Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:18]3[CH:19]=[C:20]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([F:35])[CH:27]=4)=[O:24])[CH:21]=[CH:22][C:17]=3[O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=O)[NH2:2].[C:36]([C:38]1C=C(S(Cl)(=O)=O)C=CC=1)#N>>[CH2:36]([O:32][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:23]([C:20]2[CH:21]=[CH:22][C:17]3[O:16][CH2:15][CH2:14][N:13]([S:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([C:1]#[N:2])[CH:5]=4)(=[O:11])=[O:12])[C:18]=3[CH:19]=2)=[O:24])=[CH:27][C:28]=1[F:35])[CH3:38]
Reactant: NC(=O)c1cccc(S(=O)(=O)N2CCOc3ccc(C(=O)Nc4ccc(C(=O)O)c(F)c4)cc32)c1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C#N)c2)CCO3)cc1F

Procedure:
4-{[4-(3-Carbamoyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=500.0 (M+H+.), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 3-cyano-benzenesulfonyl chloride and yielded 4-{[4-(3-cyano-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 8 at both the carboxylic acid ester and the cyano position.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][NH:10][C:11]([CH:13]1[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1)=O.FC(F)(F)C([O-])=O.[NH4+:34]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:34]=[C:11]([CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14]2)[NH:10][CH:9]=1
Reactant: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1ccccc1Cl
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: Clc1ccccc1-c1c[nH]c(C2CN(Cc3ccccc3)CCO2)n1
Temperature: 150 °C
Yield: 96.3 %

Procedure:
A mixture of N-[2-(2-chlorophenyl)-2-oxoethyl]-4-(phenylmethyl)-2-morpholinecarboxamide (350 mg, 0.939 mmol) and ammonium trifluoroacetate (615 mg, 4.69 mmol) was heated at 150° C. for 1.5 hours. Water (150 mL) was added to the residue, and the mixture was extracted with EtOAc (3×100 mL). The combined organics were dried with anhydrous Na2SO4, filtered and concentrated to afford the title compound (320 mg) as a brown solid. LC-MS (ES) m/z=354 [M+H]+.
Reaction SMILES: P(=O)([O-])[O-].[S:5]1[CH:9]=[CH:8][C:7](CP(=O)(OCC)OCC)=[CH:6]1.O1C=CC=C1[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28].FC1C=CC=CC=1CP(=O)(OCC)OCC.COC1C=C(C=C(OC)C=1OC)CP(=O)(OCC)OCC>>[S:5]1[CH:6]=[CH:7][CH:8]=[C:9]1[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: CCOP(=O)(Cc1ccsc1)OCC
Reactant: CCOP(=O)(Cc1ccco1)OCC
Agent: CCOP(=O)(Cc1cc(OC)c(OC)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccccc1F)OCC
Agent: O=[PH]([O-])[O-]
Product: CCOP(=O)(Cc1cccs1)OCC

Procedure:
The following phosphonate reagents were also prepared by the above-described method: diethyl 3-thienylmethylphosphonate. diethyl 2-furanylmethylphosphonate, diethyl 2-fluorobenzylphosphonate, and diethyl 3,4,5-trimethoxybenzylphos-phonate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[N+:11]([O-])=O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[NH2:11]
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1F
Solvent: C1CCOC1
Product: COc1cc(Br)c(N)cc1F

Procedure:
Combine 1-bromo-4-fluoro-5-methoxy-2-nitrobenzene (20.5 g, 82 mmol) and Pt-on-carbon (sulfided) in THF (600 mL) and hydrogenate at 60 psi (414 kPa) over for 4 hours. Filter the reaction through celite to remove the catalyst and remove the solvent to give 2-bromo-5-fluoro-4-methoxyaniline as a brown solid which may taken on without further purification.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[N:4][CH:3]=[CH:2]1.Cl[CH2:13][CH2:14][CH2:15][C:16]1[C:20]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=2[O:18][N:17]=1.[C:26]([O-:29])([O-:28])=O.[K+].[K+]>CN(C=O)C>[C:7]([OH:1])(=[O:18])[C:26]([OH:29])=[O:28].[F:25][C:23]1[CH:22]=[CH:21][C:20]2[C:16]([CH2:15][CH2:14][CH2:13][N:4]3[CH2:5][CH2:7][CH:8]([CH:9]4[C:10]5=[CH:11][CH:6]=[CH:5][N:4]5[CH2:3][C:2]5[CH:11]=[CH:6][CH:7]=[CH:8][C:26]=5[O:29]4)[CH2:2][CH2:3]3)=[N:17][O:18][C:19]=2[CH:24]=1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: C1=COc2ccccc2C=N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(CCCN3CCC(C4Oc5ccccc5Cn5cccc54)CC3)noc2c1
Product: O=C(O)C(=O)O

Procedure:
To 50 ml dry DMF were added 11-(piperidin-4-yl)-5H,11H-pyrrolo2,1-c][1,4]benzoxazepine (3.0 g, 0.0112 mole), 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole (4.2 g, 0.02 mole), milled K2CO3 (10 g, 0.07 mole) and KI (0.01 g).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[N:21]([CH3:22])[C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[N:18]=3)=[O:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>CN(C=O)C.C(Cl)Cl.[Cu](I)I.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>[CH3:22][N:21]1[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=[C:17]1[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: C#C[Si](C)(C)C
Reactant: Cn1c(C(=O)c2ccc(Oc3ncccc3Br)cc2)nc2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(C(=O)c2ccc(Oc3ncccc3C#C[Si](C)(C)C)cc2)nc2ccccc21

Procedure:
A solution of (4-(3-bromopyridin-2-yloxy)phenyl)(1-methyl-1H-benzo[d]imidazol-2-yl)methanone (0.18 g, 0.44 mmol), triethylamine (0.12 mL, 0.88 mmol), copper iodide (0.0084 g, 0.044 mmol), dichlorobis(triphenyl-phosphine)palladium (0.015 g, 0.022 mmol), trimethylsilylacetylene (0.093 mL, 0.66 mmol) in 1 mL DMF was heated to 110° C. overnight. The reaction mixture was diluted with DCM and then washed with water and brine. The organic layer was purified by silica gel chromatography (0-10% MeOH/DCM) to afford (1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-(2-(trimethylsilyl)ethynyl)pyridin-2-yloxy)phenyl)-methanone.
Reaction SMILES: CC[C@@]12[C@](O)(CC)CC[C@H]1[C@@H]1CCC3[C@@H]([C@H]1CC2)CCC(=O)C=3.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][CH2:34]O)[CH:29]=[CH:30][CH:31]=1.P(Br)(Br)[Br:37]>C1C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][CH2:34][Br:37])[CH:29]=[CH:30][CH:31]=1
Reactant: BrP(Br)Br
Reactant: COc1cccc(CCCO)c1
Agent: CC[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Solvent: c1ccccc1
Product: COc1cccc(CCCBr)c1

Procedure:
Referring now to FIG. 1, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, 13β,17α-diethyl-17β-hydroxygon-4-en-3-one, is illustrated. 3-(m-Methoxyphenyl)propanol (I) is heated with phosphorus tribromide in benzene after dropwise addition in the cold to form 3-(m-methoxyphenyl)propyl bromide (II). This halogen compound (II) dissolved in tetrahydrofuran is condensed with sodium acetylide in liquid ammonia to obtain 5-(m-methoxyphenyl)-1-pentyne (III). Compound III is allowed to stand under nitrogen with water, 30% formalin, acetic acid, diethylamine, dioxan, and cuprous chloride at 70° C for about 12 hours, whereby there is obtained 1-diethylamino-6-(m-methoxyphenyl)-2-hexyne (IV), which is in turn hydrated in the presence of a mercury salt and sulfuric acid to form 1-diethylamino-6-(m-methoxyphenyl)-3-hexanone (V). The ketamine (V) may eliminate diethylamine on distillation to give the vinyl ketone 6-(m-methoxyphenyl)-1-hexen-3-one (VI). Either the ketamine (V) or the ketone (VI), or mixtures thereof, is then reacted with 2-ethyl-1,3-cyclopentanedione (VII) under Michael condensation conditions, e.g. refluxing in methanolic potassium hydroxide to form 2-ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione (VIII).
Reaction SMILES: CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[OH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1I.[CH3:28][N:29](C)C.O1CCOCC1>O>[C:28]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:17]=1[OH:16])[C:21]([O:23][CH3:24])=[O:22])#[N:29]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: CN(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 154.5 %

Procedure:
(Boc)2O (44.7 g, 0.21 mol) was added portion-wise over 10 min to a 0° C. solution of compound 2 (42 g, 0.19 mol), trimethyl amine (51.9 mL, 0.37 mol), dioxane (140 mL) and water (56 mL). After another 10 min, the ice bath was removed and the reaction mixture was stirred while warming to room temperature for another 2 hours. The reaction mixture was diluted in ethyl acetate (150 mL) and washed with 0.5 N HCl (200 mL×3). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo giving compound 3 (52 g, yield 97%) which was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:12][C:13]([F:22])([F:21])/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CS(C)=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[O:1][CH:14]([C:13]([F:12])([F:22])[F:21])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: COc1cccc(C=O)c1O
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cccc(OC)c2OC1C(F)(F)F
Temperature: 70 °C

Procedure:
The 2-hydroxy-3-methoxybenzaldehyde (3.05 g, 20mmol) was dissolved in DMSO (9 mL). TEA (4.09 g, 40 mmol) and ethyl 4,4,4-trifluorocrotonate (6.93 g, 40 mmol) were added to above solution. The reaction was heated to 70° C. and monitored by TLC and GCMS until done. The reaction was quenched with 10% HCl. The compound was extracted with EtOAc and washed with water and NH4Cl. The organic was dried over MgSO4. After concentrated, the crude compound was purified by flash column with 20% EtOAc in hexane. This ester was of suitable purity to use without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12].S(Cl)(Cl)=O>CN(C)C=O>[CH2:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1)[CH3:12]
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)cn1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N)nc1
Temperature: 80 °C

Procedure:
6-Aminonicotinic acid, 40 g (or 6-aminonicotinic acid phosphoric salt, 62 g), was mixed with anhydrous ethanol 500 ml. The mixture was externally cooled by an ice water bath. Thionyl chloride, 50 ml, was slowly added into the mixture. (N,N-Dimethylformamide, 50 ml, may be added to dissolve any still undissolved phosphoric salt.) The reaction mixture was heated to 80° C. for 5 hours and was then evaporated to a syrupy reside which crystallized on addition of acetone. These crystals were separated by filtration and were redissolved in 400 g of ice water. 4N KOH was added to the solution to adjust the pH to 8. The white crystals thus formed were separated again by filtration and were washed with water. The yield of practically pure 6-aminonicotinic acid ethyl ester was 41.8 g. This product had an Rf value of 0.79 on thin-layer chromatogram using a solvent system of benzene:methanol, 1:1.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29]C(C3CCCCO3)C)=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH2:38].[C:39]1([CH3:49])C=CC(S(O)(=O)=O)=CC=1.CO.O>C(Cl)(Cl)Cl>[CH2:1]([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][CH:39]([OH:38])[CH3:49])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)C3CCCCO3)cc2)nc1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)O)cc2)nc1
Yield: 535.7 %

Procedure:
At 25° C., 6.7 g (12 mmol) of the 5-undecyloxy-2-[4-{6-(2-tetrahydropyranyl)-1-trans-heptenyl}-phenyl]-pyrimidine obtained in Example 13, 0.4 g (2 mmol) of p-toluenesulfonic acid hydrate, 50 ml of methanol and 5 ml of water were stirred for two hours. Then, water was added and the mixture was extracted with ether. The organic layer was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 4.7 g (yield 90%) of (-)-5-undecyloxy-2-{4-(6-hydroxy-1-trans-heptenyl)-phenyl}-pyrimidine, [α]D20 =-1.1 (c=1.3, CHCl3).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:9][C:8]([CH3:20])=[N:7][C:6]=1[Cl:21])C.O.O.[OH-].[Li+:26]>O1CCOCC1>[Cl:21][C:6]1[N:7]=[C:8]([CH3:20])[CH:9]=[C:10]([O:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[Cl:19])[C:5]=1[C:4]([O-:22])=[O:3].[Li+:26]
Reactant: CCOC(=O)c1c(Oc2cc(Cl)ccc2Cl)cc(C)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)[O-])c(Cl)n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 130 mg (0.36 mmol) 2-chloro-4-(2,5-dichloro-phenoxy)-6-methyl-nicotinic acid ethyl ester in 2 mL dioxane was added 2 mL water and 23 mg (0.541 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred at 100° C. for 4 hours. The reaction mixture was allowed to cool down to room temperature and was concentrated under high vacuum. The so-obtained light yellow solid was pure enough for the next step without further purification. MS (ESI): 331.965 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(O)(C)C.[SH:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>C(OCC)(=O)C.[Cu]I.COCCOC>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([S:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[N:13][CH:12]=1
Reactant: N#Cc1ccc(S)cc1
Reactant: Oc1ccc(I)nc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: COCCOC
Product: N#Cc1ccc(Sc2ccc(O)cn2)cc1
Temperature: 80 °C
Yield: 53 %

Procedure:
0.25 g (1.31 mM) of copper(I) iodide, 7.26 g (52.5 mM) of potassium carbonate and 5.8 g (26.25 mM) of 6-iodo-3-pyridinol are introduced into a tube under an argon atmosphere. 30 ml of isopropanol, 5 g of 1,2-dimethoxyethane and 3.55 g (26.25 mM) of 4-mercaptobenzonitrile are then added. The tube is sealed and heated at 80° C. for 24 hours. When the mixture has returned to room temperature, it is diluted with 120 ml of ethyl acetate and filtered, the solid on the filter is washed with ethyl acetate and the organic phases are concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column (eluent: cyclohexanol/ethyl acetate 55/45; v/v) to give the expected product in the form of a beige powder with a yield of 53%.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:31])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=3)[CH3:22])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1>CCCCCC.CC(O)C>[CH3:32][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:31])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][C@H:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=3)[CH3:22])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1
Reactant: CNc1nccc(C(C)Nc2ccccc2C(=O)Nc2ccc3c(c2)CNCC3(C)C)n1
Solvent: CCCCCC
Solvent: CC(C)O
Product: CNc1nccc([C@H](C)Nc2ccccc2C(=O)Nc2ccc3c(c2)CNCC3(C)C)n1

Procedure:
N-(4,4-Dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[1-(2-methylamino-pyrimidin-4-yl)-ethylamino]-benzamide (190 mg, 0.44 mmol) was separated on a chiral column (Chiralcel AD, 250×4.6 (mm) 10u, n-Hexane/i-PrOH/0.2% DEA (70:30), 1 mL/min). The (S) enantiomer was isolated. MS m/z: 431.3 (M+H). Calc'd. for C25H31N6O-431.55.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][C@@H:20]([CH3:22])[N:11]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=[NH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:21][C@@H:20]([CH3:22])[N:11]2[C:12]3[CH:13]=[C:14]([N:36]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)cc3N21
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(N=C(c4ccccc4)c4ccccc4)cc3N21
Temperature: 80 °C

Procedure:
A mixture of (4R,10aR)-7-bromo-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (3.0 g, 8 mmol), benzophenone imine (1.52 g, 8 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (85 mg, 0.08 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphtalene (153 mg, 0.24 mmol) and sodium tert-butylate (1.1 g, 11.4 mmol) in toluene (30 mL) was heated to 80° C. for 3 h. After cooling the mixture was diluted with diethyl ether (300 mL) and filtered through Celite®. The solvents were evaporated and the residue was purified by chromatography on silica gel with ethylacetate/n-hexane (1:4). The title product was isolated as yellowish foam (3.4 g, 89%); ISP-MS: m/e=468.3 (M+H+).
Reaction SMILES: [N-]=C=O.[C:4]1([CH3:17])[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH2:16])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.N[C:20]1[S:21][C:22]([Br:25])=[CH:23][N:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:25][C:22]1[S:21][C:20]([NH:16][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:17])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:15])=[N:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)NC(N)=O)cc1
Reactant: Nc1ncc(Br)s1
Agent: Cl
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2ncc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of toluene-4-sulfonylurea isocyanate (2.6 g, 13 mmol) in CH2Cl2 (10 ml) was added slowly to a mixture containing 2-amino-5-bromothiazole hydrochloride (3.4 g, 13 mmol) and triethylamine (5.4 ml, 39 mmol) in CH2Cl2 (60 ml) under an argon atmosphere and stirred overnight at rt. The reaction mixture was concentrated under reduce pressure, diluted with ethyl acetate and washed with NaHCO3 (half sat. 3×), 5% KHSO4/10% K2SO4, water, NaCl sat., dried (MgSO4.2H2O), filtered and concentrated under reduced pressure. Recrystallization from MeOH/water yielded a beige solid: 2.8 g (58%), MS: m/e 376.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:53][S:50]([CH:47]6[CH2:49][CH2:48]6)(=[O:52])=[O:51])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3cc(F)cc(F)c3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3cc(F)cc(F)c3)nc2c1C
Yield: 7 %

Procedure:
Reaction of the acid 169 with cyclopropane sulfonic acid amide according to the procedure described in example 159, followed by purification on HPLC using an Ace-5 C8 column (100×21.2 mm) and an ammonium acetate buffer 5 mM, pH 6.8, 5% acetonitrile, going from 35 to 60% acetonitrile, gave the title compound as a white solid (8 mg, 7%). LRMS (M+H) 738.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10])=[O:5])[CH3:2].Cl[C:15]1[N:20]=[C:19](Cl)[C:18]([F:22])=[CH:17][N:16]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([NH:10][C:15]2[N:20]=[C:19]([NH:10][C:9]3[CH:11]=[CH:12][CH:13]=[C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:8]=3)[C:18]([F:22])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CCNC(=O)Nc1cccc(Nc2ncc(F)c(Nc3cccc(NC(=O)NCC)c3)n2)c1
Yield: 66.3 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis[4-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine, the reaction of 1,3-diaminobenzene (2 g, 18.5 mmol), ethyl isocyanate (0.5 mL, 6.3 mmol) and potassium carbonate (4.36 g, 31.5 mmol) gave 3-(ethylaminocarbonylamino)aniline (940 mg, 83%). The reaction of 3-(ethylaminocarbonylamino)aniline (537 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave N2,N4-bis[3-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine (180 mg, 66%) as a white solid. 1H NMR (CD3OD): δ 1.14 (t, J=6.9 Hz, 3H), 1.15 (t, J=7.5 Hz, 3H), 3.21 (q, J=7.2 Hz, 2H), 3.22 (q, J=7.5 Hz, 2H), 7.06 (ddd, J=0.9, 2.1, 7.8 Hz, 1H), 7.10-7.28 (m, 5H), 7.53 (t, J=2.1 Hz, 1H), 7.80 (m, 1H), 7.92 (d, J=5.7 Hz, 1H); LCMS: ret. time: 17.17 min.; purity: 89.63%; MS (m/e): 453.38 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[K+].Cl>C(OCC)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:15]#[N:16])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: N#CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
A solution of 1-benzylpiperidin-4-one (7.00 g) in 1:1 diethyl ether-water (30 mL) was cooled to 0° C. and treated with potassium cyanide (6.02 g), followed by hydrochloric acid (7.71 mL). The ice bath was removed and the mixture was stirred at room temperature for 18 hours. The phases were separated, and the aqueous layer was extracted with diethyl ether, dried and evaporated in vacuo to provide the title compound (4.08 g) having the following physical data.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[C:7]([OH:27])=[C:8]2[C:16]=1[Cl:17]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2CCc1ccccc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(CCc3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-4-hydroxy-1-phenethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 433 (M+H)+.