Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=1>C1COCC1>[CH3:28][O:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[N+:24]([O-:26])=[O:25])[CH2:17][N:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Reactant: O=S1(=O)CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCS(=O)(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Thiomorpholine 1,1-dioxide (0.242 g, 1.788 mmol) and triethylamine (0.19 mL, 1.341 mmol) were added to a solution of 4-(bromomethyl)-2-methoxy-1-nitrobenzene (Preparation 74, 0.22 g, 0.894 mmol) in THF (2.2 mL). The reaction mixture was stirred overnight at room temperature before being concentrated under reduced pressure and purified via Biotage silica gel column chromatography eluting with (DCM/EtOAc 99/1 to 90/10) to afford the title product as a white solid (242 mg, 90%). 1H NMR (500 MHz, CDCl3): δ 3.00-3.04 (m, 4H), 3.09-3.12 (m, 4H), 3.71 (s, 2H), 3.98 (s, 3H), 7.01 (m, 1H), 7.09 (m, 1H), 7.84 (d, J=8.2 Hz, 1H). LC (Method C)-MS (ESI, m/z) tR 2.03 min, 301 [(M+H+), 100%].
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)[CH:32]=[CH:33][CH:34]=2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Product: COc1ccc(Oc2cccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(4-methoxyphenoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[3-(4-methoxyphenoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:23])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:26][N:27]1[CH2:31][CH2:30][CH2:29][C@:28]1([C:33]1[N:37]2[CH:38]=[C:39]([O:42][C@H:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[C@@H:46]([NH2:53])[CH2:45][CH2:44]3)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1)[CH3:32]>>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:53][C@@H:46]2[C:47]3[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:43]([O:42][C:39]3[CH:40]=[CH:41][C:36]4[N:37]([C:33]([C@:28]5([CH3:32])[CH2:29][CH2:30][CH2:31][N:27]5[CH3:26])=[N:34][N:35]=4)[CH:38]=3)[CH2:44][CH2:45]2)=[O:23])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CN1CCC[C@@]1(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@]5(C)CCCN5C)n4c3)c3ccccc32)cc1

Procedure:
The title compound was prepared as an off-white solid (80 mg, 53%) using (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 80 mg, 0.20 mmol) and Intermediate 47c (90 mg, 0.24 mmol) in a similar manner to Example 1, step d. LCMS (Method 5): Rt 3.83 min, m/z 633 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.51 (3H, s), 1.78-1.99 (5H, m), 2.02 (3H, s), 2.03-2.22 (3H, m), 2.36 (3H, s), 2.65 (1H, q, J 8.6), 3.11-3.17 (1H, m), 4.79-4.86 (1H, m), 5.32 (1H, t, J 4.2), 6.32 (1H, s), 7.11 (1H, d, J 8.6), 7.25-7.39 (9H, m), 7.75 (1H, d, J 9.8), 8.05 (1H, s), 8.43 (1H, d, J 2.2).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14]([O:17]C(Cl)=O)(Cl)Cl>O1CCOCC1>[F:11][C:9]1[CH:10]=[C:2]2[NH:1][C:14](=[O:17])[O:6][C:4](=[O:5])[C:3]2=[CH:7][C:8]=1[I:12]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(F)c(I)cc1C(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(F)c(I)cc2c(=O)o1
Yield: 90.4 %

Procedure:
Anhydrous dioxane (0.5 liters), 2-amino-4-fluoro-5-iodo-benzoic acid (46 grams, 164 mmoles), and trichloromethylchloroformate (97.4 grams, 492 mmoles) were added to a one liter one neck flask equipped with a magnetic stir bar and reflux condenser. The solution was placed under anhydrous nitrogen, stirred and heated to reflux for 16 hours. The reaction mixture was allowed to cool and was poured into one liter of hexanes. The solid was collected by suction filtration, washed with an additional 0.5 liters of hexanes, and dried under vacuum at room temperature to yield 45.5 grams (90%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 11.86 (s, 1H), 8.24 (d, 1H), 6.84 (d, 1H). ESI-MS m/z 308 (M+1).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[CH2:8]([SH:12])[CH:9]([SH:11])[CH3:10]>>[CH3:10][CH:9]1[S:11][C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[S:12][CH2:8]1
Reactant: CC(S)CS
Reactant: O=C1CCCC1Br
Product: CC1CSC2=C(CCC2)S1
Yield: 69 %

Procedure:
The procedure of Example 1(a) is followed using 2-bromocyclopentanone and 1,2-propanedithiol to give 2,3,6,7-tetrahydro-2-methyl-5H-cyclopenta-1,4-dithiin as a greenish oil, bp 92.5°-93°/1 mm, Yield 69%. NMR, 1.42 (3d), 1.6-2.2 (2m), 2.2-2.65 (4m), 2.5-3.7 (3m) (CDCl3) IR 2920, 1605, 1420, 1310, 1260, 1125, 870, 720.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([S:13]([NH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[NH2:19])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([S:13]([NH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[NH:19][C:34]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[Br:26])=[O:35])(=[O:14])=[O:15])[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:8]=1
Reactant: Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccccc1Br)Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from [2-(3,5-bistrifluoromethylphenyl) sulfonylaminoaniline (591 mg, 1.5 mmol) and 2-bromophenylisocyanate (305 mg, 1.5 mmol) according to General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (10 mg, 1%).EI-MS m/z 580 (M-H)-
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:9]=[C:10]=[O:11])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[C-]#N.[CH2:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:9][C:10](=[O:11])[N:18]([CH2:16][CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:8])[CH3:7])=[CH:12][CH:13]=1
Reactant: CCNc1ccccc1
Reactant: CC(C)(N=C=O)c1ccc(Cl)cc1
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: CCN(C(=O)NC(C)(C)c1ccc(Cl)cc1)c1ccccc1
Yield: 98.2 %

Procedure:
A solution of 3.9 g of p-chloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, in 20 ml of toluene was added to 2.7 g of N-ethylaniline and the mixture was heated under reflux for 3 hours. After allowing the reaction mixture to cool, the mixture was washed successively with 2N hydrochloric acid, 2N aqueous sodium hydroxide and water. The organic layer was dried over anhydrous sulfate and the solvent was removed by distillation under reduced pressure to obtain 6.2 g of the title compound as a light brown oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]([NH2:19])=O)=[N:15][CH:16]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]#[N:19])=[N:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: NC(=O)c1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazine-2-carboxamide from Step 4 (1.65 g, 4.17 mmol) in TBF (50 mL) at 0° C. was added triethylamine (1.45 mL, 10.5 mmol) followed by trifluoroacetic anhydride (0.885 mL, 6.26 mmol). After a period of 10 min at 0° C., the reaction mixture was raised gradually to room temperature. The mixture was then partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, dried over sodium sulfate and evaporated. The crude mixture was purified by flash chromatography (35% ethyl acetate in hexane) to provide the title compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[Br:16][C:17]1[C:18](=O)[NH:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(=O)(O)[O-].[Na+]>O>[Br:16][C:17]1[C:18]([Cl:3])=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(C(F)(F)F)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: FC(F)(F)c1cnc(Cl)c(Br)c1
Temperature: 120 °C
Yield: 77.2 %

Procedure:
To phosphorous oxychloride (2.02 mL, 21.6 mmol) was added quinoline (1.34 mL, 11.2 mmol) followed by 3-bromo-5-trifluoromethyl-2(1H)-pyridone (5.0 g, 20.07 mmol). The mixture was heated at 120° C. for 3 hrs, then cooled to 100° C., whn water (10 mL) was carefully added. After cooling to room temperature, saturated sodium bicarbonate was added (100 mL) and the mixture extracted with ethyl acetate (2×100 mL). The extracts were dried (MgSO4) and concentrated, and the residue purified by silica chromatography to give the product as a liquid (4.05 g, 15.5 mmol, 75% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[O:20][CH3:21]>>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[O:5])[C:16]([CH3:19])=[CH:15][C:14]=1[O:20][CH3:21]
Reactant: COc1ccc(C)cc1OC
Reactant: Cc1ccccc1C(=O)O
Product: COc1cc(C)c(C(=O)c2ccccc2C)cc1OC

Procedure:
By the reaction of 13.6 g (0.1 mol) of 2-methylbenzoic acid with 15.2 g (0.1 mol) of 1,2-dimethoxy-4-methylbenzene, analogously to Example 3(a), there is obtained (3,4-dimethoxy-6-methylphenyl)-(2-methylphenyl)-methanone as a brown resin-like product.
Reaction SMILES: C([NH:8][C:9](=[N:11]C(OC(C)(C)C)=O)[NH2:10])(OC(C)(C)C)=O.C(Cl)[Cl:20].[ClH:22]>CCO>[ClH:20].[ClH:22].[NH2:10][C:9]([NH2:11])=[NH:8].[NH2:10][C:9]([NH2:11])=[NH:8]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N=C(N)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: N=C(N)N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The N′,N″-di-BOCguanidine (0.45 g, 0.60 mmol) was dissolvedin CH2Cl2 (10 mL), diluted with dry EtOH (15 mL) and the chilled solution was saturated with dry HCl. The reaction was then kept stirring at room temperature for 3 days (drying tube), when by the product started forming a precipitate over time. After evaporating the solvent to dryness, the residue was washed with ether multiple times and was dried under vacuum at 50-60° C. over night to give whitish yellow solid of the bis-guanidine dihydrochloride; mp>300° C. 1H NMR (DMSO-d6): δ 7.85 (dd, J=1.5, 8.4 Hz, 4H), 7.92 (d, J=1.2 Hz, 4H), 8.00 (dd, J=1.5, 8.4 Hz, 4H ), 9.09 (br s, 4H), 11.25 (br s, 2H). 13C NMR (DMSO-d6): δ 155.98, 138.35, 137.32, 135.00, 127.79, 127.22, 124.79. MS (ESI) m/e (rel. int.): 344 (M+, 6), 173 (100). Anal. Calc. for C20H20N6-2.0HCl-1.0H2O-0.2C2H5OH: C %, 55.11; H %, 5.71; N %, 18.90. Found C %, 55.39; H %, 5.50; N %, 18.71.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.C(Cl)(Cl)Cl.[Br:33]N1C(=O)CCC1=O>C(#N)C>[Br:33][C:14]1[N:13]=[C:12]([C:15]([NH2:17])=[O:16])[C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=2)=[N:10][C:9]=1[NH:8][C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)cnc2C(N)=O)c1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Br)nc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) (150 mg), chloroform (40 mL) and acetonitrile (20 mL), N-bromosuccinimide (69 mg) was added and stirred at room temperature for 2 hours. To the reaction liquid, silica gel was added, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol=10:0:0 to 10:1). The resulting crude product was solidified with ethyl acetate and washed with ethyl acetate to give 6-bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (130 mg) as a light yellow solid.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>O1CCCC1>[CH2:1]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 143.6 %

Procedure:
A solution of N-benzyl-4-methoxybenzenesulfonamide (15.00 g, 36.06 mmol) in tetrahydrofuran (90 ml) was added to a suspension of sodium hydride (60% oil suspension 1.47 g, 36.78 mmol) in tetrahydrofuran (90 ml) and stirred for 50 minutes at room temperature. Then the suspension, with ethyl bromoacetate (6.00 ml, 54.09 mmol) added thereto, was stirred for 14 hours at room temperature. After the reaction, the mixture, with water (100 ml) added thereto, was extracted with ethyl acetate (100 ml×3). The organic layer was dried over sodium sulfate, and then the solvent was evaporated out. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane), to give ethyl 2-{benzyl[(4-methoxyphenyl)sulfonyl]amino}acetate (18.82 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH:15]([C:27](O)=[O:28])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:12])([F:11])[F:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.O[N:64]=[C:65]([O:67][CH2:68][CH3:69])[NH2:66]>CN(C)C=O>[CH2:68]([O:67][C:65]1[N:66]=[C:27]([CH:15]2[CH2:14][CH:13]([C:4]3[CH:5]=[CH:6][C:7]([CH2:8][C:9]([F:12])([F:10])[F:11])=[C:2]([F:1])[CH:3]=3)[CH2:18][N:17]([C:19]([N:21]3[CH2:22][CH2:23][S:24][CH2:25][CH2:26]3)=[O:20])[CH2:16]2)[O:28][N:64]=1)[CH3:69]
Reactant: CCOC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)c(F)c3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 400 mg (0.783 mmol, purity 85%) of the carboxylic acid from Example 79A in 10.6 ml of N,N-dimethylformamide were added, at room temperature, 357 mg (0.939 mmol) of HATU and 0.30 ml (1.72 mmol) of N,N-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 118 mg (1.02 mmol, purity 90%) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and stirred at room temperature overnight. The reaction solution was diluted with 11 ml of N,N-dimethylformamide and then stirred at 140° C. for 3 h. The reaction solution was purified directly by means of preparative HPLC. Yield: 111 mg (28% of theory)
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:5]1)(=[O:3])[CH3:2].[Br:19]Br>C(O)(=O)C.ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:19])=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)N1CC(CCS(C)(=O)=O)c2ccccc21
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N1CC(CCS(C)(=O)=O)c2cc(Br)ccc21

Procedure:
Bromination was done by treatment of 19a with bromine in a mixture of acetic acid and dichloromethane. The compound was an oil.
Reaction SMILES: CSCS(C)=O.[OH-].[Na+].C([O:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][CH3:27])=[C:21]([CH:24]=1)[CH:22]=O)C1C=CC=CC=1.[C:28]([O:31][CH2:32]C)(=[O:30])C>>[CH2:26]([O:25][C:20]1[CH:19]=[CH:18][C:17]([OH:16])=[CH:24][C:21]=1[CH2:22][C:28]([O:31][CH3:32])=[O:30])[CH3:27]
Reactant: CCOC(C)=O
Reactant: CCOc1ccc(OCc2ccccc2)cc1C=O
Agent: CSCS(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc(O)cc1CC(=O)OC
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
A mixture of methyl methylthiomethyl sulfoxide. (0.30 g) and finely triturated sodium hydroxide (0.015 g) was stirred at 70° C. for 30 min. To the reaction mixture was added 5-benzyloxy-2-ethoxybenzaldehyde (0.30 g), and the mixture was further stirred at 70° C. for 1.5 hrs. To the reaction mixture was added ethyl acetate, and the organic layer was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. A mixture of the obtained residue and 10% hydrogen chloride-methanol (15 mL) was heated under reflux for 15 hrs. To the reaction mixture was added ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-(2-ethoxy-5-hydroxyphenyl)acetate as a colorless oil (0.11 g, 44%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH2:7][C:6](=[O:17])[N:5]([CH2:4][C@H:3]([CH3:18])[CH2:2][N:26]3[CH2:27][CH2:28][CH:23]([O:22][CH2:19][CH2:20][CH3:21])[CH2:24][CH2:25]3)[C:10]=2[CH:11]=1
Reactant: CCCOC1CCNCC1
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(OC)cc32)CC1
Yield: 56.9 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.556 g, 1.5 mmol) and 4-propyloxypiperidine (0.20 g, 1.4 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF42) (0.30 g, 53%). 1H NMR (CDCl3) δ 6.89 (d, J=8.8 Hz, 1H), 6.85 (d, 2.8 Hz, 1H), 6.49 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 4.53 (q, J=14.6 Hz, 2H), 3.93 (d, J=6.6 Hz, 2H), 3.77 (s, 3H), 3.38 (t, J=6.8 Hz, 2H), 3.29-3.22 (m, 1H), 2.80-2.77 (t, 6.4 Hz, 1H), 2.65-2.61 (t, J=6.0 Hz, 1H), 2.29-2.00 (m, 5H), 1.88-1.84 (m, 2H), 1.65-1.53 (m, 4H), 0.94-0.87 (m, 6H); 13C NMR (CDCl3) δ 165.4, 155.5, 139.8, 129.8, 117.2, 107.1, 103.3, 75.1, 69.7, 68.0, 63.7, 56.0, 52.5, 51.9, 45.4, 31.6, 31.5, 29.2, 23.5, 16.9, 10.8; HPLC-MS (ammonium acetate) [M+H]+=377.3.
Reaction SMILES: [CH2:1]([C:9]#N)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][OH:17]>C(=S)=S>[OH:17][CH2:16][CH2:15][N:14]1[CH2:13][CH2:12][N:11]=[C:9]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCNCCO
Reactant: CCCCCCCCC#N
Solvent: S=C=S
Product: CCCCCCCCC1=NCCN1CCO
Yield: 58.3 %

Procedure:
13.02 g (93.51 mmoles) of octyl cyanide was treated with 12.327 g (118.36 mmoles) of 2-(2-aminoethylamino)ethanol in presence of 0.5 ml of carbon disulfide at 125° C. for 24 hrs. and worked up as outlined under Example 23. Distillation of the residue at 167°-169° C./0.5 mm gave 12.332 g (62.7%) of product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]2[C:5]=1[C:6](=O)[N:7]=[CH:8][NH:9]2)[CH3:2].O=P(Cl)(Cl)[Cl:19]>CN(C=O)C>[Cl:19][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:4]=2[O:3][CH2:1][CH3:2])[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc(OC)cc2[nH]cnc(=O)c12
Solvent: CN(C)C=O
Product: CCOc1cc(OC)cc2ncnc(Cl)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A mixture of 5-(ethyloxy)-7-(methyloxy)-4(1H)-quinazolinone (285 mg, 1.29 mmol) in POCl3 (10 mL, 107 mmol) was treated with 1 drop of DMF and stirred at 100° C. for 1 hour before being concentrated. The residue was treated with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts were dried (sodium sulfate), concentrated, and subjected to flash chromatography (1-3% MeOH—CH2Cl2) to give 4-chloro-5-(ethyloxy)-7-(methyloxy)quinazoline (260 mg, 84%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 1 H), 7.03 (d, J=2.51 Hz, 1 H), 6.84 (d, J=2.26 Hz, 1 H), 4.22 (q, J=6.86 Hz, 2 H), 3.96 (s, 3 H), 1.47 (t, J=6.90 Hz, 3 H). MS (m/z) 239.0 (M+H+).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].O>CS(C)=O>[CH2:27]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCCCCCCCCCCBr
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a suspension of sodium theobromine (2.22 g, 11.0 mmol) in dimethylsulfoxide (25 mL) was added 12-tridecenyl bromide and the reaction stirred for 16 hours at 60° C. The mixture was then poured into water (80 mL) and extracted with dichloromethane (3×50 mL). The combined organic portions were washed with water (3×100 mL), dried using magnesium sulfate, and evaporated to give a gummy residue. Purification by column chromatography using an ethyl acetate/hexane eluant yields 1.89 g (50% yield) 1-(12-Tridecenyl)-3,7-dimethylxanthine (inventive compound no. 2555) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:14][Si](C(C)(C)C)(C)C)[CH:2]=[CH2:3].[C-:22]#[N:23].[K+].C(O)C>O>[OH:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:1][CH2:2][CH2:3][C:22]#[N:23]
Reactant: [C-]#N
Reactant: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCCCc1ccc2ccccc2c1O
Yield: 35 %

Procedure:
A mixture of the product of Example 122 Part C (3.79 g, 0.010 mole), potassium cyanide (0.72 g, 0.011 mole), ethanol (15 mL) and water (2 mL) was heated at reflux for 20 hours. The cooled mixture was poured into water and extracted with ethyl acetate. The crude product was chromatographed with 1:1 ether/hexane and recrystallized (cyclohexane/toluene) to provide the title compound (0.73 g, 35%) as a white solid mp 76°-78°.