Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.[C]=O.[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=O)(=[O:16])[CH3:15]>C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[S:8])(=[O:16])[CH3:15]
Reactant: COC(=O)C(CCSC)OC(C)=O
Reactant: CSCC=COC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C
Yield: 10 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, (Z:E ratio 43:57) and 2.5 mmoles methanol were charged into a 71 cc stainless steel. bomb equipped with a glass liner and a Teflon coated stir bar. Ten mole percent, based on 1-acetoxy-3methythiopropene, of a catalyst comprising bis(triphenylphosphine)dichloropalladium, (φ3P)2PdCl2, was added. Toluene was included as an internal standard. Five milliliters of benzene as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced in a yield of 22 percent, and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced in a yield of 10 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Each of the products is hydrolyzable to methionine hydroxy analog.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21](N)=[O:22].N([O-])=[O:25].[Na+].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([OH:22])=[O:25]
Reactant: NC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl

Procedure:
3.5 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide are dissolved in 15 ml of 90 % sulfuric acid and while stirring at 20° to 30° a solution of 0.7 g sodium nitrite in a little water is passed dropwise under the surface. Gentle heating is carried out until the evolution of gas is terminated and the mixture is then poured on to an ice and water mixture. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is produced; F 179.5°-181°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[N:18][C:19]2[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([CH:27]=2)[C:24]([OH:26])=[O:25])=[CH:13][CH:12]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CS(C)=O.CCOC(C)=O>[N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[N:18][C:19]2[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([CH:27]=2)[C:24]([OH:26])=[O:25])=[CH:13][CH:12]=1)=[N+:30]=[N-:31]
Reactant: O=C(O)c1cc(N=Nc2ccc(OCCCCCCCCBr)cc2)ccc1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCCCCCCCOc1ccc(N=Nc2ccc(O)c(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.1 %

Procedure:
5-((4-(8-Bromooctyloxy)phenyl)diazenyl)-2-hydroxybenzoic acid (2.50 g, 5.6 mmol) was dissolved in DMSO (40 mL) and NaN3 (1.10 g, 16.9 mmol) was added slowly to the reaction mixture with stirring at room temperature. After 48 h, the mixture was diluted with EtOAc (100 mL), washed with water (4×20 mL), brine (20 mL), dried over Na2SO4, and filtered. Volatiles were removed in vacuo and the residue subjected to column chromatography on silica gel 60 (230-400 mesh) using EtOAc and methanol (98:2) as the elutant to give 2.10 g (5.1 mmol, 91%) of the product as a red-brown solid, mp 54-56° C. 1H NMR (500 MHz, CDCl3) δ 1.27-1.58 (m, 8H), 1.62-1.64 (m, 2H), 1.81-1.86 (m, 2H), 3.31 (t, J=5 Hz, 2H), 4.06 (t, J=6.5 Hz, 2H), 6.88-7.01 (m, 3H), 7.84 (d, J=10 Hz, 2H), 7.91 (dd, J=15 Hz, 2.5 Hz, 1H), 8.47 (d, J=2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3+CD3OD) δ 22.0, 25.3, 25.4, 28.5, 28.6, 28.8, 31.2, 50.8, 67.7, 114.1, 116.5, 117.5, 123.6, 126.2, 144.6, 146.2, 160.7, 175.0; HRMS (ESI) calculated for C21H26N5O4 (M+H)+412.1979, observed 412.1971.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[C:34]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH:33]=[N:32][C:31]=23)[CH:22]=1)=[O:19])(C)(C)C>C(Cl)Cl>[NH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[C:34]([C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)[CH:33]=[N:32][C:31]=23)[CH:22]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Nc1cccc(-c2cnn3cc(-c4ccc(F)cc4)cnc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNC(=O)Nc1cccc(-c2cnn3cc(-c4ccc(F)cc4)cnc23)c1
Yield: 49.6 %

Procedure:
TFA (2 ml) was added slowly to a stirred suspension of [2-(3-{3-[6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]phenyl}ureido)-ethyl]carbamic acid tert-butyl ester (390 mg, 0.80 mmol) in CH2Cl2 (4 ml) at RT. After 1 hour the volatiles were removed in vacuo. The residue was taken up in MeOH and loaded on a SCX cartridge (20 g). Eluting with 2M NH3. MeOH and removal of the solvent in vacuo gave the title compound (155 mg) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[OH:9][CH2:10][CH:11]1[CH2:20][N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH:14]2[CH2:13][CH2:12]1.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>>[O:9]([CH2:10][CH:11]1[CH2:20][N:15]2[CH2:16][CH2:17][N:18]([C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=3)[CH2:19][CH:14]2[CH2:13][CH2:12]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCC1CCC2CNCCN2C1
Reactant: Clc1ccc(Cl)nc1
Reactant: Oc1ccccc1
Agent: Cl
Product: Clc1ccc(N2CCN3CC(COc4ccccc4)CCC3C2)nc1

Procedure:
The title compound was prepared according to Example 15 using 2,5-dichloropyridine, (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (U.S. Pat. No. 5,326,874), and phenol. mp (—HCl) 218-224° C. 13C NMR (base, CDCl3): δ27.0, 29.1, 36.4, 45.3, 50.9, 54.6, 58.8, 60.5, 70.9, 107.8, 114.5, 120.1, 120.7, 129.4, 137.1, 146.2, 157.6, 159.0. Anal. calcd for C20H24ClN3O C, 67.12; H, 6.76; N, 11.74; found: C, 67.22; H, 6.85; N, 11.49.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][Br:7])(=[O:3])[CH3:2].[CH2:8]([O:11][C:12]([N:14]1[C@H:18]([CH2:19][C:20]2[S:24][C:23]3=[CH:25][N:26]=[C:27]([CH3:28])[N:22]3[CH:21]=2)[CH2:17][C@H:16]([S:29][C:30]2[C@H:31]([CH3:47])[C@@H:32]3[C@@H:42]([C@H:43]([OH:45])[CH3:44])[C:41](=[O:46])[N:33]3[C:34]=2[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])[CH2:15]1)=[O:13])[CH:9]=[CH2:10]>CC(C)=O>[Br-:7].[CH2:8]([O:11][C:12]([N:14]1[C@H:18]([CH2:19][C:20]2[S:24][C:23]3=[CH:25][N:26]([CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])[C:27]([CH3:28])=[N+:22]3[CH:21]=2)[CH2:17][C@H:16]([S:29][C:30]2[C@H:31]([CH3:47])[C@@H:32]3[C@@H:42]([C@H:43]([OH:45])[CH3:44])[C:41](=[O:46])[N:33]3[C:34]=2[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])[CH2:15]1)=[O:13])[CH:9]=[CH2:10]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4c(C)ncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: CC(=O)OCCBr
Solvent: CC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4c(C)n(CC(=O)OCC)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [Br-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromoethyl acetate (0.04 ml) is added to a solution of 42.6 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, described in Example 31-a), in 0.7 ml of dry acetone, and the mixture is stirred in an argon atmosphere at room temperature for one hr. The solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 49.7 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-ethoxycarbonylmethyl-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate bromide as a brown oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].O=S(Cl)Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[S:18])=[C:12]([CH3:19])[CH:11]=1>>[OH:1][CH2:2][C:3]1([NH2:4])[CH2:12][CH2:11][CH2:10][CH2:15]1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]2[S:18][CH2:2][C:3]3([CH2:12][CH2:11][CH2:10][CH2:15]3)[NH:4]2)=[C:12]([CH3:19])[CH:11]=1
Reactant: NCCO
Reactant: Cc1cc(Br)ccc1N=C=S
Solvent: O=S(Cl)Cl
Product: Cc1cc(Br)ccc1N=C1NC2(CCCC2)CS1
Product: NC1(CO)CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-bromo-2-methylphenyl isothiocyanate according to Method C2a to give 2-(4-bromo-2-methylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method1 D2b to give 2-(4-bromo-2-methylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.CN(C)[C:9](=[O:11])[CH3:10].Br.[NH2:14][C@@H:15]1[C:41](=[O:42])[N:17]2[C:18]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:19]([CH2:23][Br:24])[CH2:20][S@:21](=[O:22])[C@H:16]12.[CH3:43][OH:44]>ClCCl.C1OC1C>[Br:24][CH2:23][C:19]1[CH2:20][S@:21](=[O:22])[C@@H:16]2[C@H:15]([NH:14][C:25](=[O:26])[C:18]([C:19]3[O:11][CH:9]=[CH:10][CH:20]=3)=[N:17][O:44][CH3:43])[C:41](=[O:42])[N:17]2[C:18]=1[C:25]([O:27][CH:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:26]
Reactant: CO
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)C[S@](=O)[C@H]12
Reactant: CC(=O)N(C)C
Agent: Br
Agent: CC1CO1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)C[S@](=O)[C@H]12)c1ccco1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of phosphorus pentachloride (3.7 g) in dried dichloromethane (40 ml) at -10° was added N,N-dimethylacetamide (8.25 ml.) and then, slowly, syn-2-(fur-2-yl)-2-methoxyiminoacetic acid (3.00 g), the temperature being kept at approximately -10°. The resulting solution was stirred for 15 minutes, then ice (9 g) was added and the temperature of the solution allowed to rise to 0° over 10 minutes. The organic layer was added to a stirred suspension of diphenylmethyl (1S,6R,7R)-7-amino-3-bromomethylceph-3-em-4-carboxylate 1-oxide, hydrobromide (7.34 g) in dried dichloromethane (100 ml) and propylene oxide (10 ml) at 0°. The reaction mixture was stirred for 45 minutes, during which time it was allowed to warm up to room temperature. To the resulting suspension was added methanol (60 ml) and this mixture was stirred for 10 minutes and then filtered. The white solid was washed with methanol and dried to give the title ester as a white microcrystalline powder (5.26 g, 64%), m.p. 186°-190° (decomp.); [α]D -4.5° (c 1.0, DMSO); λmax (EtOH) 281 nm (ε 22,600). IR and NMR spectroscopy confirmed the structure as that of the title ester.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[Cl:28][C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[Cl:28][C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([CH3:21])(=[O:19])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=2)[CH:34]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)c(Cl)c2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)c(Cl)c4)nc(N4CCOCC4)c3s2)CC1
Yield: 18.1 %

Procedure:
4-(2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (100 mg) was reacted with 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (83 mg) according to General Procedure Suzuki to afford 377 (22 mg) following reverse phase HPLC purification. MS (Q1) 524 (M)+
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.[H][H]>CO.O1CCOCC1.[Pd]>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([NH:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:23])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: O=C(Nc1ccccc1)Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)Nc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 50 °C

Procedure:
460 mg (1.1 mmol) of 1-[4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-yl]-3-phenylurea in 20 ml of a methanol/dioxane mixture (1/1) are placed in a reactor. The reaction medium is degassed and 560 mg (1.2 equivalents by mass) of 10% palladium-on-charcoal are then added. The system is placed under 3 bar of hydrogen and heated at 50° C. for hours. The reaction medium is filtered through Celite and evaporated, and the residue obtained is purified by chromatography on a column of silica with a gradual increase in the polarity of a 9/1 mixture of heptane and ethyl acetate to a 4/6 mixture of heptane and ethylacetate. After evaporation of the solvents, 150 mg (33%) of 1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-yl]-3-phenylurea are obtained in the form of a white solid with a melting point of 185° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].Cl.[NH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:36]12([NH:35][C:27]([C:24]3[CH:25]=[CH:26][C:21]([S:18]([N:8]4[C:7]5[CH:32]=[CH:33][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=5[N:10]([CH:11]5[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]5)[C:9]4=[O:17])(=[O:19])=[O:20])=[C:22]([O:30][CH3:31])[CH:23]=3)=[O:29])[CH2:43][CH:42]3[CH2:41][CH:40]([CH2:39][CH:38]([CH2:44]3)[CH2:37]1)[CH2:45]2
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC23CC4CC(CC(C4)C2)C3)cc1OC
Yield: 42.2 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 100 starting from 0.5 g of the compound obtained in EXAMPLE 13, 0.3 g of 1-aminoada- mantane hydrochloride, 0.5 g of BOP, 2 ml of DIPEA and 25 ml of DCM. It is chromatographed on silica using a DCM/MeOH mixture (99/1; v/v) as the eluent to give 0.27 g of the expected product after crystallization from an EtOH/iso ether mixture (80/20; v/v). M.p.=228° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)[CH2:4][CH2:3]1.[C:17]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[C:17]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:2]2[CH2:7][CH2:6][C:5]3([C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:16])[O:8]3)[CH2:4][CH2:3]2)=[O:33])=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1ccc(C(=O)c2ccccc2)cc1)Oc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(NC(=O)N2CCC3(CC2)OC(=O)c2ccccc23)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (48 mg), phenyl N-(4-benzoylphenyl)carbamate (58 mg) and triethylamine (0.14 mL) in chloroform (5 mL) was stirred at 80° C. for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20 mL). The organic layer was washed with saturated saline solution (20 mL), then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) and recrystallized from ethyl ether-hexane to give the subject compound (81 mg) as colorless crystals (melting point 161-163° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5]O.Cl.Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:15].C([O-])(O)=[O:17].[Na+].C(O)(CC)(C)C>>[OH:17][CH:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:15]
Reactant: O=C([O-])O
Reactant: [O-][n+]1ccccc1Cl
Reactant: NCCCCO
Agent: Cl
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: CC(O)CCNc1cccc[n+]1[O-]
Reaction time: 24 h
Yield: 63.4 %

Procedure:
A mixture of 4-amino-1-butanol (2.0 mL, 21.7 mmole), 2-chloropyridine-N-oxide hydrochloride (3.00 g, g, 18.0 mmole), NaHCO3 (7.56 g, 90.0 mmole), and tert-amyl alcohol (22 mL) was heated at reflux. After 24 hr, the mixture was cooled and filtered, then the filtrate was concentrated under reduced pressure. Silica gel chromatography (10% MeOH/CHCl3) gave the title compound (2.08 g, 63%) as a yellow solid: MS (ES) m/e 183 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CN1C(=O)CCC1.[OH-].[K+].[CH:25]([C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][N:36]2C(=O)C3C(=CC=CC=3)C2=O)=[N:31][CH:32]=1)=[CH2:26]>O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][CH2:25][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][NH2:36])=[N:31][CH:32]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(CCCN2C(=O)c3ccccc3C2=O)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(CCCN)nc2)CCN(C)C1
Temperature: 120 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.005 mol) was taken into NMP (3 mL), and to it was added finely crushed KOH (280 mg, 0.005 mol) and 2-(3-(5-vinylpyridin-2-yl)propyl)isoindoline-1,3-dione (146 mg, 0.005 mol). The reaction was heated at 120° C. for 12 h. The reaction was monitored by LCMS. After 12 h, 2 mL of water was added to the reaction mixture and heated at 120° C. for 12 h. The reaction was monitored by LCMS. After completion of reaction the mixture was cooled and water was added, followed by extraction with EtOAc. The organic extract was dried over sodium sulfate and concentrated under vacuum to yield 800 mg of crude product. 1HNMR (CDCl3, Oxalate salt) d (ppm): 8.17 (s, 1H), 7.22 (s, 1H), 1.18 (d, 1H), 7.15 (d, 1H), 6.95 (m, 2H), 4.20 (t, 2H), 3.70 (s, 2H), 3.0 (t, 2H), 2.90 (t, 2H), 2.80 (t, 2H), 2.70 (t, 2H), 2.58 (s, 3H), 2.40 (s, 3H), 2.37 (m, 2H), 1.80 (t, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=2)[N:8]=1.C(#N)C.O.C(O)(C(F)(F)F)=O>Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=2)[N:8]=1
Reactant: COc1ccc2cc(C(=O)O)cn2n1
Agent: Br
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc2ccc(O)nn2c1
Temperature: 50 °C

Procedure:
2-Methoxypyrrolo[1,2-b]pyridazine-6-carboxylic acid (1.06 g, 5.50 mmol) was suspended in HBr (10 mL, 33% solution in acetic acid) and heated to 50° C. for 2 hrs. The solvent was evaporated in vacuo and used directly (500 mgs). An analytical standard was prepared using reverse phase HPLC with a gradient of acetonitrile/water and 0.05% TFA as modifier. MS m/z 179.1 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 12.29 (bs, 1H), 11.60 (bs, 1H), 7.89-7.86 (m, 2H), 6.76 (d, J=2.0 Hz, 1H), 6.36 (d, J=9.6 Hz, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9]1>O>[Cl:3][CH2:6][CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9]1
Reactant: O=c1c2ccccc2ncn1CCO
Reactant: O=S(Cl)Cl
Solvent: O
Product: O=c1c2ccccc2ncn1CCCl
Temperature: 85 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
This thionyl chloride (1,095 mL, 15 mmol) was added to 3-(2-hydroxyethyl)quinazoline-4 (3H)-one (2.0 g, 10.52 mmol) in a reactor, forming a white suspension that heated spontaneously to 85° C. The reaction medium was kept at this temperature under agitation for thirty minutes, after which it was left to cool to about 40° C. Next, 50 mL of water was added, forming a pinkish suspension, which was kept under agitation for two hours. The product was then vacuum filtered and washed with three portions of 10 mL of an ethanol/water mixture (50% v/v), yielding 3-(2-chloroethyl) quinazoline-4 (3H)-one as a pale white solid (1.8 g, 8.63 mmol, yield=82%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[C:4]([N+:18]([O-])=O)[CH:3]=1.C(O)C>C1C=CC=CC=1.[Pt]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[C:4]([NH2:18])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1N1CCCc2ccccc21
Agent: [Pt]
Solvent: c1ccccc1
Solvent: CCO
Product: Nc1cc(Br)ccc1N1CCCc2ccccc21
Reaction time: 6.5 h
Yield: 99.9 %

Procedure:
1-(4-Bromo-2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (11.6g, 0.035 mole) was dissolved in benzene (125 ml), and ethanol added (75 ml), followed by 1% platinum-on-charcoal (0.40 g). The mixture was shaken under an initial pressure of 56 psi for 6.5 hours. The mixture was filtered and the filtrate was evaporated at 50° C. under vacuum to provide 10.6 g (100%) of product, as a gum.
Reaction SMILES: [C:1]([N:5]=[C:6]=[S:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:16][C@H:17]([CH2:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)[CH2:18][OH:19]>C(O)C.O>[C:1]([NH:5][C:6]([NH:16][C@H:17]([CH2:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)[CH2:18][OH:19])=[S:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@@H](CO)Cc1ccsc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccsc1

Procedure:
0.9 cm3 of tert-butyl isothiocyanate and then 0.82 cm3 of triethylamine are added to a suspension of 0.9 g of (2R)-2-amino-3-(3-thienyl)-1-propanol hydrochloride in 9 cm3 of absolute ethanol stirred and under an inert atmosphere. After stirring for 66 hours at room temperature, the reaction medium is evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. The thick brown oil obtained is taken up in 6 cm3 of water and then extracted with twice 12 cm3 of ethyl acetate. The organic phase is filtered through Celite and washed with twice 4 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. A brown oil is obtained, which crystallizes rapidly under cold conditions and which is dried in an oven under vacuum (10 Pa) at a temperature in the region of 48° C. to give 0.97 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]thiourea in the form of a beige-colored solid melting at 109° C. 1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.43 (s: 9H); 2.84 (mt: 2H); 3.38 (mt: 2H); 4.42 (unres. mult.: 1H); 4.86 (broad t, J=4.5 Hz: 1H); 7.04 (broad d, J=5 Hz: 1H); from 7.10 to 7.20 (mt: 2H); 7.25 (broad s: 1H); 7.46 (dd, J=5 and 3 Hz: 1H).