Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([S:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[C:56]([N+:57]([O-])=O)=[C:55]([NH2:60])[CH:54]=[CH:53][C:52]=3[S:61]([C:63]3[CH:68]=[CH:67][C:66]([NH2:69])=[C:65]([N+:70]([O-])=O)[C:64]=3[C:73]3[CH:78]=[CH:77][C:76]([S:79][C:80]4[CH:85]=[CH:84][C:83]([Cl:86])=[C:82]([N+:87]([O-])=O)[CH:81]=4)=[CH:75][CH:74]=3)=[O:62])=[CH:47][CH:46]=2)=[CH:40][C:39]=1[N+:90]([O-])=O>>[Cl:86][C:83]1[CH:84]=[CH:85][C:80]([S:79][C:76]2[CH:75]=[CH:74][C:73]([C:64]3[C:65]([NH2:70])=[C:66]([NH2:69])[CH:67]=[CH:68][C:63]=3[S:61]([C:52]3[CH:53]=[CH:54][C:55]([NH2:60])=[C:56]([NH2:57])[C:51]=3[C:48]3[CH:49]=[CH:50][C:45]([S:44][C:41]4[CH:42]=[CH:43][C:38]([Cl:37])=[C:39]([NH2:90])[CH:40]=4)=[CH:46][CH:47]=3)=[O:62])=[CH:78][CH:77]=2)=[CH:81][C:82]=1[NH2:87]
Reactant: Nc1ccc(S(=O)c2ccc(N)c([N+](=O)[O-])c2-c2ccc(Sc3ccc(Cl)c([N+](=O)[O-])c3)cc2)c(-c2ccc(Sc3ccc(Cl)c([N+](=O)[O-])c3)cc2)c1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1cc(Sc2ccc(-c3c(S(=O)c4ccc(N)c(N)c4-c4ccc(Sc5ccc(Cl)c(N)c5)cc4)ccc(N)c3N)cc2)ccc1Cl

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)- 4-methylphenyl sulfoxide a corresponding amount of [4-(4-chloro-3-nitrophenylthio)-phenyl]-4-amino-3-nitrophenyl sulfoxide, the title compound is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([CH:11]=1)[C:8]([NH:26][C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1)=[O:10])#[N:2]
Reactant: Nc1cccnc1
Reactant: N#Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1

Procedure:
A solution of 5-cyano-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 14; 160 mg, 0.63 mmol), 3-pyridinamine (65.4 mg, 0.70 mmol), HOBT (116 mg, 0.76 mmol) and EDC (145 mg, 0.76 mmol) in DMF (10 ml) was stirred at room temperature overnight. Water (30 ml) was added and the mixture was then filtered. The residue was dried to yield the title compound as a white solid. 90 mg.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([CH2:10][CH3:11])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.CN1CCOCC1.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:2]([CH3:1])[C@@H:3]([CH2:10][CH3:11])[CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC[C@@H](CN1CCCC1)NC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC[C@@H](CN1CCCC1)N(C)C(=O)c1ccc(Br)cc1
Yield: 61.4 %

Procedure:
To a solution of (S)—N-methyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M5) (75 mg, 0.48 mmol) in DCM (1.5 mL) was NMM (0.058 mL, 0.53 mmol) and 4-bromobenzoyl chloride (137 mg, 0.62 mmol) added. The resultant mixture was stirred at rt overnight. The mixture was diluted with DCM (5 mL), washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (100 mg, 62%). Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ 0.92, 1.33-1.66, 1.66-1.97, 2.55, 2.94, 3.64, 4.70-4.83, 7.21-7.49, 7.49-7.76. Ratio major:minor:3:2. Total no of protons: 23.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN1CCCC1=[O:18].[NH2:19][CH2:20][CH2:21][O:22][CH:23](O)[CH3:24].C([O-])([O-])=O.[K+].[K+]>O>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:18])=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: CN1CCCC1=O
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(O)OCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(NCCOCCO)ccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
2 g of 5-fluoro-2-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.63 g of 2-aminoethoxyethanol and 2.14 g of K2CO3. The reaction medium was heated at 60° C. for 12 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 1.9 g of 2-[2-(4-nitro-3-methylphenylamino)ethoxy]ethanol (15) were obtained after purification on a column of silica.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[CH2:37][C:38]1[S:42][C:41]([NH2:43])=[N:40][N:39]=1>C(#N)C>[Cl:33][C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[CH2:37][C:38]1[S:42][C:41]([NH:43][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][C@@H:11]3[CH2:10][CH2:9][C@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[N:16][CH:17]=2)=[O:21])=[N:40][N:39]=1
Reactant: Nc1nnc(Cc2cccc(Cl)c2)s1
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cn2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(Cc4cccc(Cl)c4)s3)cn2)CC1
Reaction time: 96 h

Procedure:
0.321 g of cis-6-(4-tert-butoxycarbonylcyclohexyloxy)nicotinic acid (1 mmol, 1 eq.) is placed in 50 mL of acetonitrile at room temperature. 0.33 mL of diisopropylethylamine (2 mmol, 2 eq.), 0.466 g of bromotris-pyrrolidinophosphonium hexafluorophosphonate (1 mmol, 1 eq.) and 0.270 g of 5-(3-chlorobenzyl)[1.3.4]thiadiazol-2-ylamine (1.2 mmol, 1.2 eq.) are successively added with stirring. After 4 days at room temperature, the reaction medium is evaporated and 15 mL of DMF are added. The medium is stirred again for 18 hours, diluted in ethyl acetate, washed three times with brine, dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 5% to 50%. After evaporating the fractions of interest, the residue is chromatographed on silica gel with a gradient of ethyl acetate in dichloromethane ranging from 2% to 20%. 0.262 g of tert-butyl cis-4-{5-[5-(3-chlorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]pyridin-2-yloxy}cyclohexanecarboxylate is obtained.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](=S)[NH:23][CH3:24])C1C=CC=CC=1.CI.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH:38][NH2:39])=O)=[CH:31][CH:30]=1.CN(C=O)C>C(#N)C>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][C:36]2[N:23]([CH3:24])[C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:20])[CH3:21])=[N:39][N:38]=2)=[CH:33][CH:34]=1
Reactant: CNC(=S)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Reactant: NNC(=O)Cc1ccc(F)cc1
Solvent: CI
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cn1c(Cc2ccc(F)cc2)nnc1-c1nc2n(c(=O)c1O)CCOC2(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
To a solution of 3-(benzyloxy)-N,9,9-trimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.1 g, 0.278 mmol, 1.0 equiv) in acetonitrile (0.9 mL) under a nitrogen atmosphere, was added MeI (0.070 mL, 1.11 mmol, 4 equiv). The reaction was heated at 50° C. (oil bath) for 45 min. The reaction was then cooled to ambient temperature and concentrated in vacuo. 2-(4-Fluorophenyl)acetohydrazide (0.14 g, 0.84 mmol, 3 equiv) was then added to the residue followed by DMF (2 mL) and the slurry was heated at 140° C. (oil bath). After stirring 16 h, the reaction was cooled to ambient temperature and concentrated in vacuo. The residue was added to a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was treated with DMF (˜1.5 mL). After trying to dissolve material, the insoluble portion was filtered and washed with methanol to provide the title compound (0.024 g, 22% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.21 (dd, J=8.81, 5.29 Hz, 2H), 7.03 (t, J=8.69 Hz, 2H), 4.24 (s, 2H), 4.04 (q, J=2.77 Hz, 4H), 3.93 (s, 3H), 1.57 (s, 6H); LCMS (ES+, (M+H)+) m/z 386.22.
Reaction SMILES: Br[C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=[O:6].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CCOCC.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>[OH:11][C:3]1[C:4]([CH:5]=[O:6])=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Br)c(O)c(C=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(C=O)c(O)c(-c2ccccc2)c1
Temperature: 80 °C
Yield: 50.5 %

Procedure:
A mixture of 3-bromo-2-hydroxy-5-methylbenzaldehyde (0.30 g, 1.40 mmoles), phenyl boronic acid (0.20 g, 1.67 mmoles) and tetrakis(triphenylphosphine)palladium(0) (81 mg, 0.07 mmoles) in toluene (10 ml) and 2M K2CO3 (3 ml) was heated to 80° C. for 2 hr. The reaction mixture was cooled to ambient temperature, diluted with ether (100 ml) and washed with NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated to yield a residue which was purified using flash chromatography (10% ethyl acetate/hexanes) to yield 0.15 g (49%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]([CH2:15][OH:16])=[CH:13][C:12]3[CH:17]=[CH:18][S:19][C:11]=3[S:10]2(=[O:21])=[O:20])[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.[S:27](=[O:29])=[O:28].[NH2:30]OS(O)(=O)=O>>[OH:16][CH2:15][C:14]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[S:10](=[O:21])(=[O:20])[C:11]2[S:19][C:18]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:17][C:12]=2[CH:13]=1
Reactant: NOS(=O)(=O)O
Reactant: O=S=O
Reactant: COc1cccc(N2C(CO)=Cc3ccsc3S2(=O)=O)c1
Agent: [Li]CCCC
Product: COc1cccc(N2C(CO)=Cc3cc(S(N)(=O)=O)sc3S2(=O)=O)c1
Yield: 72 %

Procedure:
A solution of the product from Step D (2.0 g, 6.19 mmol) was treated sequentially with n-butyllithium, sulfur dioxide and hydroxylamine-O-sulfonic acid in a manner essentially analogus to that described in Example 15, Step E to give an orange solid (1.78 g, 72%): mp 180°-182° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:21]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCCBr
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccccc1O
Temperature: 60 °C
Yield: 40.9 %

Procedure:
A mixture of catechol (11 g, 100 mmole), bromododecane (32.4 g, 130 mmoles) and potassium carbonate (18.2 g, 130 mmole) in dry DMF (100 ml) was stirred and heated at 60° C. for 48 h. The mixture was poured into water (500 ml) and extracted with diethyl ether (3×100 ml). The combined ether extracts were washed with saturated sodium chloride solution (2×100 ml) and dried with anhydrous magnesium sulphate. The ether was removed to give a solid. Distillation at reduced pressure gave 2-dodecyloxyphenol (11.4 g, 41%), b.p. 175° C./0.5 mmHg, (Found C, 77.80; H, 10.80; C18H30O2 requires C,77.65; H, 10.86; MS (CI) m/e 296 (M+ +NH4+), δH (200 MHz, CDCl3) 0.90(t, 3H), 1.28(br s, 18H), 1.82(q, 2H), 4.04(t, 2H), 5.70(s, 1H) and 6.85(m, 4H) and Catechol bis-decyl ether (11.2 g, 25%), b.p. 225° C./0.5 mmHg, m.p. 46° C. (Lit. 46° C.)5.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[C:26]([O:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH3:27])[CH:20]([NH:33]C(OC(C)(C)C)=O)[C:19]2=[O:41])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.C(Cl)Cl>[NH2:33][CH:20]1[C:19](=[O:41])[N:18]2[CH:21]1[S:22][CH2:23][C:24]([CH:25]=[C:26]([O:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH3:27])=[C:17]2[C:15]([O:14][CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1)OS(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2SC1)OS(C)(=O)=O
Reaction time: 1 h

Procedure:
A solution of the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3- (2-mesyloxyprop-1-en-1-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1 g) in acetonitrile (12 cc) is heated to 38° C. A solution of p-toluenesulphonic acid monohydrate (0.63 g) in acetonitrile (10 cc) is added in the course of 20 minutes and the mixture is then kept at 38° C. for 1 hour. It is diluted with methylene chloride (30 cc) and the solution obtained is washed with a saturated solution of sodium bicarbonate (20 cc) and then with distilled water (50 cc), dried over sodium sulphate and concentrated to a volume of 15 cc under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields a solution of the Z form of 7-amino-2-benzhydryloxycarbonyl-3-(2-mesyloxyprop-1-en-1-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, to which triethylamine (0.7 cc) is added (Solution A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:18][C:19](=[CH2:21])[CH3:20].[OH-].[Na+].[CH2:24](Cl)Cl>>[CH2:1]([O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([O:8][C:19]([CH3:20])([CH3:18])[CH3:21])=[O:7])[CH3:24]
Reactant: ClCCl
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(C(=O)OC(C)(C)C)ccc1C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution of 3-methoxy-4-methylbenzoic acid (10.0 g), concentrated sulfuric acid (1 ml), and condensed isobutylene (200 ml) in methylene chloride (200 ml) was placed in a pressure vessel and stirred for 16 hours. The vessel was then opened to vent unreacted isobutylene. The remaining liquid was poured into 10% (w/v) sodium hydroxide solution (150 ml) and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), and evaporated. The residue was purified by flash chromatography on silica gel (700 ml), eluting with 1:9 ethyl acetate:hexane, to give t-butyl 3-ethoxy-4methylbenzoate (9.1 g, 70%) as a colorless oil; NMR (80 MHz, CDCl3) 1.6[s, 9H, C(CH3)3 ], 2.27(s, 3H, CH3), 3.86(s, 3H, OCH3), 7.11(d, 1H), 7.49(m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](SC)=[NH:14])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C(OC([N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]1)=O)(C)(C)C.C(N(CC)CC)C>CN(C=O)C.C(O)(C)C>[NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]([NH:30][CH:26]2[CH2:27][CH2:28][CH2:29][NH:24][CH2:25]2)=[NH:14])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N=C(NC(=O)c1nc(Cl)c(N)nc1N)NC1CCCNC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A mixture of 1.17 g (4.5 mmol) 4-Aminomethyl-4-phenethyl-piperidine-1-carbocylic acid tert-butyl ester (intermediate 3), 1 mg (4.9 mmol) (S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester and 125 μl triethylamin in 50 ml DMF/iso-propanol (1:3) is stirred at 70° C. overnight. Then the reaction mixture is concentrated under reduced pressure. Then 50 ml 25% TFA in dicholoromethane is added and the mixture is stirred for 2 h at room temperature and evaporated. The residue is treated with excess HCl in methanol and evaporated again to yield 430 mg N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N′-piperidin-3-yl-guanidine. Step B: 100 mg N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N′-piperidin-3-yl-guanidine, 125 μl triethylamine and 62 mg 3-bromomethyl-benzoic acid methyl ester in 3 ml DMF were stirred at room temperature for 6 h. Then the reaction mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC (gradient of acetonitrile and water+0.2% trifluoroacetic acid, 25° C.). Fractions containing the title compound were concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13]C)[C:11]=1[Cl:12])[C:5]([O:7]C)=[O:6].B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[Cl:12])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(Cl)c(OC)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cc(O)c(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.7 %

Procedure:
Methyl 3,4-dichloro-5-methoxybenzoate (5) (518 mg, 2.34 mmol) was suspended in DCM (10 mL) under a reflux condenser fitted with a CaCl2 drying tube. BBr3 (554 μL, 5.86 mmol) was added and the reaction mixture was stirred at RT for 15 h. The reaction mixture was cautiously poured in to iced water (20 mL) and the mixture stirred for 10 min. The product was extracted with EtOAc (50 mL), then the organic solution was washed with brine (2×50 mL) and dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue purified by silica gel chromatogrpahy (40 g, 0-100% EtOAc in isohexane) to afford 3,4-dichloro-5-hydroxybenzoic acid (6) (260 mg, 51% yield) as a white solid: m/z 205 [M−H]− (ES−).
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([O:8][C:9]2[CH:10]=[C:11]([N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])[CH:25]=3)[CH2:16][CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].[CH2:41](O)[CH3:42]>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[C:11]([N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:35])([F:36])[CH:32]([F:33])[F:34])[CH:25]=3)[CH2:16][CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:13][CH:14]=2)=[CH:37][CH:38]=1.[CH2:41]([NH:1][C:4]1[CH:38]=[CH:37][C:7]([O:8][C:9]2[CH:10]=[C:11]([N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])[CH:25]=3)[CH2:16][CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)[CH3:42]
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(Oc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: CCNc1ccc(Oc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)cc1
Product: Nc1ccc(Oc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)cc1

Procedure:
A solution of 3-[[3-(4-nitrophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol (33.8 mg, 0.06 mmol) in ethanol and 5% palladium on carbon (4 mL) was placed under 40 psi hydrogen gas for 7 h. The mixture was filtered through celite, the solvent was evaporated, and the residue was purified by silica gel chromatography eluting with 25% ethyl acetate in hexane to give 13.4 mg (42%) of (EX-450A) as 3-[[3-(4-aminophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol and 13.9 mg (41%) of (EX-450B) as 3-[[3-[4-(ethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol both as orange oils. 3-[[3-(4-aminophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol: HRMS calcd. for C24H22F7N2O3: 519.1519 [M+H]+, found: 519.1529. 1H NMR (acetone-d6) δ3.63 (dd, 1H), 3.96 (dd, 1H), 4.42-4.58 (m, 1H), 4.80 (s, 2H), 5.88 (m, 1H), 6.20 (m, 1H), 6.32-6.77 (m, 6H), 6.92 (d, 1H), 7.06-7.26 (m, 3H), 7.43 (m, 1H). 3-[[3-[4-(ethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol: HRMS calcd. for C26H26F7N2O3: 547.1832 [M+H]+, found: 547.1819. 1H NMR (acetone-d6) δ1.23 (t, 3H), 3.17 (q, 2H), 3.63 (dd, 1H), 3.96 (dd, 1H), 4.42-4.58 (m, 1H), 4.79 (s, 2H), 5.85 (d, 1H), 6.20 (m, 1H), 6.33 (m, 1H), 6.47 (m, 1H), 6.50 (tt, 1J), 6.61 (d, 2H), 6.78 (d, 2H), 7.09 (t, 1H), 7.20 (m, 1H), 7.23 (d, 1H), 7.42 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCN1CCCCC1)C(C)(C)CCC2(C)C
Yield: 93.9 %

Procedure:
In a manner similar to that of Example 16(a), by reaction of 1.4 g (3.4 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) and 760 mg (4.08 mmol) of 1-(2-chloroethyl)-piperidine hydrochloride, 1.57 g (89%) of the expected compound was obtained in the form of a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([C:16]1[CH:17]=[C:18]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C1CCN2C(=NCCC2)CC1.Cl>CO.C(#N)C>[Cl:12][C:11]1[C:2]([NH:25][S:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)(=[O:24])=[O:23])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Temperature: 5 °C

Procedure:
1 kg of 2,3 dichloroquinoxaline and 1 kg of 3-nitrobenzenesulfonamide are mixed in 5 volumes of acetonitrile. The reaction mixture is heated to reflux. 2.3 kg of DBU and 1 volume of acetonitrile are added. After completion of the reaction, cool down at 5° C. Add 12 volumes of methanol and 1.53 kg of HCl, filter the reaction mixture. Wash the cake with 6 volumes of methanol and dry under vacuum.
Reaction SMILES: Cl.[CH:2]1([NH2:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[N-:13]([C:16]#[N:17])[C:14]#[N:15].[Na+]>O>[C:14]([NH:13][C:16](=[NH:17])[NH:12][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1)#[N:15]
Reactant: NC1CCCc2ccccc21
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CNC(=N)NC1CCCc2ccccc21
Yield: 18.1 %

Procedure:
A solution of 18.4 grams (g) of 1,2,3,4-tetrahydro-1-naphthylamine hydrochloride and 8.90 g of sodium dicyanamide in 220 milliliters (ml) of water was heated at 95° C. (steam bath) for 21 hours, after which time a viscous oil had precipitated from the hot solution. The reaction mixture was then cooled and extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and the sodium sulfate removed by filtration. The methylene chloride was then removed by evaporation in vacuo, leaving the crude product as a pale yellow gum. The gum was crystallized from isopropyl acetate to give an off-white, crystalline solid, melting point (mp) 153.5°-156.5° C. Recrystallization from aqueous ethanol gave 3.87 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 157°-158° C.