Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:12][C:13]#[C:14][CH3:15])[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7]>C(OCC)(=O)C.[Pd]>[CH3:1][CH:2]([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:6][CH3:7])[O:8][CH3:9]
Reactant: CC#CCC(C)C(=O)CP(=O)(OC)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC(C)C(=O)CP(=O)(OC)OC
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of dimethyl 3-methyl-2-oxo-5-heptynylphosphonate (10.0 g, 0.043 mol) in ethyl acetate (100 ml) was added 10% palladium on active carbon (5.0 g) and the mixture was stirred under hydrogen atmosphere for one hour. The reaction mixture was filtered and the filtrate was concentrated. The residue was distilled under reduced pressure to give colorless oily product dimethyl 3-methyl-2-oxo-heptylphosphonate (8.12 g, 0.034 mol, 80%, b.p. 90°-92° C./0.05 mmHg). The structure was identified by the following data.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:23])=[C:6]([CH2:20][CH2:21][CH3:22])[C:7]2[O:12][C:11]([CH3:18])([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9][C:8]=2[CH:19]=1)(=[O:3])[CH3:2].O.[C:25]1(C)C=CC(S(O)(=O)=O)=C[CH:26]=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:25]([O:16][C:15](=[O:17])[CH2:14][CH2:13][C:11]1([CH3:18])[CH2:10][CH2:9][C:8]2[CH:19]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]([OH:23])=[C:6]([CH2:20][CH2:21][CH3:22])[C:7]=2[O:12]1)[CH3:26]
Reactant: CCCc1c(O)c(C(C)=O)cc2c1OC(C)(CCC(=O)O)CC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(O)c(C(C)=O)cc2c1OC(C)(CCC(=O)OCC)CC2
Yield: 385.4 %

Procedure:
A solution of 692 mg of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid and 100 mg of p-toluenesulfonic acid monohydrate in 10 ml of absolute ethanol was stirred and refluxed for 17 hours. The resulting solution was cooled and treated with a small amount of saturated sodium bicarbonate then concentrated in vacuo to remove the ethanol. The residue was treated with ether and the ether solution was processed in the usual manner given 752 mg of a yellow oil. This material was chromatographed on 50 g of silica gel. Elution with 4:1 toluene-ethyl acetate provided 706 mg (92.9%) of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[CH:8]=[C:9]([S:14](Cl)(=[O:16])=[O:15])[CH:10]=[C:11]([Cl:13])[CH:12]=1>O1CCOCC1>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][S:14]([C:9]1[CH:8]=[C:7]([Cl:6])[CH:12]=[C:11]([Cl:13])[CH:10]=1)(=[O:16])=[O:15]
Reactant: NCCCN
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Solvent: C1COCCO1
Product: NCCCNS(=O)(=O)c1cc(Cl)cc(Cl)c1
Yield: 29.2 %

Procedure:
1,3-Diaminopropane (6 g, 81.5 mmol) was dissolved in 45 ml of 1,4-dioxane, and at 15-20° C. a solution of 3,5-dichlorobenzenesulfonyl chloride (2 g, 8.15 mmol) in 5 ml of 1,4-dioxane was slowly added over 3 hours under stirring. Stirring was continued at RT. After 30 hours the formed precipitate was filtered off and the filtrate concentrated in vacuo. The residue was distributed between ethyl acetate and water. The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated in vacuo to yield 2.0 g of crude material. 750 mg of this material was purified by HPLC to yield 675 mg of the title compound as TFA salt (MS=283.0 (M+H)+). 200 mg of this product was dissolved in ethyl acetate and treated with 5 ml of diluted potassium carbonate solution. The organic layer was separated, dried, filtered, and concentrated in vacuo to yield the TFA free title amine.
Reaction SMILES: Cl.[C:2](O)(=O)[CH3:3].[Cl:6][C:7]1[C:8]([F:34])=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25]C)[N:18]=1)[CH:14]=[C:13]([C:27]([O:29]CC)=[O:28])[C:12]2=[O:32]>O>[Cl:6][C:7]1[C:8]([F:34])=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH2:2][CH3:3])[N:18]=1)[CH:14]=[C:13]([C:27]([OH:29])=[O:28])[C:12]2=[O:32]
Reactant: CCOC(=O)c1cn(-c2nc(NC)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CCNc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reaction time: 2.5 h

Procedure:
To 3 ml of a mixed solution (1:1, v/v) of 4 ml of 4N hydrochloric acid and 1 ml of acetic acid was added 510 mg of ethyl 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-methylamino-pyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 2.5 hours. After adding 2 ml of distilled water, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 454 mg of the title compound as a gray powder.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.[SH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C[O-].[Na+].O>CO>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][S:13][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1)[CH3:19]
Reactant: Clc1nc(-c2ccccc2)no1
Reactant: CCOC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CSc1nc(-c2ccccc2)no1
Reaction time: 3 h
Yield: 75 %

Procedure:
5-chloro-3-phenyl-1,2,4-oxadiazole (36 parts) was added portionwise to a solution of ethyl mercaptoacetate (24 parts) and sodium methoxide (11 parts) in methanol (500 parts). The temperature rose to about 50° C. and the mixture was allowed to stand for three hours. The product was poured into an excess of cold water, and extracted with benzene, washed with water and the solvent then evaporated off. Recrystallisation gave ethyl(3-phenyl-1,2,4-oxadiazol-5-ylthio)acetate (40 parts, 75% yield), melting point 50-52° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=O.[CH3:11][NH:12][NH2:13]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1/[CH:8]=[N:13]/[NH:12][CH3:11]
Reactant: CNN
Reactant: O=Cc1c(Br)cncc1Br
Product: CN/N=C/c1c(Br)cncc1Br
Temperature: 100 °C
Yield: 96.4 %

Procedure:
In analogy to GP 1, 2.15 g of 3,5-dibromo-pyridine-4-carbaldehyde (8.12 mmol, 1 eq; commercially available or prepared as described in U.S. Pat. No. 6,232,320 or WO2005110410) were dissolved in 36 mL 1-propyl alkohol, treated with 0.65 mL N-methyl hydrazine (12.17 mmol, 1.5 eq.) and heated to 100° C. for 30 min (employing a Biotage Initiator® microwave oven in batch mode). The reaction mixture was concentrated, the residue partitioned between water and ethyl acetate, the aqueous layer reextracted with ethyl acetate, the combined organic layers dried and concentrated in vacuo to yield 2.29 g of the desired product (7.82 mmol, 96% yield), which was used in the subsequent cyclization without further purification steps.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]([F:28])([F:27])[C:23](OC)=[O:24].Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:23](=[O:24])[C:22]([F:28])([F:27])[F:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(F)(F)F
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: -40 °C

Procedure:
A solution of 91.2 ml (0.23 mol) of 2.5M n-butyllithium solution was added dropwise at -40° C. to a solution of 50.0 g (0.19 mol) of 4-bromophenol benzyl ether in 250 ml of tetrahydrofuran. The mixture was subsequently stirred for a short time at -40° C., then cooled to -78° C., and 34 g (0.27 mol) of methyl trifluoroacetate were added dropwise. The mixture was allowed to come to room temperature and then stirred at 0° C. for 3 hours. For working up, 120 ml of dilute hydrochloric acid were added dropwise, the mixture was diluted with toluene, and the organic phase was separated off, washed with water, dried and concentrated. A brown solid was obtained which was recrystallized from petroleum ether/ethyl acetate 10:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=O)[CH:7]=[CH:6]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([N:28]1[CH2:29][CH2:30][N:25]([C:23](=[O:24])[C:22]3[CH:31]=[C:32]([O:36][CH3:37])[C:33]([O:34][CH3:35])=[C:20]([O:19][CH3:18])[CH:21]=3)[CH2:26][CH2:27]1)=[O:17])[CH:7]=[CH:6]2
Reactant: COc1cc2ccc(C(=O)O)cc2cc1OC
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Product: COc1cc2ccc(C(=O)N3CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)CC3)cc2cc1OC

Procedure:
In a manner as that described in Example 62, 6,7-dimethoxy-2-naphthoic acid and 1-(3,4,5-trimethoxybenzoyl)piperazine are subjected to amidation to give 1-(6,7-dimethoxy-2-naphthoyl)-4-(3,4,5-trimethoxybenzoyl)piperazine. This product is recrystallized from ethyl acetate to give colorless needles, m.p. 224°-226° C.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:28][CH2:27]2)=[CH:22][C:21]=1[F:29])=[O:9])=C>CO.ClCCl>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:28][CH2:27]2)=[CH:22][C:21]=1[F:29])=[O:9]
Reactant: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Solvent: ClCCl
Solvent: CO
Product: O=C(NOCCO)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Yield: 71.4 %

Procedure:
8-(4-Cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (2-vinyloxy-ethoxy)-amide (56 mg, 0.14 mmol) was dissolved in methanol and loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. The eluent was collected and concentrated to give a residue. The residue was subjected to flash chromatography (Si-PPC, gradient 0% to 20%, methanol in dichloromethane) to afford the title compound as a pale yellow solid (37 mg, 71%). LCMS (method A): RT=6.40 min, [M+H]+=371. 1H NMR (CH3OH-d4): 8.20 (1 H, d, J=0.71 Hz), 7.67-7.65 (1 H, m), 7.17-7.11 (1 H, m), 6.94-6.87 (2H, m), 6.73 (1 H, d, J=7.38 Hz), 6.39 (1 H, s), 4.00-3.97 (2 H, m), 3.75-3.72 (2 H, m), 1.98-1.89 (1 H, m), 1.04-0.98 (2 H, m), 0.73-0.68 (2 H, m).
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:29]3[C:28]4[C@@H:27]([CH2:30][CH2:31][OH:32])[CH2:26][CH2:25][C:24]=4[S:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:45][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C=O)C.O>[C:6]([O:5][C:4]([N:3]([CH2:1][CH3:2])[CH:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[C:29]3[C:28]4[C@@H:27]([CH2:30][C:31]([OH:45])=[O:32])[CH2:26][CH2:25][C:24]=4[S:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH2:15][CH2:16]1)=[O:10])([CH3:8])([CH3:7])[CH3:9]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)O)CC4)CC1
Yield: 67.2 %

Procedure:
A solution of tert-butyl N-ethyl-N-(4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (450 mg, 0.97 mmol, 1.00 equiv) and PDC (1791 mg, 4.76 mmol, 4.88 equiv) in 5 mL of DMF was stirred for 14 hrs at 25° C. After completion, the resulting solution was diluted with water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to give 310 mg (67%) of 2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](ethyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetic acid as a colorless oil. MS (ES): m/z 476 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][O:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[Si]([O:31][CH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1)(C(C)(C)C)(C)C>>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:20][CH2:21][O:22][CH3:23])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=2[C:5]2[CH:4]=[CH:3][C:2]([C:35]3[CH:34]=[C:33]([CH2:32][OH:31])[CH:38]=[N:37][CH:36]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: COCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(B(O)O)c1
Product: COCCc1nc2c(N)nc3cc(-c4cncc(CO)c4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was coupled with 5-(tert-butyldimethylsilanyloxymethyl)pyridine-3-boronic acid according to the method described in Examples 118-121. The reaction was heated at reflux for 2.25 hours, and the work-up procedure described in Part F of Examples 125-131 was followed. The crude product was purified and deprotected according to the procedure described in Example 144. The resulting solid was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 55:45) followed by recrystallization from acetonitrile to provide {5-[4-amino-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyridin-3-yl}methanol as white needles, mp 202-204° C.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][S:13][C:14]3[N:15]=[C:16]4[CH:25]=[CH:24][CH:23]=[CH:22][N:17]4[C:18](=[O:21])[C:19]=3[CH3:20])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:20][C:19]1[C:18](=[O:21])[N:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]2=[N:15][C:14]=1[S:13][CH2:12][C:11]1[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=2)=[CH:9][CH:10]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1c(SCc2ccc(C(=O)c3ccc(O)cc3)cc2)nc2ccccn2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(SCc2ccc(C(=O)c3ccc(OCCN4CCOCC4)cc3)cc2)nc2ccccn2c1=O
Yield: 66.4 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (214 mg), 4-(2-chloroethyl)morpholine hydrochloride (157 mg) and potassium carbonate (247 mg) in DMF (7 ml) was stirred at 80° C. for 4 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was recovered by filtration and dried to provide the title compound as colorless solid (182 mg).
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]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)=[O:11])[CH:17]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)nn1

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-chloro-2-(pyrimidin-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 491 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH:13]([CH3:15])[CH3:14])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2.[CH3:24][C:25]([CH3:40])([C:29]([NH:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[O:30])[C:26](O)=[O:27]>>[CH:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:26](=[O:27])[C:25]([CH3:24])([CH3:40])[C:29]([NH:31][CH2:32][C:33]([F:38])([F:39])[C:34]([F:35])([F:36])[F:37])=[O:30])[C:3]2[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=2[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]1=2)([CH3:15])[CH3:14]
Reactant: CC(C)OCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: CC(C)OCCN1C(=O)[C@@H](NC(=O)C(C)(C)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-Amino-5-(2-isopropoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as example 1c (78%). White solid. MS: m/e=556(M+H+).
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:24])[CH2:9][C@@H:10]([OH:23])[C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.Cl>N1C=CC=CC=1>[CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:24])[CH2:9][CH:10]([O:23][C:25]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@H](O)C[C@]12C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3C(OC(=O)CCC(=O)O)C[C@]12C

Procedure:
According to the general principles outlined by Erlanger et al. (Method in Immunology and Immunochemistry Vol. I, p. 148, Ed. C. A. Williams and M. W. Chase. Academic Press N.Y., 1967), and by Buzby et al. (J. Med. Chem. 10:199, 1967), a solution of 11α-hydroxyprogesterone (10 g) (Sigma Chem. Co., St. Louis, MO) and of succinic anhydride (10 g) in dry pyridine (100 ml) was prepared and refluxed under nitrogen atmosphere for 20 hours. The cooled reaction mixture was poured into cold aqueous hydrochloric acid (3 N, 500 ml) containing crushed ice, and extracted with chloroform. After evaporation of the chloroform, the residue was recrystallized repeatedly from acetone-hexane, and from acetone yielding 4.5 gm of white crystals, melting point 148°-152° C. Absorption maximum in 0.1 NaOH was at 243 nm. These characteristics were consistent with those described in the literature (Lindner et al., Steroids 19:357-375, 1972) for 11α-hydroxyprogesterone hemisuccinate.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:20]([C:21]([OH:23])=[O:22])[CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Nc1cccc(C(=O)O)c1
Product: CC(C)(C)C1=CC(=Nc2cccc(C(=O)O)c2)C=C(C(C)(C)C)C1=O

Procedure:
Using the method of Example 1, 2,6-di(tertiary-butyl)-p-benzoquinone was reacted with 3-aminobenzoic acid to provide red-orange crystals of 2,6-di(tertiary-butyl)-4-(3'-carboxyphenylimino)-2,5-cyclohexadien-1-one, m.p. 230°-231° C. Analysis: Calculated for %C, 74.3; H, 7.4; %N, 4.1; Found: %C, 74.1; %H, 7.6; %N, 3.7.
Reaction SMILES: [C:1]1(=O)[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([CH2:11][NH3+:12])[CH2:9][NH3+:10]>>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1[NH:12][CH2:11][CH2:8][CH2:9][N:10]=1
Reactant: O=C1CCCCO1
Reactant: [NH3+]CCC[NH3+]
Product: OCCCCC1=NCCCN1
Yield: 49 %

Procedure:
Using a method similar to Example 1, valerolactone was reacted with 1,3-DAP. At a temperature of 170° C. in the liquid in the flask, 48% of the open-chain amide and 49% of 2-(4-hydroxybutyl)-1,3-diazacyclohex-1-ene were obtained after 8 hours. After a further 8 hours at 180° C. and 8 hours at a liquid-phase temperature of 190° C., the ratio shifted further to 5% of amide and 92% of 2-(4-hydroxybutyl)-1,3-diazacyclohex-1-ene. The subsequent product diazabicyclodecene was obtained in an amount of only 1 or 3%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3cccc(F)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-fluoro-phenylboronic acid to give [1-(3-Fluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 349(MH+).
Reaction SMILES: C(N(CC)CC)C.[NH:8]([CH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[NH:11]1)[NH2:9].[O:21]([C:28](Cl)=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[O:21]([C:28]([NH:9][NH:8][CH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[NH:11]1)=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNC1NS(=O)(=O)c2ccccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(NNC1NS(=O)(=O)c2ccccc21)Oc1ccccc1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
5 g (0.05 mol) of triethylamine are added to 9.8 g (0.05 mol) of 3-hydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide in 100 ml of dioxane, and 8.6 g (0.55 mol) of phenoxycarbonyl chloride, dissolved in 25 ml of dioxane, are then added dropwise to the stirred mixture. After about 2 hours, the precipitated salt is filtered off under suction and washed with 15 ml of cold dioxane, and the combined mother liquors are evaporated down. Crystallization from ethanol gives 12.8 g (81% of theory) of 3-phenoxycarbonylhydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide of melting point 216° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C1C=CC=CC=1.[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH:5]=[CH:4][N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccnc(Br)c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)Nc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.2 %

Procedure:
2-Bromo-4-aminopyridine (433 mg, 2.5 mmol) was added to 15 ml of dry benzene and the mixture warmed to dissolve the pyridine. 298 mg (2.5 mmol) of phenyl isocyanate was added to the solution and the resulting mixture stirred at room temperature for 20 hrs. The crystals which formed were collected by filtration and subjected to chromatography in a conventional manner using alumina. After developing the column with a benzene-ethyl acetate (2.5:1 volume) solvent mixture, the eluate containing the objective compound was collected. After distilling solvent off under reduced pressure, the residue was recrystallized from 70% methanol to give 308 mg of N-(2-bromo-4-pyridyl)-N'-phenylurea: yield 42.1%; m.p. 188°-189° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[Cl:9]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]1[C:7]([Cl:9])=[C:6]([CH3:8])[O:5][N:4]=1
Reactant: ClCl
Reactant: CNc1cc(C)on1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CNc1noc(C)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
Compound (15) (19.06 g) was dissolved in methylene chloride (150 ml) and a solution of chlorine (13.1 g) in carbon tetrachloride (139 ml) was added thereto dropwise. The mixture was stirred at room temperature for 10 minutes, then washed with a 50% potassium carbonate solution and water, dried and evaporated to give 3-methylamino-4-chloro-5-methylisoxazole (20) (21.07 g); mp. 43°-47° C.