Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:19])[CH:5]=[C:6]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl.[CH3:21][C:22]1[N:23]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=2)[CH:24]=[CH:25][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([O:19][CH2:31][C:30]2[CH:29]=[CH:28][C:27]([N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH3:21])=[CH:34][CH:33]=2)[CH:5]=[C:6]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Reactant: CCOC(=O)C1(c2cc(O)cc(F)c2)CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Temperature: 100 °C
Yield: 67.5 %

Procedure:
A stirred mixture of ethyl 4-(5-fluoro-3-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (2.01 g, 7.5 mmol), 4-(2-methylimidazol-1-yl)benzyl chloride hydrocloride (1.82 g, 7.5 mmol) and potassium carbonate (5.18 g, 37.5 mmol) in DMF (30 ml) was heated at 100° C. for 1.33 hr. After cooling to room temperature, the mixture was diluted with a mixture of ethyl acetate and toluene (2:1, 200 ml), and washed with water (4×100 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated to give 3.38 g of crude product as amber solids. Recrystallization from a mixture of isopropyl ether (25 ml) and ethyl acetate (2 ml) gave the titled compound (2.22 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:22]([CH3:24])[CH3:23])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][CH:10]1[CH2:14][N:13](CC)[N:12]([CH2:17][CH3:18])[CH2:11]1)=[O:8].Cl[O-].[Na+]>>[CH2:17]([N:12]1[CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:19]=[C:2]([Cl:1])[C:3]([N:22]([CH3:23])[CH3:24])=[CH:4][C:5]=2[O:20][CH3:21])[CH:14]=[N:13]1)[CH3:18]
Reactant: CCN1CC(NC(=O)c2cc(Cl)c(N(C)C)cc2OC)CN1CC
Agent: [Na+]
Agent: [O-]Cl
Product: CCN1CC(NC(=O)c2cc(Cl)c(N(C)C)cc2OC)C=N1

Procedure:
In accordance with the procedure of Example 12, 5-chloro-4-(dimethylamino)-2-methoxy-N-(1,2-diethyl-4-pyrazolidinyl) benzamide is reacted with sodium hypochlorite and the product is isolated.
Reaction SMILES: [OH:1][CH2:2][C@:3]1([C:32]([O:34]C)=[O:33])[CH2:7][CH2:6][CH2:5][C@H:4]1[N:8]([CH3:31])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[OH-].[Na+].Cl.[CH2:39](N(CC)CC)C>>[CH3:39][C@@:4]1([N:8]([CH3:31])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:30])[CH:21]=3)=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH2:5][CH2:6][CH2:7][C@:3]1([CH2:2][OH:1])[C:32]([OH:34])=[O:33]
Reactant: CCN(CC)CC
Reactant: COC(=O)[C@@]1(CO)CCC[C@H]1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@]3(C)CCC[C@]3(CO)C(=O)O)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 56, Step 4, methyl (1S,2R)-1-(hydroxymethyl) -2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (213 mg, 0.439 mmol), 5M sodium hydroxide solution (0.44 mL), and triethylamine hydrochloride (365 mg, 2.63 mmol) provided methyl (1S,2R)-1-(hydroxymethyl)-2-[methyl({4-[(2-methylquinolin -4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid. To the acid was added BOP (867 mg, 1.96 mmol), hydroxylamine hydrochloride (649 mg, 9.27 mmol), and triethylamine (2.1 mL) to give (1S,2R)-N-hydroxy-1-(hydroxymethyl) -2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide (86.7 mg, 41%) as a colorless solid after purification via HPLC, eluting with a gradient of 15-100% MeCN/H2O (10 min). LCMS (M−H): 1.57 min, 484.3; 1H NMR (400 MHz, MeOD) δ ppm 1.44-1.49 (m, 1H) 1.56-1.62 (m, 2H) 1.64-1.68 (m, 1H) 2.02-2.12 (m, 1H) 2.67 (s, 3H) 3.43-3.53 (m, 2H) 3.67 (d, J=11.37 Hz, 1H) 5.58 (s, 2H) 7.21 (d, J=9.09 Hz, 2H) 7.50 (s, 1H) 7.56 (t, J=7.71 Hz, 1H) 7.69-7.75 (m, 1H) 7.84 (d, J=8.84 Hz, 2H) 7.96 (d, J=8.59 Hz, 1H) 8.01 (d, J=8.34 Hz, 1H).
Reaction SMILES: O=O.[K+].Br[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10].C1OCCOCCOCCOCCOCC[O:23]C1.O>CS(C)=O>[OH:23][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=C(CCCCBr)N1CCCc2ccccc21
Agent: O=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(CCCCO)N1CCCc2ccccc21

Procedure:
Potassium superoxide (0.50 g) was added to a solution of 1-(5-bromopentanoyl)-1,2,3,4-tetrahydroquinoline (1.8 g) and 18-Crown-6 (0.4 g) in dimethylsulfoxide (25 ml). After 8 hours the solution was added to water and extracted with ether. The extract was washed, dried and evaporated and the residue was chromatographed on silica gel, eluting with 95:5 methylene chloride:methanol, to yield 1-(5-hydroxypentanoyl)-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[C:2]1[C:3]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)c(OC)c1
Yield: 18.7 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 2,4-dimethoxyphenylboronic acid (103.7 mg, 0.57 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) afforded 21 mg (18%) of 3-(2,4-dimethoxyphenyl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[H-].[Na+].I[CH3:32].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([CH3:32])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (5.0 g) in DMF (50 mL) was added sodium hydride (60%, 576 mg) at 0° C., and the mixture was stirred at 0° C. for 30 min. Iodomethane (978 was added, and the mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (3.40 g).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[O:12])[C@@H:5]([NH:13]C(=O)OC(C)(C)C)[CH2:4][C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[NH2:13][C@H:5]1[CH2:4][C@@H:3]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:2]([CH3:1])[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]1=[O:12]
Reactant: CC(C)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@@H](c2ccccc2)[C@H]1C
Solvent: CCOC(C)=O
Product: CC(C)CN1C(=O)[C@@H](N)C[C@@H](c2ccccc2)[C@H]1C
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl [(3S,5S,6R)-6-methyl-1-(2-methylpropyl)-2-oxo-5-phenylpiperidin-3-yl]carbamate (140 mg, 0.39 mmol) in ethyl acetate (10 mL), pre-cooled to 0° C. was sparged with HCl gas for ˜1 min. The ice-bath was removed and the acidic solution was allowed to warm to 23° C. as stirring was continued for 2 h. The mixture was then concentrated to dryness to afford the title compound as a hydrochloride salt. MS: m/z=261.3 (M+1).
Reaction SMILES: O.Cl.[NH2:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6].C1COCC1.[OH-].[Na+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]([NH:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)C(C)(C)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(C)(C)NC(=O)OCc1ccccc1

Procedure:
3-Amino-3-methyl-2-butanone hydrochloride hydrate [J. Org. Chem. 49, 1209 (1984)] (10.6 g., 0.076 mol was dissolved in 700 ml. 1:1 THF:H2O and the pH adjusted to 6.8 with dilute NaOH. Benzylchloroformate (11.93 ml., 0.084 ml.) was added dropwise, maintaining pH 6.8-7.0 by the simultaneous dropwise addition of dilute NaOH. The pH was so maintained until it stabilized. The reaction mixture was extracted 4×100 ml. CHCl3. The organic extracts were combined, filtered and stripped to yield title product as an oil, 9.26.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=O)[CH2:9][CH2:8]2)#[N:2].Cl.[CH3:15][NH:16][CH3:17].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>C(#N)C.[OH-].[NH4+]>[CH3:15][N:16]([CH3:17])[CH:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1
Reactant: N#Cc1cccc2c1CC(=O)CC2
Reactant: CNC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC#N
Product: CN(C)C1CCc2cccc(C#N)c2C1
Reaction time: 4 h
Yield: 22.2 %

Procedure:
8-Cyano-2-tetralone (2 gm, 11.7 mMol) in acetonitrile (30 mL) with dimethylamine hydrochloride (5.72 gm, 70 mMol), sodium acetate (5.76 gm, 70 mMol), sodium cyanoborohydride (520 mg, 8.2 mMol) and 3A molecular sieves (1.2 gm) were stirred together for 4 days at room temperature. The reaction mixture was then diluted with conc. ammonium hydroxide and stirred for 4 hours. This mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo to give a dark oil. Purification on a basic alumina column (Activity I, 2% methanol in dichloromethane) gave a brown oil which was converted to its hydrochloride salt. Recrystallization (methanol/diethyl ether) gave colorless crystals (520 mg, m.p.=229°-230° C.).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].O1CCCC1>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCC=Cc1cc(-c2ccccc2)c2ccccc2n1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCc1cc(-c2ccccc2)c2ccccc2n1
Reaction time: 1 h

Procedure:
A mixture of 1.75 g of 7-(4-phenyl-2-quinolyl)-6-hepten-1-oic acid, 0.18 g of palladium on activated carbon (10% w/w) and 100 cc of tetrahydrofuran is hydrogenated under normal pressure for 1 hour at room temperature. After filtration and concentration in vacuo, the solid residue is stirred in 100 cc diethyl ether and then recrystallized from 40 cc acetone to give 7-(4-phenyl-2-quinolyl)heptanoic acid as a whitish solid. (m.p.=137°-139° C).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then, under nitrogen atmosphere, pyrrolidine (1.99 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature over the weekend. The precipitate which had formed was filtered and the filtrate was evaporated to dryness. The solid residue was triturated with water and dried under high vacuum at 50° C. overnight. The solid was recrystallized from isopropyl alcohol with refrigeration. The precipitate was collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at room temperature overnight to give 2.84 g (60%) of title compound, mp 224°-225° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:38]([N:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][NH2:53])[CH2:47][CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:53][CH2:52][CH2:51][N:48]2[CH2:49][CH2:50][N:45]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:46][CH2:47]2)=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: NCCN1CCN(Cc2ccccc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc(C(=O)NCCN2CCN(Cc3ccccc3)CC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of Example 104A (32.5 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL) was added, followed by the addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50.4 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). Then, 2-(4-benzylpiperazino)ethan-1-amine (41.3 mg, 0.19 mmol) dissolved in N,N-dimethylacetamide (0.6 mL) was added followed by the addition of diisopropyl ethyl amine (57.9 uL, 0.31 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). The mixture was shaken at room temperature overnight. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 dimethyl sulforxide/methanol and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to give the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.33 (t, 3H) 2.19-2.51 (m, 9H) 3.14-3.20 (m, 1H) 3.35 (t, 2H) 3.42-3.49 (m, 2H) 4.41-4.49 (m, 2H) 6.97-7.11 (m, 1H) 7.19-7.44 (m, 5H); MS (ESI) positive ion 409 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]2[S:8][CH2:9][CH:10]([NH:11][C:12]([NH:14][CH2:15][CH2:16][OH:17])=[S:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>CN(C1C=CN=CC=1)C.C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:7]2[S:8][CH2:9][CH:10]([NH:11][C:12](=[S:13])[NH:14][CH2:15][CH2:16][O:17][C:24](=[O:26])[CH3:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCCNC(=S)NC1CSc2c(F)cccc21
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OCCNC(=S)NC1CSc2c(F)cccc21
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a solution of 1-(7-Fluoro-2,3-dihydro-benzo[b]thiophen-3-yl)-3-(2-hydroxy-ethyl)-thiourea (200 mg, 0.73 mmol), pyridine (0.07 mL, 0.88 mmol) and DMAP (20 mg, 0.16 mmol) in THF (5 mL) was added a solution of acetyl chloride (0.06 mL, 0.81 mmol) in THF (2 mL) and the reaction mixture stirred for 16 h. The mixture was diluted with ethyl acetate (20 mL) and extracted with water (4 times). The organic phase was dried over Na2SO4, solvents evaporated and the residue purified by column chromatography to yield Acetic acid 2-[3-(7-fluoro-2,3-dihydro-benzo[b]thiophen-3-yl)thioureido]-ethyl ester (125 mg, 0.40 mmol, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[CH:10]([S:12]([CH:15]=[CH2:16])(=[O:14])=[O:13])=[CH2:11]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:11]=[CH:10][S:12]([CH:15]=[CH2:16])(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: ClSc1ccc(Cl)cc1
Reactant: C=CS(=O)(=O)C=C
Solvent: ClCCl
Product: C=CS(=O)(=O)C=CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Fifty grams of 4-chlorophenylsulfenyl chloride was added slowly to 33.0 g of divinyl sulfone in 150 ml of dichloromethane with cooling to remove the heat of reaction. After a few hours of standing at ambient temperature, the solvent was stripped and the crude adduct was dissolved in 200 ml of benzene. Thirty-one g of triethylamine was added slowly with cooling to maintain ambient temperature. After standing for one hour, the triethylamine hydrochloride was removed by filtration. After washing with water and drying over magnesium sulfate, the solvent was stripped to give 64 g of crude product. This was purified by chromatography over silica gel to give 48 g of vinyl 2-(4-chlorophenylthio)vinyl sulfone; calculated for C10HgClO 2 S2 :S, 24.6; found: S, 24.4.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][C:24]1[N:25]([C:29]2[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=2)[C:32](O)=[O:33])[CH:26]=[CH:27][N:28]=1>>[CH3:23][C:24]1[N:25]([C:29]2[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=2)[C:32]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]3[C:16]4[N:12]([N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[CH:11]=[CH:10]3)[CH:4]=2)=[O:33])[CH:26]=[CH:27][N:28]=1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: Cc1nccn1-c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: Cc1ccc(NC(=O)c2cc(-n3ccnc3C)cc(C(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
35 mg (0.12 mmol) of the compound of Example 6A and 33 mg (0.12 mmol) of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid [lit.: WO 2004/005281 A1, Example 91b] were reacted and worked up analogously to the procedure of Example 16. This gave 53 mg (81% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:8]2[C:6]3[N:7]=[C:2]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4ccc(F)cc4)ncnc23)CC1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4ccc(F)cc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-(4-fluorobenzylamino)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 210°-212° C.) and piperazine in dioxane at 80° C.
Reaction SMILES: [C:1]([O:20]C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(OC)(=O)CCCCCCC/C=C\CCCCCCCC>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
A blanker oil generally similar to that of Example 3 was prepared except that 300 grams of methyl stearate was substituted for the methyl oleate. The blanker oil thus produced gave results similar to that of the material of Example 3 with regard to surface quality and electrocoat primer compatibility.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:38](C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:28]1([S:25]([NH:24][C@@H:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([NH:1][CH3:38])[CH:3]=2)[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:12])(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1cc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)ccc1O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CNc1cc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)ccc1O
Reaction time: 8 h

Procedure:
(2S)-3-(3-Amino-4-hydroxy-phenyl)-2-benzenesulfonylamino-N-(4-phenyl-butyl)-propionamide (502 mg, 1.07 mmol) is dissolved in dichloroethane (5 mL). 37% formaldehyde (120 mg, 1.47 mmol) and NaBH(OAc)3 (1.1 g, 5 mmol) are added. The mixture is stirred overnight. Saturated NaHCO3 (20 mL) is added and the crude mixture is extracted with ETOAC three times. The organic phase is dried and concentrated in vacuo. The small volume of solution is filtered through silica gel plug to provide a crude solution of (2S)-2-benzenesulfonylamino-3-(4-hydroxy-3-methylamino-phenyl)-N-(4-phenyl-butyl)-propionamide which is used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]4[CH2:24][CH2:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH2:16]4)=[CH:6][CH:7]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC1CCc2ccccc2C1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC4CCc5ccccc5C4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,2,3,4-tetrahydro-naphthalen-2-yl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.