Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[CH2:20]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH2:20]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:43])=[CH:37][CH:36]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(C(=O)OCC)c2)cc1
Reaction time: 2.5 h

Procedure:
A solution of 10.13 g of ethyl 3-amino-benzoate and 6.82 g of triethylamine in 100 ml of methylene chloride is added dropwise to a solution of p-tetradecyloxyphenylacetyl chloride in 100 ml of methylene chloride over 15 minutes. The mixture is stirred for an additional 2.5 hours then washed with dilute hydrochloric acid. The organic layer is evaporated and the residue dissolved in 1.5 liter of ether then washed with dilute sodium hydroxide. The organic layer is dried and evaporated to a residue which is crystallized from carbon tetrachloride:hexane to give 24.4 g of the desired product as a white solid, m.p. 91°-94° C.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH3:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=1[C:21]#[N:22])C1C=CC=CC=1.O=[C:26]([CH3:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[NH2:22][C:21]1[C:15]2[C:16](=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C@H:11]([NH2:10])[CH3:23])[N:20]=[C:26]([CH3:33])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CC(C)=O
Reactant: C[C@H](COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)N)c2c1N

Procedure:
Prepared as in Example 2a from (R)-benzyl(1-(3-amino-2-cyanophenoxy)propan-2-yl)carbamate (Example 86c) and ethyl 3-oxobutanoate as brown solid. MS 304 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:43]4[CH2:42][CH2:41][N:40]([C:35]5[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=5)[CH2:45][CH2:44]4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(3,4-dichlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=659.92 (M+H+); retention time=1.12 minutes.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[O:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:22]([OH:23])=[C:19]([O:20][CH3:21])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:22]=1[O:23][CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8])[CH:16]=[O:15]
Reactant: Cc1sc(N2CCOCC2)nc1CCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1nc(N2CCOCC2)sc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A mixture of 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)morpholine (5.0 g), vanillin (3.27 g), potassium carbonate (2.97 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde as crystals (7.25 g, yield 96%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=1)[C:11]([CH3:30])=[CH:10]2.CN(C)[CH:33]=[O:34]>>[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:21]=1)[C:11]([CH3:30])=[C:10]2[CH:33]=[O:34]
Reactant: CN(C)C=O
Reactant: Cc1cc2cc(F)ccc2n1-c1ccc(OCc2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c2cc(F)ccc2n1-c1ccc(OCc2ccccc2)cc1
Yield: 85 %

Procedure:
Phosphorous oxychloride (5 mL) was added to anhydrous dimethylformamide (10 mL) and the mixture allowed to stir at room temperature for 15 min whereupon a solution of 5-fluoro-1-(4-benzyloxyphenyl)-2-methyl-1H-indole (1.63 g, 4.9 mmol) in dimethylformamide (10 mL) was added and reacted according to the procedure used in Example 2a to afford a tan solid (85%): mp 219-220° C.; 1H NMR (DMSO-d6): δ 2.53 (3H, s), 5.22 (2H, s), 6.99-7.06 (2H, m), 7.27 (2H, d, J=8.9 Hz), 7.37-7.53 (7H, m), 7.86 (1H, dd, J=2.5 Hz, J=9.5 Hz); MS m/z (M+H)+ 360. Anal. for C23H18FNO2·0.5H2O: Calc'd: C, 74.99; H, 5.20; N, 3.80. Found: C, 74.91; H, 4.96; N, 3.59.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:26](Cl)(=[O:28])=[O:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:26]([C:20]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=3)(=[O:28])=[O:27])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(OC)c(OC)c3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
To a solution of intermediate 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 3,4-dimethoxybenzenesulfonyl chloride (320 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12b as a solid (200 mg, 53.0%). HPLC: 99% (Rt 6.507 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].C(Cl)Cl.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[CH3:12][C:5]1([CH3:13])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[O:25])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: CC1(C)C(=O)Nc2ccc(N)cc21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)Nc2ccc(NC(=O)c3ccncc3)cc21

Procedure:
A suspension of 5.0 g. (0.028 mol) 5-amino-3,3-dimethylindolin-2-one in 100 ml. methylene chloride containing 14 ml. triethylamine is mixed, while cooling, with 7.0 g. (0.04 mol) isonicotinic acid chloride hydrochloride. Subsequently, the reaction mixture is evaporated and the residue is digested with water, filtered with suction and recrystallised from ethanol. Yield: 5.8 g. (73% of theory); m.p.>300° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[CH2:21]1[C:24]2([CH2:27][C:26](=[CH:28][C:29]#[N:30])[CH2:25]2)[CH2:23][O:22]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:26]4([CH2:28][C:29]#[N:30])[CH2:27][C:24]5([CH2:23][O:22][CH2:21]5)[CH2:25]4)[CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: N#CC=C1CC2(COC2)C1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CC5(COC5)C4)c3)n2)cn1
Temperature: 50 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
A mixture of 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (25 mg; 0.094 mmol), 2-(2-oxaspiro[3.3]heptan-6-ylidene)acetonitrile (19 mg; 0.14 mmol) and DBU (7.2 mg; 0.047 mmol) in acetonitrile (1 mL) was stirred in a sealed vial at 50° C. for 24 hours. The solvent was removed under reduced pressure and the material was purified by silica gel chromatography, eluting with (6% ammonium hydroxide in methanol)/methylene chloride (1:25 to 1:15 gradient) to provide pure desired product as a white solid (27.5 mg). MS (apci) m/z=401.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1ccc(Br)nc1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1H-pyrazol-1-yl)phenyl)methanone and 2-bromo-5-cyanopyridine. MS (ESI) 415 (M+H).
Reaction SMILES: CO[C:3]([O:13][CH3:14])(OC)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1.OC[C:17]([CH2:22][CH2:23][CH3:24])([CH2:20][SH:21])[CH2:18][SH:19]>>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]23[S:21][CH2:20][C:17]([CH2:22][CH2:23][CH3:24])([CH2:18][S:19]2)[CH2:14][O:13]3)=[CH:9][CH:8]=1
Reactant: COC(OC)(OC)c1ccc(Br)cc1
Reactant: CCCC(CO)(CS)CS
Product: CCCC12COC(c3ccc(Br)cc3)(SC1)SC2

Procedure:
1-(4-Bromophenyl)-4-n-propyl-2-oxa-6,7-dithiabicyclo[2,2,2]octane was prepared from trimethyl 4-bromo-orthobenzoate and 2-hydroxymethyl-2-n-propyl-propan-1,3-dithiol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18](CO)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35]NC.CN1[C:44](=[O:45])CCC1>C(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[C:18]([CH2:32][N:33]4[CH2:38][CH2:44][O:45][CH2:35][CH2:34]4)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CN1CCCC1=O
Reactant: CNCCN(C)C
Reactant: OCc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Clc1ccc2c(Nc3ccc(N4CCOCC4)c(CN4CCOCC4)c3)ccnc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a suspension of {5-[(7-chloroquinolin-4-yl)amino]-2-(morpholin-4-yl)phenyl}methanol hydrochloride (compound of step C of example 31) (0.100 g, 0.25 mmol) in 4 mL of NMP at 0° C. was added thionyl chloride (90 μL, 1.23 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 h. The reaction mixture was then slowly added to N,N,N′-trimethylethylenediamine (0.65 mL, 7.38 mmol) in 1 mL of NMP at 0° C. and then stirred at room temperature for 2 h. This solution was diluted in 100 mL of CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, evaporated and purified by flash chromatography (DCM/MeOH///90/10) to yield expected compound as a yellow solid (83 mg, 77% yield). LC-MS: m/z (ESI) 439.3 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29])#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CNCCc1cccc(C(=O)OCCOC)c1
Product: COCCOC(=O)c1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2n produced 3as. MS found M+H=497. The oxalate salt of 3ar was recrystallized from methanol/ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH3:15][S-:16].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13][S:16][CH3:15])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(CCl)ccc1OC
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CSC)ccc1OC
Temperature: 75 °C
Reaction time: 5.5 h

Procedure:
Combine methyl 2-methoxy-5-chloromethylbenzoate (5 mmol) and dimethylformamide (10 mL). Cool in an ice bath and add sodium thiomethoxide (15 mmol). Heat to 75° C. After 5.5 hours, partition the reaction mixture between water and ethyl acetate. Extract the organic layer with water, dry over Na2SO4, filter, and concentrate in vacuo to give methyl 2-methoxy-5-(methylthiomethyl)benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[C:5](N)=[C:4]([Cl:14])[CH:3]=1.C([N:17](CC)CC)C.[C:22]([CH2:26][C:27](Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[C:5]([CH:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:27]([NH2:17])=[O:28])=[C:4]([Cl:14])[CH:3]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1c(Cl)cc(Br)cc1OC(F)(F)F
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(C(N)=O)c1c(Cl)cc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 4-bromo-2-chloro-6-trifluoromethoxy-aniline (2.9 g, 10 mmol) and triethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane (50 mL) was added dropwise tert-butylacetyl chloride (1.6 g, 12 mmol) with stirring at room temperature. The reaction mixture was stirred for 3 hours at room temperature, than the reaction mixture was diluted with dichloromethane and washed with water and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) to give a white solid (3.6 g, 93%).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]([O:25][CH2:26][CH3:27])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O>[ClH:1].[CH2:26]([O:25][C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[CH2:12][CH2:11]1)=[O:15])=[O:24])[CH3:27]
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCOC(=O)c1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1NC(=O)[C@H]1CC[C@H](CNC(=N)N)CC1

Procedure:
Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (10.0 g, 0.042 mole) (which is prepared by the method as disclosed in Japanese Patent First Publication No. 19694/1977, C.A., 87, 53269x) and ethyl anthranilate (10.4 g, 0.063 mole) are added to pyridine (50 ml), and the mixture is stirred for a while, and thereto is added dicyclohexylcarbodiimide (13 g, 0.063 mole), and the mixture is stirred at room temperature for 72 hours. After the completion of the reaction, water (30 ml) is added to the reaction mixture, and the mixture is stirred for 30 minutes, and the undissolved materials are filtered off. The filtrate is concentrated to dryness. The resulting residue is washed with ethyl acetate (300 ml) and recrystallized from water to give the title compound (6.74 g) as white crystals. m.p. 92°-95° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[N:7]=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:33][N:34]([CH2:35][CH2:36][CH2:37][NH:38][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([N:3]2[C:2](=[O:1])[C:6]3[N:7]=[N:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]=3[NH:4]2)=[CH:16][CH:17]=1)[CH3:39]
Reactant: CN(C)CCCN
Reactant: O=C(O)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCCNC(=O)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(3-oxo-1,3-dihydro-2H-pyrazolo[4,3-c]cinnolin-2-yl)benzoic acid (25 mg, 0.08 mmol) was mixed with DMF (1 ml). Diisopropylethylamine (21 mg, 28 μl, 0.16 mmol) and 3-dimethylaminopropylamine (8.2 mg, 10.0 μl, 0.09 mmol) were added followed by HBTU (30.3 mg, 0.08 mmol). The mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC. The title compound was isolated as a red solid (12.6 mg, 0.032 mmol, 40%). LCMS: m/z 391 [M+H]+.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][OH:10]>C(O)C>[OH:10]/[N:9]=[C:1](\[NH2:8])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: NO
Solvent: CCO
Product: N/C(=N\O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of ethanol (5.0 mL), benzonitrile (203 mg, 1.97 mmol) and hydroxylamine (520 mg, 7.87 mmol) were refluxed for 1 hour. The reaction was then cooled to room temperature and concentrated in vacuo to give the a clear oil which was taken to the next step without further purification (268 mg, 100%). 1H NMR (500 MHz, CDCL3) δ(ppm): 4.92 (2H, bs), 7.38-7.44 (3H, m), 7.62-7.65 (2H, m). 13C NMR (125 MHz, CDCL3) δ(ppm): 126.1 (CH), 128.9 (CH), 130.2 (CH), 132.6, 152.8. MS (FAB+): 137 (MH+). HRMS for C7H8N2O (MH+): calculated: 137.0715; found 137.0718.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[N:6][C:7](Cl)=[CH:8][CH:9]=1.[NH2:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=1>CS(C)=O>[Cl:3][C:4]1[N:5]=[N:6][C:7]([O:19][C:15]2[C:14]([CH3:20])=[CH:13][C:12]([NH2:11])=[C:17]([CH3:18])[CH:16]=2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cc1cc(O)c(C)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(Oc2ccc(Cl)nn2)c(C)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4.8 g of sodium hydride was added in portions to a stirred solution of 30 g of 3,6-dichloropyridazine and 27.4 g of 4-amino-2,5-dimethylphenol in 300 ml of dimethyl sulfoxide. The temperature of the mixture rose to 65° C. The mixture was then stirred for 18 hours at room temperature, poured over ice water and filtered. Recrystallization of the filter cake from methanol gave 4-(6-chloro-3-pyridazinyloxy)-2,5-dimethylbenzeneamine, as a brown solid (5A), mp: 138°-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]1[C@H:20]2[C@H:15]([CH2:16][CH2:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=32)[NH:14][CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:14]2[C@@H:15]3[C@@H:20]([C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[CH2:17][CH2:16]3)[CH2:11][CH2:12][CH2:13]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1
Yield: 66 %

Procedure:
The title compound is prepared from 4-amino-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 66% of theory; LC (method 4): tR=1.81 min; Mass spectrum (ESI+): m/z=307 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10]1
Reactant: COC(=O)CCCCBr
Reactant: c1ccc(CC2CCCNC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCCCN1CCCC(Cc2ccccc2)C1
Temperature: 110 °C
Yield: 64.7 %

Procedure:
To a solution of 3-benzylpiperidine hydrochloride (2 g, 9.4 mmol) in DMF (40 mL) were added methyl 5-bromovalerate (1.6 mL, 11.3 mmol) and potassium carbonate (3.2 g, 23.6 mmol). This heterogeneous mixture was heated at 110° C. for 1 hr then cooled at 25° C., diluted with water (200 mL) and diethyl ether (200 mL). The aqueous solution was extracted with diethyl ether (100 mL) and the collected organic phase was washed with brine (200 mL), dried and concentrated in vacuum. The crude compound was purified by silica gel column chromatography using CH2Cl2/MeOH as eluant to afford the title compound as an oil (1.76 g, 65%). 1H-NMR (CDCl3): 0.8-1.0 (m, 1H); 1.4-1.7 (m, 8H); 1.8-1.95 (m, 2H); 2.25-2.35 (m, 4H); 2.4-2.6 (m, 2H); 2.75-2.9 (m, 2H); 3.65 (8, 3H); 7.132 (d, J=7.0, 2H); 7.186 (d, J=7.2, 11); 7.264 (t, J=7.2, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:12])[C:3]=1[S:13](Cl)(=O)=O>O1CCCC1.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:12])[C:3]=1[S:13][S:13][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:5][C:4]=1[CH3:12]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)cc(C)c1SSc1c(C)cc(C(C)(C)C)cc1C
Temperature: 60 °C
Yield: 64.1 %

Procedure:
A two liter, three-neck flask, was obtained. A condenser with a drying tube, a thermometer, and a dropping funnel were each attached to the flask. Zinc dust (<10 micron, 43.6 g, 0.667 mol) and anhydrous tetrahydrofuran (400 mL) were added to the flask. The mixture was stirred and cooled on an ice-water bath and 58.6 ml (0.534 mmol) of titanium tetrachloride added drop wise (˜45 min). During the entire addition of titanium tetrachloride, the temperature of the mixture was maintained below 25° C. Once the addition was complete, a solution of 2,6-dimethyl-4-tert-butylbenzenesulfonyl chloride (69.48 g, 0.267 mol) in 200 mL of anhydrous tetrahydrofuran was added drop wise (˜60 min). During the entire addition of the material, the temperature of the mixture was maintained below 20° C. At the conclusion of the 2,6-dimethyl-4-tert-butylbenzenesulfonyl chloride addition, the ice-water bath was removed, the mixture was allowed to stir an additional 30 min. The mixture was then heated on an oil bath at 60° C. for 4 hours. The mixture was then cooled to room temperature and 800 mL of 1N hydrochloric acid and 300 mL of ice water added. The resultant pale yellow precipitates were collected by filtration and washed with water (300 mL×3). The precipitate was then dried under vacuum and the precipitates recrystallized from hexanes, giving 33.1 g bis(2,6-dimethyl-4-tert-butylphenyl) disulfide (see Formula III, Table 3). The yield of the reaction was 70% and the material had the following spectral data: 1H NMR (CDCl3) δ 7.04 (s, 4H, aromatic protons (Ar—H)), 2.23 (s, 12H, CH3), 1.30 (s, 18H, C(CH3)3).