Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CC[N:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26]C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C2C(=CC=CC=2)CN1>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:25]1[CH2:26][C:30]2[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28]1)=[O:6]
Reactant: O=C(Cl)c1ccc(OC2CCN(C3CCC3)CC2)cc1Cl
Reactant: CCN(CC)Cc1ccccc1
Agent: C=Cc1ccc(C=C)cc1
Agent: Cl
Agent: c1ccc2c(c1)CNC2
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc(OC2CCN(C3CCC3)CC2)cc1Cl)N1Cc2ccccc2C1
Reaction time: 16 h
Yield: 65.2 %

Procedure:
A stirred mixture of 2-chloro-4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D36) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.0 g) in DCM (10 ml) at rt was treated with isoindoline (0.08 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound as a white solid (0.08 g). MS electrospray (+ion) 411/413 (MH+). 1H NMR δ (DMSO-d6): 10.55 (1H, s), 7.45 (2H, m), 7.27 (4H, m), 7.11 (1H, m), 4.89-4.68 (3H, m), 4.52 (2H, m), 3.67 (1H, m), 3.46-3.18 (2H, m), 2.90 (2H, m), 2.40-1.63 (10H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+]>CN(C=O)C>[C:19]([O:22][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(CCl)nc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(COC(C)=O)nc12
Temperature: 50 °C
Reaction time: 6 h
Yield: 107 %

Procedure:
To a solution of methyl 2-(chloromethyl)-6-nitro-1H-benzimidazole-4-carboxylate (Example 58, Step 1) (99 mg) in DMF (1 mL), was added sodium acetate (17 mg), and the mixture was stirred at 50° C. for 6 hours. To the reaction mixture was added ice water, and it was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified on column chromatography to obtain the titled compound (65 mg) as colorless powder.
Reaction SMILES: CC1(C)[O:17][CH:5]2[CH:6]([O:13][CH2:14][O:15][CH3:16])[CH2:7][C:8]3[CH:9]([CH2:10][O:11][N:12]=3)[CH:4]2[O:3]1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)C>[OH:3][CH:4]1[CH:9]2[CH2:10][O:11][N:12]=[C:8]2[CH2:7][CH:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]1[OH:17]
Reactant: COCOC1CC2=NOCC2C2OC(C)(C)OC12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCOC1CC2=NOCC2C(O)C1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
4,5-(Dimethylmethylenedioxy)-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (257 mg) was dissolved in 10 ml of tetrahydrofuran, and 1 ml of 1N hydrochloric acid was added, followed by stirring the mixture at room temperature for 4 hours. The reaction mixture was diluted with diethyl ether, and neutralized with a sodium hydrogen carbonate aqueous solution. The organic layer was washed with a sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford 167 mg of 4,5-dihydroxy-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]2([NH2:43])[CH2:42][CH2:41]2)[N:35]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:43][C:40]5([C:36]6[N:35]=[C:34]([CH3:33])[CH:39]=[CH:38][N:37]=6)[CH2:41][CH2:42]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1ccnc(C2(N)CC2)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nccc(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.092 mmol, 1 eq), 1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.028 g (53%). 1H NMR (400 MHz, CD3OD): δ 8.49 (d, J=5.3 Hz, 1H), 8.07-7.95 (m, 2H), 7.92 (s, 1H), 7.69-7.51 (m, 2H), 7.39-7.23 (m, 3H), 7.16 (d, J=5.3 Hz, 2H), 4.08 (s, 3H), 2.95 (s, 3H), 2.49 (s, 3H), 2.37 (s, 3H), 1.87-1.76 (m, 2H), 1.57-1.45 (m, 2H). 19F NMR (376.47 MHz, CD3OD): δ −78.09 (TFA), −113.44 LCMS: (ES+) m/z=565.2 (M+H)+
Reaction SMILES: [C:1](/[N:3]=[C:4](\SC)/[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]#[N:14])=[C:8]([Cl:15])[CH:7]=1)#[N:2].[NH2:18][NH2:19]>C(O)C>[NH2:2][C:1]1[NH:19][N:18]=[C:4]([NH:5][C:6]2[CH:11]=[C:10]([Cl:12])[C:9]([C:13]#[N:14])=[C:8]([Cl:15])[CH:7]=2)[N:3]=1
Reactant: CS/C(=N\C#N)Nc1cc(Cl)c(C#N)c(Cl)c1
Reactant: NN
Solvent: CCO
Product: N#Cc1c(Cl)cc(Nc2n[nH]c(N)n2)cc1Cl
Yield: 70.6 %

Procedure:
A solution of (Z)-methyl N′-cyano-N-(3,5-dichloro-4-cyanophenyl)carbamimidothioate (234 mg, 821 μmol, Eq: 1.00) and hydrazine (263 mg, 258 μl, 8.21 mmol, Eq: 10) in ethanol (10 mL) was heated at 65° C. o/n. The reaction mixture was concentrated and chromatographed (23 Supelco, 100% DCM to 5% to 10% MeOH/DCM to give 156 mg (71%) of desired product as an off-white solid.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:52][C:53]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][C:54]=1[O:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:59]2[CH2:58][CH2:57][CH:56]([O:55][C:54]3[CH:62]=[C:63]([F:66])[CH:64]=[CH:65][C:53]=3[Cl:52])[CH2:61][CH2:60]2)=[O:12])=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: Fc1ccc(Cl)c(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.1 g, 0.00039 mole) in DMF (2 mL) was added HOBt (0.065 g, 0.00047 mole) and DIPEA (0.126 g, 0.00098 mole). The mixture was cooled to 10° C. and EDCI.HCl (0.090 g, 0.00047 mole) followed by 4-(2-chloro-5-fluoro-phenoxy)-piperidine hydrochloride (0.114 g, 0.00043 mole) were added. The resulting mixture was stirred at the ambient temperature overnight. The mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (35% ethyl acetate in hexane) afforded 0.024 g (13%) of N-biphenyl-4-yl-3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionamide. LCMS: 467 (M+1)+, 97.5%, 1H NMR (CDCl3): δ 10.0 (s, 1H), 7.66 (d, 2H), 7.58 (m, 4H), 7.42 (t, 2H), 7.34 (m, 2H), 6.68 (m, 2H), 4.64 (m, 1H), 4.3 (m, 1H), 3.7 (m, 3H), 3.52 (s, 2H), 1.96 (m, 4H).
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].[C:20]1([S:26]([OH:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.C1C=CC=CC=1>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH2:9][CH:8]([S:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:28])=[O:27])[C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Reactant: O=S(O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1CC(S(=O)(=O)c2ccccc2)C(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Yield: 88 %

Procedure:
38 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared as in Example 1, were dissolved in 250 ml. of benzene, 15 g. of freshly generated benzene sulfinic acid were added and then a few drops of water were added. This reaction mixture was heated at 40°-45° C. for 12 hours and then the benzene was evaporated. The white solid residue obtained was recrystallized from benzene twice and yielded white crystals, m.p. 157°-158° C. The yield was about 88%.
Reaction SMILES: N1(CCNC2C3OC=CC=3C=C(N)C=2)CCOCC1.[CH2:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:27][NH:28][C:29]1[C:37]2[O:36][CH:35]=[CH:34][C:33]=2[CH:32]=[C:31]([N+:38]([O-])=O)[CH:30]=1)[CH3:21]>>[CH2:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:27][NH:28][C:29]1[C:37]2[O:36][CH:35]=[CH:34][C:33]=2[CH:32]=[C:31]([NH2:38])[CH:30]=1)[CH3:21]
Reactant: CCN1CCC[C@@H]1CNc1cc([N+](=O)[O-])cc2ccoc12
Agent: Nc1cc(NCCN2CCOCC2)c2occc2c1
Product: CCN1CCC[C@@H]1CNc1cc(N)cc2ccoc12

Procedure:
The title compound was prepared according to the procedure described for Intermediate 28 using {[(2R)-1-ethylpyrrolidin-2-yl]methyl}(5-nitro-1-benzofuran-7-yl)amine (Intermediate 37). The obtained product was used directly in the subsequent reaction.
Reaction SMILES: [CH2:1]([NH:6][C:7]([NH:9][CH2:10][CH2:11][Cl:12])=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O)C.[N:16]([O-])=[O:17].[Na+]>Cl.O>[CH2:1]([NH:6][C:7]([N:9]([CH2:10][CH2:11][Cl:12])[N:16]=[O:17])=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CNC(=O)NCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)CNC(=O)N(CCCl)N=O
Reaction time: 2 h

Procedure:
The entire yield of 1-neopentyl-3-(2-chloroethyl) urea (0.08 mol) was dissolved in 120 ml of concentrated HCl:ethanol, 2:1 at 5° C. in a 500 ml round bottom flask equipped with magnetic stirring. Sodium nitrite (5.5 g, 0.08 mol) was dissolved in 30 ml of water and added to the solution over a ten-minute period. Stirring continued for 2 hrs, and the yellow, crystalline precipitate was filtered and washed with five 100 ml portions of chilled distilled water. The product was dried in vacuo for 18 hrs. giving 15 g (84%) which melted with decomposition at 52°-3° C. IR analysis showed peaks at 1730/cm (C=O) and 1520/cm (C--N--H). NMR showed a singlet (9H) at 1 ppm, a doublet (2H, J=6.5 HZ) at 3.3 ppm, a triplet (2H, J=6.5 Hz) at 3.6 ppm, and a triplet (2H, J=6.5 Hz) at 4.2 ppm.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.Cl.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CN(C)CCCl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O)cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCN(C)C)cc2c1=O
Yield: 87.5 %

Procedure:
N-Cyclopropyl-3-(6-hydroxy-4-oxoquinazolin-3 (4H)-yl)-4-methylbenzamide (0.15 g), 2-dimethylaminoethyl chloride hydrochloride (0.084 g), potassium carbonate (0.62 g), and sodium iodide (0.007 g) were stirred in acetone (9 ml) at 60° C. for 18 hours. The reaction mixture was filtered, the solids washed with acetone, and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 2N NaOH solution, brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate+1% aqueous ammonia solution gave the title compound (0.159 g) as a white solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 2.13 (s, 3H), 2.23 (s, 6H), 2.68 (t, 2H), 2.85 (m, 1H), 4.19 (t, 2H), 7.52 (m, 2H), 7.60 (s, 1H), 7.72 (d, 1H), 7.83 (s, 1H), 7.91 (d, 1H), 8.19 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 407.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]1([CH2:15][N:16]2[CH2:20][CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>CS(C)=O>[C:9]1([CH2:15][N:16]2[CH2:20][CH:19]3[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][N:22]=4)([CH2:4]3)[CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: FC(F)(F)c1ccc(C2=CCN(Cc3ccccc3)C2)nc1
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(C23CC2CN(Cc2ccccc2)C3)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a slurry of sodium hydride (83 mg) and trimethylsulfoxonium iodide (0.46 g) DMSO (anhydrous, 3 mL) was added dropwise (gas evolution). The resulting mixture was allowed to stir at room temperature for 0.5 h. A solution of 2-[1-(phenylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-5-(trifluoromethyl)pyridine (330 mg) in DMSO (anhydrous, 6 mL) was added at room temperature. After 1 h a saturated solution of ammonium chloride (4 mL) was added and the mixture extracted with dichloromethane (2×10 mL). Volatiles from the organic phase were evaporated under reduced pressure, the residue charged onto an SCX column and eluted with MeOH followed by MeOH/NH3 0.25 M. The methanole/ammonia fractions were concentrated under reduced pressure to give 0.31 g of the title compound (y=89%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2>S(=O)(=O)(O)O>[Br:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2c(Br)cccc2N1
Agent: O=S(=O)(O)O
Product: O=C1Cc2c(ccc([N+](=O)[O-])c2Br)N1
Reaction time: 1 h

Procedure:
A mixture of concentrated sulfuric acid (3.6 mL) and concentrated nitric acid (0.7 mL) was added slowly to a solution of 4-bromo-1,3-dihydro-2H-indol-2-one (2 g, 9.48 mmol) (see below) in concentrated sulfuric acid (20 mL) at −5° C. with stirring. The mixture was stirred for an additional 1 h at −5° C. then poured in ice. After standing for 1 h, precipitate formed was collected by filtration and washed with water, and dried in a vacuum oven to give 4-bromo-1,3-dihydro-5-nitro-2H-indol-2-one. (Yield 2.33 g, 96%).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O-2].[Zn+2:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Zn+2:22].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A molten stearic acid (22.2 grams, Industrene 7018) was added gradually to a stirred slurry mixture of zinc oxide (4 grams), citric acid (0.1 gram), and water (70 grams) at 60° C. The mixture was stirred at 60-70° C. for 30 minutes to afford a product mixture with zinc stearate floating, which was filtered and dried to give a quantitative yield of zinc stearate as shown by its infrared spectrum.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:8](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH:9]=[O:10])[CH2:4][CH2:5][CH2:6][CH3:7]>CO>[CH2:3]([C:8](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH2:9][OH:10])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(C=O)=Cc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(=Cc1ccc(Cl)cc1Cl)CO
Yield: 61.5 %

Procedure:
54.5 g of NaBH4 were added, in portions, to a solution of 150 g of (I) in 1.5 l of methanol. The mixture was refluxed for 1 hour and then concentrated, 1 l of 2N HCl was added, and the mixture was refluxed for a further hour and then extracted with CH2Cl2. The organic phase was washed with water, dried over Na2SO4 and concentrated. Distillation of the residue gave 93 g of (II) of boiling point 156°-160° C./0.2 mbar.
Reaction SMILES: [P:1]([Cl:15])(Cl)([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2].[Cl-].[CH2:17]([O:21][C:22](=[O:26])[C@@H:23]([NH3+:25])[CH3:24])[CH2:18][CH2:19][CH3:20].CCN(CC)CC>C(Cl)Cl>[Cl:15][P:1]([NH:25][C@H:23]([C:22]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[O:26])[CH3:24])([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: CCCCOC(=O)[C@H](C)[NH3+]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)[C@H](C)NP(=O)(Cl)Oc1cccc2ccccc12
Temperature: -78 °C

Procedure:
To 1-naphthyl dichlorophosphate in DCM (0.086 M) was added (25)-1-butoxy-1-oxopropan-2-aminium chloride (1.0 eq.). After cooling to −78° C., neat Et3N (2.0 eq.) was added and the reaction was left to warm to RT overnight. All volatiles were removed and the resulting white solid was washed with Et2O, filtered and evaporated in vacuo to obtain a colorless oil as a 1:1 mixture of diastereoisomers. 31P NMR (400 MHz, CDCl3): δ 8.39 and 8.11 ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][NH:5][C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1.CN([CH:17]=[O:18])C>>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:17]1=[O:18]
Reactant: CN(C)C=O
Reactant: CN(C)CCNc1ccccc1N
Product: CN(C)CCn1c(=O)[nH]c2ccccc21
Yield: 85 %

Procedure:
A mixture of N-[2-(dimethylamino)ethyl]benzene-1,2-diamine (3.11 g, 17.3 mmol) and 1,1-carbonyldiimidazole (CDI) (3.2 g, 19 mmol) are heated in DMF to 110°-120° C. until reaction is complete by TLC, cooled and extracted with EtOAc. The combined extracts are washed with water, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, 94:5:1 CH2Cl2, methanol, concentrated NH4OH as eluent) to give the title compound as a dark purple solid, 3.03 g (85% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:15][C:16]([NH2:18])=[NH:17].CN(C)[CH:21]=[CH:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=O>>[CH3:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:15][C:16]1[N:18]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][N:17]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=N)N
Solvent: O=[N+]([O-])O
Product: Cc1cc([N+](=O)[O-])ccc1Nc1nccc(-c2cccnc2)n1
Yield: 61 %

Procedure:
2-Methyl-4-nitrophenyl-guanidine nitrate (26.3 g, 0.1 mol) and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (15 g, 0.08 mol) were reacted according to the same procedure as Step 1.3 of Preparation 1 to give N-(2-methyl-4-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (15 g).
Reaction SMILES: C(OC(N1C[C@H](OC(C)(C)C)C[C@H]1C(O)=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]([N:34]1[CH2:38][C@@H:37]([NH2:39])[CH2:36][C@H:35]1[C:40]1[O:41][CH:42]=[CH:43][N:44]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]([N:34]1[CH2:38][C@@H:37]([NH2:39])[CH2:36][C@H:35]1[C:40]1[O:41][C:42]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:43][N:44]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Product: N[C@H]1C[C@@H](c2ncc(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1

Procedure:
(2S,4S)-4-amino-2-(5-phenyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester. MS calcd. for C21H22N3O3 [(M+H)+] 364, obsd. 364.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[CH:14][C:13]=1[NH:21][C:22]1[C:31]2[C:26](=[CH:27][C:28](F)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]=1[C:35]#[N:36].CS(C)=O>O1CCCC1>[CH2:3]([S:10][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:21][C:13]3[CH:14]=[C:15]([O:19][CH3:20])[C:16]([Cl:18])=[CH:17][C:12]=3[Cl:11])=[C:23]([C:35]#[N:36])[CH:24]=[N:25]2)=[CH:30][C:29]=1[O:32][CH3:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(SCc4ccccc4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
A mixture of sodium hydride (169 mg, 4.2 mmol), benzyl mercaptan (145 mg, 1.2 mmol) and 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (250 mg, 0.64 mmol) in 1 mL of tetrahydrofuran is heated at 70° C. for 1 hour, then stirred at room temperature overnight. Upon addition of 1 mL of dimethyl sulfoxide a solution is obtained. Additional amounts of sodium hydride and benzyl mercaptan are added and the reaction mixture is heated at 100° C. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative thin layer chromatography, eluting with 1:2 ethyl acetate:hexane to provide 150 mg of 7-benzylthio-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-quinolinecarbonitrile, mp 123-125° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([Cl:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ncc2ccc(Br)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncc2ccc(Br)cc2n1
Temperature: 25 °C
Yield: 65 %

Procedure:
A 0.5M suspension of 7-bromoquinazolin-2-ol in phosphorus oxychloride was heated to 110° C. in an oil bath for 1 h. The mixture was cooled to room temperature. Volatiles were removed under reduced pressure. The residue was triturated with ice water. The solid was collected by filtration and air dried to give product in 65% yield. ES/MS m/z 243/245 (MH+).