF complex (16.7 mL, 16.7 mmol) was slowly added to a solution of (1-(4-fluorophenyl)cyclohexane carboxylic acid (928 mg, 4.18 mmol) in THF (15 mL) at room temperature under a nitrogen atmosphere. After 20 min., the reaction mixture was refluxed for 16 hrs, cooled to room temperature and quenched by the dropwise addition of 1N HCl until further addition caused no more gas evolution. Ethyl acetate and 1N sodium hydroxide were added. The organic layer was washed with 1N sodium hydroxide (2×), brine, dried over sodium sulfate, filtered, and evaporated in vacuo to yield the (1-(4-fluorophenyl)cyclohexyl)methanol (950 mg, 100% yield) as a light tan oil containing some solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH3:29][CH:18]1[N:17]2[C:22]([CH2:23][O:24][C:25]3[C:16]2=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:27][CH:26]=3)=[N:21][NH:20][C:19]1=[O:28]
Reactant: CC1C(=O)NN=C2COc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3ccc(C4CCNCC4)cc3N21
Yield: 99 %

Procedure:
A solution of 4-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.020 g, 0.050 mmol) in DCM (6 mL) and TFA (1 mL) was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo to give 4-methyl-6-piperidin-4-yl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale yellow solid (0.019 g, 99%). LC/MS (Table 1, Method 5) Rt=1.684 min.; MS m/z: 301 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[N:8][O:9][N:10]=[C:6]2[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1>CC(O)=O.CCOC(C)=O.O.[Fe]>[NH2:11][C:5]1[C:6]2[C:7](=[N:8][O:9][N:10]=2)[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c2nonc12
Temperature: 80 °C
Yield: 94 %

Procedure:
A solution of 1.0 g (5.02 mmol) of 4-chloro-7-nitrobenzofurazan in 20 mL AcOH, 10 mL EtOAc and 2 mL H2O was heated at 50° C. and treated with iron powder (1.4 g, 251 mmol). The mixture was heated at 80° C. for 30 min and then allowed to cool to rt. The mixture was filtered through Celite eluting with EtOAc. The filtrate was washed with sat. aq. NaHCO3, dried over MgSO4, and concentrated under reduced pressure to give compound 258A (0.80 g, 94%) as a red solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1Cl
Product: Cc1c(F)c(F)cc(C(=O)Cl)c1Cl
Reaction time: 1 h

Procedure:
To 2-chloro-4,5-difluoro-3-methylbenzoic acid (3.1 g) is added thionyl chloride (6 ml), and the mixture is reflexed for one hour. The mixture is concentrated under reduced pressure to give 2-chloro-4,5-difluoro-3-methylbenzoyl chloride (3.3 g).
Reaction SMILES: C(C1N(CC2C=CC=CC=2Cl)[C:7](/C=C(\CC2SC=CC=2)/C(O)=O)=[C:8]([CH2:10][OH:11])N=1)CCC.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][OH:38])=[CH:35][CH:34]=1>>[C:10]([O:38][CH2:37][C:36]1[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)(=[O:11])[CH:8]=[CH2:7]
Reactant: COc1ccc(CO)cc1
Reactant: CCCCc1nc(CO)c(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Product: C=CC(=O)OCc1ccc(OC)cc1

Procedure:
(E)-3-[2-n-Butyl-1-[(2-chlorophenyl)methyl]-4-hydroxymethyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid, prepared as in Example 19, is esterified with 4-methoxy-benzyl alcohol to give the p-methoxybenzyl propenoate. The 4-hydroxymethyl group in acetone is oxidized using an acidic aqueous solution containing chromic acid (Jones' reagent) and the ester is hydrolyzed using 10% sodium hydroxide to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(CCl)c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: Cc1cccc(Cn2ccc3ccc(CC(=O)O)cc32)c1

Procedure:
The titled compound (43 mg) as a reddish brown solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 3-methylbenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: CN(C)[CH:3]=[C:4]([N:10]1[CH:14]=[C:13]([C:15]#[N:16])[N:12]=[N:11]1)[C:5](OCC)=[O:6].[NH:18]([C:20]1[N:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:21]=1)[NH2:19].FC(F)(F)C(O)=O>O>[O:29]1[CH2:30][CH2:31][CH2:32][N:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:18]3[C:5](=[O:6])[C:4]([N:10]4[CH:14]=[C:13]([C:15]#[N:16])[N:12]=[N:11]4)=[CH:3][NH:19]3)[CH:21]=2)[CH2:27][CH2:28]1
Reactant: CCOC(=O)C(=CN(C)C)n1cc(C#N)nn1
Reactant: NNc1cc(N2CCCOCC2)ncn1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CCCOCC4)ncn3)c2=O)nn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 200 mg (0.9 mmol) of the compound from Example 7A, 178 mg (0.9 mmol) of the compound from Example 14A and 33 ml (49 mg, 0.4 mmol) of trifluoroacetic acid in 3 ml of water is stirred at 100° C. for 16 h. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried under reduced pressure. Yield: 80 mg (27% of theory) LC-MS (Method 4): Rt=1.40 min; MS (ESIpos): m/z=354 [M+H]+;
Reaction SMILES: [CH2:1]([N:3]([CH3:10])[CH2:4][CH2:5][C:6]([CH3:9])([NH2:8])[CH3:7])[CH3:2].[C:11](ON1C(=O)CCC1=O)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C1COCC1>[CH2:1]([N:3]([CH3:10])[CH2:4][CH2:5][C:6]([NH:8][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:9])[CH3:7])[CH3:2]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCN(C)CCC(C)(C)N
Solvent: C1CCOC1
Product: CCN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
Crude N1-ethyl-N1,3-dimethylbutane-1,3-diamine (1.87 g, 12.9 mmol) was dissolved into THF (100 mL) and cooled in an ice bath. Solid CbzOSu (3.23 g, 1 equiv, 12.9 mmol) was added to the reaction in one portion. The reaction was left to stir at room temperature for 16 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (50 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (3.29 g). The crude oil was purified on an ISCO purification system with gradient elution from 15 to 100% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a pale yellow oil (1.81 g, yield: 55.5%). 1H NMR (CDCl3, 400 MHz): δ 1.05-1.09 (t, J=8, 3H), 1.38 (s, 6H), 1.64-1.67 (t, J=6, 2H), 2.22 (s, 3H), 2.39-2.44 (q, J=6.6, 2H), 2.46-2.49 (t, J=6, 2H), 5.07 (s, 2H), 7.16 (bs, 1H), 7.28-7.41 (m, 5H). LRMS (ESI+) for C16H26N2O2 (278.2); Found: 279 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9].[CH3:10][Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>CN(C=O)C>[Br:9][C:3]1[C:2]([NH2:1])=[N:7][C:6]([O:8][CH3:10])=[CH:5][CH:4]=1
Reactant: Nc1nc(O)ccc1Br
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(Br)c(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13 %

Procedure:
To a solution of 6-amino-5-bromo-pyridin-2-ol (1.0 g) in DMF (30 mL) was added at 0° C. 0.5 M potassium bis(trimethylsilyl)amide in toluene (11.7 mL, 5.83 mmol) under Ar atmosphere. After stirring for 10 minutes, dimethyl sulfate (0.64 mL, 5.26 mmol) was added at 0° C. The mixture was allowed to warm to room temperature, and was stirred for an additional two hours. Buffer (pH 7) was added and mixture was extracted with diethyl ether. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness. Purification of the residue by flash chromatography (hexane/toluene 45:55) gave pure 3-bromo-6-methoxy-pyridin-2-ylamine (260 mg, 13% overall).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([CH3:14])[CH2:11][CH:12]=O)=[C:5]([CH3:16])[CH:4]=1.[NH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>Cl.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([N:18]3[C:22](=[O:23])[C:21]4[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]3=[O:28])[CH:12]=[CH:11][C:10]=2[CH3:14])=[C:5]([CH3:16])[CH:4]=1
Reactant: COc1ccc(C(=O)C(C)CC=O)c(C)c1
Reactant: NN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(C)ccn2N2C(=O)c3ccccc3C2=O)c(C)c1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A mixture of the 4-(4-methoxy-2-methylphenyl)-3-methyl-4-oxobutanal (0.31 g, 1.40 mmol) and N-aminophthalimide (0.28 g, 1.55 mmol) in HCl (5N, 0.15 mL) and dioxane (10.0 mL) was refluxed for 2 h. After cooling down to room temperature, the mixture was concentrated in vacuo and the residue was subjected to column chromatography (silica gel, 1/9 EtOAc/heptane) to give 0.42 g (86%) of pale yellow solid as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.91–7.89 (m, 1H), 7.81–7.73 (m, 3H), 7.09 (d, J=8 Hz, 1H), 6.74–6.72 (m, 2H), 6.58 (dd, J=3, 8 Hz, 1H), 6.29 (s, 1H), 3.73 (s, 3H), 2.23 (s, 3H), 1.97 (s, 3H); MS m/z 347.1 (M++H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.5 g, 1.84 mmol) in CH2Cl2 (10 mL) at 0° C. was added dropwise a solution of tert-butyl(R)-piperidin-3-ylcarbamate (0.37 g, 1.84 mmol) in CH2Cl2 (5 mL), then triethylamine (0.51 mL, 3.68 mmol). The mixture was allowed to warm to room temperature and was stirred for 3 h. After quenching with water, it was extracted with CH2Cl2. The organic layers were combined, dried over MgSO4, and concentrated. Purification via silica gel chromatography using 5:1 CH2Cl2: hexanes gave tert-butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate (0.54 g, 68%). LC/MS: m/z 435.5 (M+H)+ at 2.80 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].Br[C:13]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:13]([C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccc(Br)c(C(=O)O)c1
Product: COc1ccc(C(=O)c2ccccc2OC)c(C(=O)O)c1

Procedure:
This compound is obtained according to the procedure described in 1.1. by reacting 2-methoxybenzoyl chloride and 2-bromo-5-methoxybenzoic acid after halogen-lithium exchange. It is used in crude form in the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:18][C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.Br[C:20]1[CH:33]=[CH:32][C:23]([O:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:22]([O:34][CH3:35])[CH:21]=1.CNCCNC.C([O-])([O-])=O.[K+].[K+].[ClH:48].CCO>C1(C)C=CC=CC=1.CCOC(C)=O.CO.[Cu]I>[ClH:48].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:18][C:12]3[C:13](=[O:17])[N:14]([C:20]4[CH:33]=[CH:32][C:23]([O:24][CH2:25][CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)=[C:22]([O:34][CH3:35])[CH:21]=4)[CH2:15][CH2:16][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1cc(Br)ccc1OCCN1CCCC1
Reactant: COc1ccc(-c2cc3c(s2)C(=O)NCC3)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(OCCN4CCCC4)c(OC)c2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
Combine 2-(4-methoxy-phenyl)-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (0.234 g, 0.90 mmol), 1-[2-(4-bromo-2-methoxy-phenoxy)-ethyl]-pyrrolidine (Bastian, J. A., et al WO 9725033 A1) (0.271 g, 0.90 mmol), N,N′-dimethyl-ethane-1,2-diamine (16 mg, 0.18 mmol), K2CO3 (0.249 g, 1.81 mmol), and CuI (17 mmol, 0.09 mmol) in toluene (10 mL) and stir at 110° C. for 48 h. Dilute with EtOAc (100 mL) and wash with water (50 mL), containing NH3—H2O (5 mL) three times. Dry over Na2SO4, filter and purify the material by chromatography, eluting with 7% 2 M NH3 in CH3OH, and 93% CH2Cl2 to give 0.125 g. Dissolve the material in CH3OH (5 mL) and treat with 1.0 M HCl in EtOH (270 μL, 0.27 mmol). Stir at RT for 5 min and concentrate to give the title compound (0.133 g, 0.26 mmol, 100%). LC-MS/ES m/z 479.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH2:9]([SH:13])[CH2:10][CH2:11][SH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClCCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[S:13][CH2:9][CH2:10][CH2:11][S:12]1
Reactant: O=Cc1ccccn1
Reactant: SCCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: c1ccc(C2SCCCS2)nc1
Temperature: 5 °C
Yield: 85.2 %

Procedure:
A solution of pyridine-2-carboxaldehyde (26.7 g), propane-1,3-dithiol (94.4 g) and paratoluenesulphonic acid (3.7 g) in 1,2-dichloroethane (2500 cc) is kept at the boil for 20 hours so that the water formed is removed by azeotropic distillation. After cooling to 5° C., the reaction mixture is washed twice with an approximately 7 N aqueous solution of potassium hydroxide (540 cc in total) and then four times with distilled water (1400 cc in total). The organic solution is dried over anhydrous sodium sulphate and filtered and the filtrate is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. 2-(Pyrid-2-yl)-1,3-dithiane (41.9 g) is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1c(O)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1c(O)cccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.7 %

Procedure:
To a cold (0° C.) solution of 2-fluoro-6-hydroxybenzoic acid (5.00 g, 32.029 mmol) in dimethyl formamide (200 mL) were added N,O-dimethylhydroxylamine hydrochloride (6.25 g, 64.057 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.82 g, 48.043 mmol), 1-hydroxybenzotriazole (5.19 g, 38.435 mmol), and triethylamine (8.93 mL, 64.057 mmol). The mixture was stirred at room temperature for 15 hrs. The reaction mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate/hexane=2/1) to give 2-fluoro-6-hydroxy-N-methoxy-N-methylbenzamide as an orange solid (4.320 g, yield; 68%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:18]([CH:19]=[CH2:20])=[CH:17][C:16]([C:21]#[N:22])=[CH:15][C:14]=1[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[Cl:12][C:13]1[C:18]([CH:19]2[CH2:20][O:9]2)=[CH:17][C:16]([C:21]#[N:22])=[CH:15][C:14]=1[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc(C#N)cc(NC(=O)OC(C)(C)C)c1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(C2CO2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
Added m-CPBA 50% (1.92 gm, 5.56 mmol) in portions to an ice-cooled solution of tert-butyl (2-chloro-5-cyano-3-vinylphenyl)carbamate (Example 399A)(517 mg, 1.86 mmol) in DCM (30 mL). The bath was removed and the reaction was left stirring at room temperature overnight. Added additional 50% MCPBA (0.6 gm) and left stirring overnight. Added 20 mL of 0.5 M NaHCO3 solution and left stirring for 4 hr. The aqueous phase was separated and washed with DCM. The combined organic phases were washed three times with 1 N Na2CO3 solution. After drying with sodium sulfate, the solvents were removed to leave crude tert-butyl (2-chloro-5-cyano-3-(oxiran-2-yl)phenyl)carbamate (516 mg, 94% yield). This was dissolved in a mixture of DCE (12 mi) and MeOH (6 mL) in a microwave vial. Ethanolamine (2.12 mL, 35.0 mmol) was added and the vial was sealed and heated at 60° C. overnight. The solvent was removed and the residue was taken up in DCM and washed with water (2×) and brine. After drying with sodium sulfate, the solvent was removed and radial silica gel chromatography eluting with DCM containing 0 to 14% MeOH and then 10% 2N NH3 in MeOH afforded tert-butyl (2-chloro-5-cyano-3-(1-hydroxy-2-((2-hydroxyethyl)amino)ethyl)phenyl)carbamate (337 mg).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.CC(O)C>ClCCl>[CH2:1]([S:8]([C:9]1[N:10]=[CH:11][C:12]([Cl:15])=[CH:13][N:14]=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1cnc(SCc2ccccc2)nc1
Solvent: CC(C)O
Solvent: ClCCl
Product: O=S(Cc1ccccc1)c1ncc(Cl)cn1
Yield: 88 %

Procedure:
The oxidation of 2-benzylthio-5-chloropyrimidine was carried out using one molar equivalent of 85% m-chloroperbenzoic acid in dichloromethane, initially at -10° C. and then at 0° C., as described in Example 40 above; yield 88%, m.p. 92° C. (iPrOH). 1H NMR (CDCl3) δ4.30 and 4.33 (CH2), 7.23 (Ph), 8.73 (H-4, H-6).