Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1C(O)=O.[CH2:21]([O:23][C:24]([N:26]=[C:27]=NC(C)(C)C)=[O:25])[CH3:22].C1C[O:36]CC1>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:27]([NH:26][C:24](=[O:25])[O:23][CH2:21][CH3:22])=[O:36]
Reactant: CCOC(=O)N=C=NC(C)(C)C
Reactant: C1CCOC1
Reactant: COc1ccc2c(C(=O)O)c(F)ccc2c1C(F)(F)F
Product: CCOC(=O)NC(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C

Procedure:
According to the procedure of O. Mitsunobu et al, Bull. Chem. Soc. Japan, 45, 3607 (1972), a solution of 2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthoic acid (2.30 g, 8.00 mmol, prepared by the process of Example 10), and ethoxycarbonyl-t-butylcarbodiimide (1.50 g, 1.1 eq) in anhydrous THF (40 mL) was heated to reflux for 21/2 hours under a dry nitrogen atmosphere. The reaction was cooled to room temperature and the THF was removed. The crude product was triturated with ether to provide the title compound as an off white solid (2.37 g, 82%). A small sample was recrystallized from CHCl3 :petroleum ether for analysis, m.p. 172°-174° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li][CH2:10]CCC.[CH3:14][O:15][CH:16]([O:25][CH3:26])[CH2:17][CH2:18][C:19](N(OC)C)=[O:20]>CCOCC>[CH:7](=[C:2](/[N:3]=[C:4]([Br:8])[CH:5]=[CH2:10])\[C:19](=[O:20])[CH2:18][CH2:17][CH:16]([O:15][CH3:14])[O:25][CH3:26])/[CH3:6]
Reactant: Brc1cccc(Br)n1
Reactant: COC(CCC(=O)N(C)OC)OC
Reactant: [Li]CCCC
Solvent: CCOCC
Product: C=CC(Br)=N/C(=C\C)C(=O)CCC(OC)OC
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
To a suspension of 2,6-dibromopyridine (8.1 g, 34.03 mmol) in 80 mL of ether at −70° C., is added BuLi (12.3 mL, 26.17 mmol, 2.5 M in Hexane) in on portion. After stirring at −70° C. for 5 min, 4,4,N-Trimethoxy-N-methyl-butyramide (5.0 g, 26.17 mmol) is added to the solution dropwise. After stirring at −70° C. for 1.5 hr, the reaction mixture is quenched with 120 mL of water and extracted with 3×130 mL of EtOAc. The combined organic layers is concentrated and purified by chromatography (Hexane/EtOAc:70/30) to give N-[1-Eth-(Z)-ylidene-5,5-dimethoxy-2-oxo-pentyl]-acrylimidoyl bromide (5.96 g, 60.5%) as light yellow liquid. M/Z=288.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O-:8])=[CH:4][CH:3]=1.[Na+].[CH3:10][C:11]([C:14]([CH2:16]Br)=[O:15])([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:14](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: [O-]c1ccc(Cl)cc1
Agent: [Na+]
Product: CC(C)(C)C(=O)COc1ccc(Cl)cc1

Procedure:
226 g (1 mol) of 1-(4-chlorophenoxy)-3,3-dimethylbutan-2-one (obtained from sodium 4-chlorophenolate and α-bromopinacolone; in this respect, see German Patent Specification No. 2,201,063), together with 120 g (1.07 mols) of glycerol, 19 g (0.1 mol) of p-toluenesulphonic acid monohydrate and 30 ml of butanol, are dissolved in 1,000 ml of toluene, and the mixture is heated under reflux for 16 hours in a water separator. After the mixture has been cooled, the toluene phase is washed with 4 times 250 ml of water, dried over magnesium sulphate, filtered, and evaporated down in vacuo. 186 g (65.4% of theory) of 2-(t-butyl)-2-(4-chlorophenoxymethyl)-4-hydroxymethyl-1,3-dioxolane of boiling point b.p.0.1 : 161° C.-163° C. are obtained by distillation.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH:25]([OH:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.CCN(CC)CC.[C:37](Cl)(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>C(Cl)Cl>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]4[O:27][C:37](=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OC1c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-2,3-dihydro-3-hydroxy-1H-isoindol-1-one (1.4 g, 3.5 mmol) in DCM (30 ml) was added Et3N (1.2 ml, 8.8 mmol) followed by decanoyl chloride at 0 C. under nitrogen. After stirring for 1 h in the cooling bath, the solvent was removed using a stream of nitrogen. The remaining residue was diluted with EtOAc and the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated and the remaining oil was flushed through alumina with ether to give 1.6 g (83%) of the desired product as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][NH2:15])[CH:11]=[CH:12][C:4]=2[O:3]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.[BH4-].[Na+].O>CO.O1CCCC1>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][NH:15][CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[C:17]([Cl:16])[CH:18]=3)[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1Oc2ccc(CCN)cc2NC1=O
Reactant: O=Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1Oc2ccc(CCNCc3cccc(Cl)c3)cc2NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
915 mg (4.437 mmol) of 2-methyl-3-oxo-6-(2-amino-ethyl)-3,4-dihydro-2H-1,4-benzoxazine is dissolved in 16 ml of a methanol/tetrahydrofuran mixture (4:1). After adding 623.7 mg (4.437 mmol) of 3-chlorobenzaldehyde, the batch is stirred for two hours at room temperature. Then, 91.1 mg (2.408 mmol) of sodium borohydride is added in portions and stirred for another two hours at room temperature. The batch is added to 50 ml of water, and after three-fold extraction with ethyl acetate, the combined organic extracts are washed with brine, dried and the solvent is spun off. The remaining residue is chromatographed on silica gel (mobile solvent: ethyl acetate/methanol). Yield 584.6 mg (39.8%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][C:2]1=[O:11].C(N(C(C)C)CC)(C)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[C:21]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][C:2](=[O:11])[CH2:3]1)(=[O:23])[CH3:22]
Reactant: O=C1CNc2ccccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of 3,4-dihydroquinoxalin-2(1H)-one (1.0 g, 6.7 mmol; J. Med. Chem. 758, 1994) and N,N-diisopropyl-N-ethylamine (1.7 mL, 10.1 mmol) in dichloromethane (30 mL) under an atmosphere of nitrogen, acetic anhydride (0.76 mL, 8.1 mmol) was added and stirred at room temperature overnight. The resultant solution was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1% methanol in chloroform. Collection and concentration of appropriate fractions provided the acetylation product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]3[CH3:27])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>ClCCl>[CH:2]([C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:25])([CH3:26])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]3[CH3:27])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[O:1]
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(CO)cc3ccccc13)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.36 g (1 mmol) of 5'-hydroxymethyl-1,3,3-trimethylspiro[indoline-2,3'-[3H]-naphtho[2,1-b][1,4]oxazine] in 30 ml of dichloromethane is added to 0.42 g (1 mmol) of Dess-Martin reactant prepared according to the method published in J. Org. Chem., 1983, 48, 4155, in solution in 60 ml of anhydrous dichloromethane. The mixture is then stirred for 1 hour at ambient temperature. 100 ml of ethyl ether are then added. The solution is then filtered and then evaporated. The product is purified by chromatography on a column of silica (CH2Cl2 eluent).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[CH:18][N:17]=1.O>CN(C)C=O>[C:3]([O:7][C:8]([C:10]1[CH:14]=[CH:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[CH:18][N:17]=2)[CH:11]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)c1cc[nH]c1
Reactant: FC(F)c1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccn(-c2ccc(C(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
Sodium hydride (230 mg) was added to a solution of 1H-pyrrole-3-carboxylic acid tert-butyl ester (804 mg) in N,N-dimethylformamide (9.6 ml) at room temperature and stirred at the same temperature for 0.5 hour. 2-Bromo-5-(difluoromethyl)pyridine (1.0 g) was added and stirred at 60° C. for an hour. After completion of the reaction, the reaction solution was cooled to room temperature, water was added and the precipitated solid was filtered. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-[5-(difluoromethyl)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid tert-butyl ester (1.01 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([OH:26])[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[OH:27][CH2:28][CH2:29][CH2:30][S:31]([NH:34][C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][C:38]=1[O:46][CH:47]([CH3:49])[CH3:48])=[O:36])(=[O:33])=[O:32].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[OH:27][CH2:28][CH2:29][CH2:30][S:31]([NH:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([OH:26])[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=2)=[CH:39][C:38]=1[O:46][CH:47]([CH3:49])[CH3:48])=[O:36])(=[O:33])=[O:32]
Reactant: CC(C)Oc1cc(B(O)O)ccc1C(=O)NS(=O)(=O)CCCO
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Oc1cc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(=O)(=O)CCCO
Temperature: 80 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (331 mg) in 1,4-dioxane (3.3 ml) were added [4-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3-isopropoxyphenyl]boronic acid (325 mg), tetrakis(triphenylphosphine)palladium (91 mg) and aqueous solution of sodium carbonate (2M, 1.4 ml), and the mixture was stirred at 80° C. for 3 hours under nitrogen. The mixture was portioned into a mixture of ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/methanol=100/3) to give tert-butyl [2-[4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3′-isopropoxy-4-biphenylyl]-ethyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (108 mg).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:19])[CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>CC(N(C)C)=O.C(#N)C>[C:20]([N:16]1[CH2:15][CH2:14][N:13]([CH2:12][C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH2:6][CH2:7]2)=[O:19])[CH2:18][CH2:17]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(CN1CCNCC1)N1CCN(C2CCC2)CC1
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: O=C(CN1CCN(C(=O)c2ccccc2)CC1)N1CCN(C2CCC2)CC1
Temperature: 50 °C

Procedure:
Dissolve 1-cyclobutyl-4-(piperazin-1-ylacetyl)piperazine (32 mg, 0.12 mmol) and benzoic acid (17.6 mg, 0.14 mmol) in dry DMA (0.75 mL), TEA (0.033 mL, 0.24 mmol) and toluene (0.75 mL). Add a solution of DMC (41 mg, 27.3 mmol) in acetonitrile (1.2 mL). Heat the mixture at 50° C. for 3 h. Cool and concentrate. Partition the residue between EtOAc (10 mL) and 1 N NaOH (10 mL). Extract the organic phase and place directly on an SCX ion exchange resin cartridge. Wash the resin first with EtOAc (4 mL). Discard this wash. Second, wash the resin with EtOAC/MeOH/TEA (10/1/1). Collect this wash and evaporate to yield the title compound. 1H NMR (CDCl3). δ 7.41-7.39 (m, 5H), 6.89 (d, 1H), 3.86-3.78 (m, 2H), 3.63-3.57 (m, 4H), 3.44-3.40 (m, 2H), 3.23 (s, 2H), 2.74-2.66 (m, 1H), 2.6-2.43 (m, 4H) 2.33-2.26 (m, 4H), 2.08-2.00 (m, 2H), 1.90-1.84 (m, 2H), 1.76-1.70 (m, 2H); LC-MS (M+1) 371.02.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)=[C:14]([O:24][CH3:25])[CH:13]=2)[S:9][CH:10]=1)C.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.NC1C=CC=CC=1.C[Al](C)C>>[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:4](=[O:3])[CH2:5][C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]4)=[C:14]([O:24][CH3:25])[CH:13]=3)[S:9][CH:10]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)Cc1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: Nc1ccc(F)cc1
Agent: C[Al](C)C
Solvent: Nc1ccccc1
Product: COc1cc(Nc2nc(CC(=O)Nc3ccc(F)cc3)cs2)ccc1-n1cnc(C)c1
Yield: 89 %

Procedure:
The title compound was prepared in analogy to example 27 from 92 mg (0.25 mmol) ({2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-acetic acid ethyl ester and 98 mg (0.87 mmol) 4-fluoroaniline. After the first addition conversion was not complete. Therefore the same amount of the aniline and trimethylaluminium were added and the reaction was heated again over night. Workup as in example 27 and subsequent purification on silica gel with methylene chloride/methanol 19/1 yielded 95 mg (89%) N-(4-fluoro-phenyl)-2-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-acetamide as a brown oil. MS ISP (m/e): 438.1 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=9.08 (s, 1H), 7.65 (s, 2H), 7.45 (dd, 2H), 7.31 (s, 1H), 7.21 (d, 1H), 7.06-6.88 (m, 3H), 6.51 (s, 1H), 3.80 (s, 3H), 3.73 (s, 2H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:15]>[OH-].[Na+].C(I)CCC>[CH2:10]([S:15][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[Cl:1])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCI
Product: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cl
Reaction time: 50 h

Procedure:
To a stirred solution of 4-chloro-3-mercapto-5-sulfamylbenzoic acid (5.5 g) in 1 N sodium hydroxide (29.5 ml), butyl iodide (2.1 ml) is added. After additional stirring for 50 hours precipitates the sodium salt of 3-butylthio-4-chloro-5-sulfamylbenzoic acid which is collected and washed with ice water. The sodium salt is suspended in water (25 ml) and 1 N hydrochloric acid added slowly until a pH value of 1. The precipitate is collected by filtration and recrystallized from aqueous ethanol to yield 3-butylthio-4-chloro-5-sulfamylbenzoic acid with a melting point of 202° - 203°C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:24]2[CH2:25][CH2:26][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)nc(NCCO)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41a) was treated with 4-phenyl-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at room temperature to yield 4-chloro-2-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=358.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:30][C@H:31]1[C@@H:34]([CH2:35][N:36]2[CH:40]=[N:39][C:38]([CH3:41])=[N:37]2)[NH:33][C:32]1=[O:42].CCN=C=NCCCN(C)C.N1C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:24][C:22]([NH:21][C:18]1[S:19][CH:20]=[C:16](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:13]([NH:30][C@@H:31]2[C:32](=[O:42])[NH:33][C@@H:34]2[CH2:35][N:36]2[CH:40]=[N:39][C:38]([CH3:41])=[N:37]2)=[O:14])[N:17]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1ncn(C[C@H]2NC(=O)[C@H]2N)n1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
To a solution of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (310 mg, 0.72 mmol), (3S,4R)-3-amino-4-((3-methyl-1H-1,2,4-triazol-1-yl)methyl)azetidin-2-one (130 mg, 0.72 mmol) and EDCI (150 mg, 0.79 mmol) in DMF (5 mL) at 0° C. was added pyridine (64 μL, 0.79 mmol). After stirring at rt for 24 h, more (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (310 mg, 0.72 mmol) and EDCI (150 mg, 0.79 mmol) were added, along with HOBt (110 mg, 0.79 mmol) and DIPEA (250 μL, 1.44 mmol). After an additional 16 h of stirring it was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 5%), affording the title compound (230 mg, 54%) as a white solid. LCMS: m/z=593.0 (M+1).
Reaction SMILES: C(N(CC)CC)C.O=C1CCC(=O)N1[O:15][C:16](=O)[CH2:17][C:18]#[N:19].[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]3[C:36](=[O:41])[NH:37][CH:38]=[CH:39][CH:40]=3)[N:29]=2)[CH2:22]1>ClCCl>[O:15]=[C:16]([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]3[C:36](=[O:41])[NH:37][CH:38]=[CH:39][CH:40]=3)[N:29]=2)[CH2:22]1)[CH2:17][C:18]#[N:19]
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: O=c1[nH]cccc1Nc1nccc(N[C@@H]2CCCNC2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CCC[C@@H](Nc2ccnc(Nc3ccc[nH]c3=O)n2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.5 %

Procedure:
Triethylamine (33 μL, 0.24 mmol) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropane nitrile (prepared as described in BE875054(A1), 51 mg, 0.28 mmol) were added to a solution of (R)-3-(4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridin-2(1H)-one (Preparation 19c, 67 mg, 0.23 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at ambient temperature for 24 hours and solvent was evaporated. Water was added and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4), evaporated under reduced pressure and the residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (11 mg, 12%) as a solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](Cl)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][OH:24].C(N(CC)CC)C>ClCCl.[Cl-].[Na+].O>[OH:24][CH2:23][CH2:22][CH2:21][N:20]([CH3:19])[C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: CNCCCO
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN(CCCO)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Yield: 100 %

Procedure:
A solution of 9-fluorenylmethoxycarbonyl chloride (15.22 g, 58.85 mmol) in dichloromethane (100 ml) was added over 1 h to an ice-cooled solution of 3-methylamino-1-propanol (5.25 g, 58.85 mmol) and triethylamine (9.0 ml, 64.74 mmol) in dichloromethane (50 ml). The resultant suspension was left overnight at −18° C., and then diluted with brine. The organic phase was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica eluting with 1:4 ethyl acetate/dichloromethane to give (9H-fluoren-9-yl)methyl 3-hydroxypropylmethylcarbamate (100% yield). p-Toluoyl chloride (4.26 g, 27.56 mmol) was added dropwise over 10 min to an ice-cooled solution of (9H-fluoren-9-yl)methyl 3-hydroxypropylmethylcarbamate (7.8 g, 25.05 mmol) in pyridine (100 ml). The resultant mixture NA as stirred for 2 h at 0° C., concentrated in vacuo and redissolved in ethyl acetate. The solution was washed with 10% citric acid and brine, then separated, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica eluting with 30% ethyl acetate/hexane to give (9H-fluoren-9-yl)methyl 3-(4-methylbenzoyloxy)propylmethylcarbamate (97% yield). A solution of (9H-fluoren-9-yl)methyl 3-(4-methylbenzoyloxy)propylmethylcarbamate (0.91 g, 2.12 mmol) and triethylamine (5.0 ml) in DMF (5 ml) was stirred for 1 h at +80° C. The resultant mixture was cooled to room temperature and compound 1 (2.01 g, 1.74 mmol) was added. The reaction was diluted with DMF (5), stirred for 2 days, and then diluted with ether (100 ml). The precipitated solid was isolated by filtration, washed with ether and vacuum dried to afford compound 2b (89% yield) as a pale solid, which was sufficiently pure to be used in the next step without additional purification.
Reaction SMILES: [CH3:1][NH2:2].S(O[CH2:14][CH2:15][O:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:19]([CH2:20][CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@:23]3([OH:41])[CH2:24][CH2:25][C@@H:26]2[C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)[CH2:18]1)(C1C=CC(C)=CC=1)(=O)=O>CO>[CH3:1][NH:2][CH2:14][CH2:15][O:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:19]([CH2:20][CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@:23]3([OH:41])[CH2:24][CH2:25][C@@H:26]2[C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)[CH2:18]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Solvent: CO
Product: CNCCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1

Procedure:
To 7 ml of a solution of methylamine 3.2 M in methanol, 0.090 g of 3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as an intermediate in Ex.7, were added. The solution was kept at reflux under nitrogen for 11 hrs, then was evaporated. The resulting solid was washed with n-hexane to give 0.045 g of the title compound (I-an) as a light yellow pasty solid.