Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C@@:6]1([CH3:44])[CH2:10][C@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])(=O)=O.[NH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C)C=O>[N+:41]([C:38]1[CH:37]=[CH:36][C:35]([CH2:34][O:33][C:31]([N:7]2[CH2:8][C@@H:9]([S:11][C:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:10][C@H:6]2[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:32])=[CH:40][CH:39]=1)([O-:43])=[O:42]
Reactant: C[C@]1(OS(C)(=O)=O)C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCNCC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 51.2 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)-methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.0 g) in dimethylformamide (90 ml) was added piperazine (2.0 g) and the mixture was stirred at 80°]90°C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(piperazin-1-yl)methyl-4-(triphenylmethylthio)pyrrolidine (2.52 g).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:48]=[CH:49][C:50]=1[F:51])[O:30][C:31]1[CH:45]=[CH:44][C:34]2[N:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[S:37][C:33]=2[C:32]=1[C:46]#[N:47]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:26][C:27]2[CH:28]=[C:29]([O:30][C:31]3[CH:45]=[CH:44][C:34]4[N:35]=[C:36]([NH:38][C:39]([CH:41]5[CH2:43][CH2:42]5)=[O:40])[S:37][C:33]=4[C:32]=3[C:46]#[N:47])[CH:48]=[CH:49][C:50]=2[F:51])=[O:11])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: N#Cc1c(Oc2ccc(F)c(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)c3cccc(C4(C#N)CC4)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoic acid (51 mg, 0.272 mmol) in tetrahydrofuran (1.5 ml) were added oxalyl chloride (29 μL, 0.340 mmol) and N,N-dimethylformamide (15 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Amino-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (84 mg, 0.227 mmol) produced in Example 30(vi) was added to the solution, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (25 mL) and saturated brine (25 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (105 mg, 86%) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[CH3:11][I:12].[C:13](=[S:15])=[S:14]>>[IH:12].[CH3:11][S:14][C:13](=[S:15])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1
Reactant: NCCSCc1nccs1
Reactant: S=C=S
Reactant: CI
Product: CSC(=S)NCCSCc1nccs1
Product: I

Procedure:
(i) 2-[(2-Aminoethyl)thiomethyl]thiazole was successively treated with carbon disulphide and methyl iodide according to the general procedure of Example 1(a)(b) to give S-methyl-N-[2-(2-thiazolylmethylthio)ethyl]dithiocarbamate hydriodide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([F:15])=[CH:13][C:12](B(O)O)=[CH:11][C:10]=2[F:19])=[CH:5][CH:4]=1)[CH3:2].Br[C:21]1[S:22][C:23]([CH2:26][CH2:27][CH3:28])=[CH:24][CH:25]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:21]3[S:22][C:23]([CH2:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:11][C:10]=2[F:19])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2c(F)cc(B(O)O)cc2F)cc1
Reactant: CCCc1ccc(Br)s1
Product: CCCc1ccc(-c2cc(F)c(-c3ccc(CC)cc3)c(F)c2)s1

Procedure:
The compound 2-(4′-ethyl-2,6-difluorobiphenyl-4-yl)-5-propylthiophene (SUP-3-2) is prepared analogously to Example 1 from 4′-ethyl-2,6-difluoro-4-biphenylboronic acid and 2-bromo-5-propylthiophene.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[C:43]([CH3:51])[CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[OH:31][C:30]1[C:25](=[O:24])[NH:26][N:27]=[C:28]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:48])[F:50])=[C:43]([CH3:51])[CH:42]=2)[CH:29]=1
Reactant: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Product: Cc1cc(CCc2cc(O)c(=O)[nH]n2)ccc1C(F)(F)F
Yield: 4 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((3-methyl-4-(trifluoromethyl)phenyl)-ethynyl)pyridazine (Intermediate 74) except THF was used as the solvent. The reaction mixture was filtered through a diatomacious earth cartridge, eluting with further THF and methanol. The filtrate was concentrated under reduced pressure and purified by reverse phase column chromatography (eluting with 5-100% aqueous acetonitrile with acid modifier). The desired fractions were combined and freeze dried to give a pale yellow solid, which was recrystallised from methyl tert-butyl ether to give a white solid. The filtrate was concentrated under reduced pressure, and the filtrate and crystals purified separately by preparative HPLC. The two batches were combined and recrystallised from a mixture of methyl tert-butyl ether and ethyl acetate to afford 4-hydroxy-6-(3-methyl-4-(trifluoromethyl)-phenethyl)pyridazin-3(2H)-one as a white solid (31 mg, 4%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]([F:49])([F:48])[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][CH2:40][C:39]([F:48])([F:49])[F:38])[CH2:47][CH2:46]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC(F)(F)F)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(3,3,3-trifluoro-propyl)-piperazine (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C36H43Cl2F3N5O2 [(M+H)+] 704.2741, observed 704.274.
Reaction SMILES: [OH:1][C:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]2[CH:17]=[C:18]([OH:23])[CH:19]=[C:20]([OH:22])[CH:21]=2)=[CH:10][CH:9]=1>[Pd]>[OH:1][C:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([OH:23])[CH:17]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(O)CCCCCc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Agent: [Pd]
Product: CC(C)(O)CCCCCc1ccc(CCc2cc(O)cc(O)c2)cc1

Procedure:
In a manner similar to Example 9(a), by reacting 1 g (2.9 mmol) of 5-{2-[4-(6-hydroxy-6-methylheptyl)phenyl]vinyl}benzene-1,3-diol with 100 mg of 10% palladium/carbon, whitish crystals (m=728 mg; Y=91%) are obtained. m.p.=128-30° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][N:7]([C:15]1[C:20]([N+:21]([O-])=O)=[CH:19][N:18]=[C:17]([Cl:24])[N:16]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:14])[CH3:13])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][N:7]([C:15]1[C:20]([NH2:21])=[CH:19][N:18]=[C:17]([Cl:24])[N:16]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:14])[CH3:13])[CH3:2]
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1N)C1CCCC1(C)C
Yield: 78.9 %

Procedure:
A mixture of 3.3 g (0.0093 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-cyclopentyl)-amino]-propionic acid ethyl ester (IV-59) in 30 mL of ethyl acetate and 0.5 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration under reduced pressure gave 2.5 g of (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-cyclopentyl)-amino]-propanoic acid ethyl ester (V-59). This material was used directly in the next step without further purification.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:18]Br>ClCCl>[Br:18][C:4]1[CH:5]=[CH:6][C:1]([C@H:7]2[CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][CH2:12]2)=[CH:2][CH:3]=1
Reactant: BrBr
Reactant: O[C@H]1CC[C@H](c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Temperature: -8 °C
Reaction time: 0.25 h

Procedure:
(trans)-4-Phenylcyclohexanol (2 g) is dissolved in dichloromethane (40 mL) and cooled to −8° C. AlCl3 (3 g) is added portionwise and the mixture is stirred for further 15 minutes after addition is complete. Then a solution of bromine (1.87 mL) in dichloromethane (10 mL) is added dropwise. The mixture is stirred for 10 minutes and is then partitioned between dichloromethane and ice-water. Concentrated hydrochloric acid (20 mL) is added, the phases are separated and the aqueous phase is extracted 3 times with dichloromethane. The combined organic phases are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 2:1) to give the title compound. TLC: rf=0.3 (silicagel, cyclohexane/ethylacetate 2:1).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].N1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[Si:13]([O:20]S(C(F)(F)F)(=O)=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:4][CH2:12][CH2:6][C@@H:7]1[CH:8]=[CH:9][CH2:10][C@@H:11]1[O:20][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])(=[O:3])[CH3:2]
Reactant: Cc1cccc(C)n1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCC[C@@H]1C=CC[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
To a stirred solution of the above acetate (54 mg, 0.32 mmol) and 2,6-lutidine (74 μL, 0.63 mmol) in CH2Cl2 (1 mL) was added tert-butyldimethylsilyltrifluoromethanesulfonate (125 mg, 108 μL) at −78° C. under argon. The mixture was stirred for 10 min at which point reaction completion was observed. Sat. aq. NaHCO3 solution (1 mL) and additional CH2Cl2 (2 mL) were added. The two layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×2 mL). The combined organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica gel using hexanes/EtOAc (20:1) as the eluent to afford silylated product 5 (90 mg, >99%) as a colorless oil. TLC: Rf=0.68 (hexanes/EtOAc=3:1); 1H NMR (CDCl3, 300 MHz) δ 5.68 (s, 2H), 4.45 (dt, J=5.1, 6.3 Hz, 1H), 4.14 (t, J=6.9 Hz, 2H), 2.67-2.55 (m, 1H), 2.47 (dd, J=6.9, 15.4 Hz, 1H), 2.23 (dd, J=4.8, 15.4 Hz, 1H), 2.04 (s, 3H), 2.01-1.85 (m, 1H), 1.72-1.56 (m, 1H), 0.88 (s, 9H), 0.06 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 171.2, 132.7, 128.4, 73.6, 63.8, 45.9, 41.0, 27.4, 25.8, 21.0, 18.1, −4.6, −5.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:31])[CH:3]=1.Cl.[NH2:33][OH:34].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:33]\[OH:34])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:31])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(NS(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(NS(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, N-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-phenyl}-methanesulfonamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing 4% of the corresponding Z isomer as a colourless solid, MS (ESI+): m/z=474.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C:17]#[CH:18])[C:12]([Br:19])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH2:20]([N:23]=[C:24]=[S:25])[CH:21]=[CH2:22]>C(#N)C>[CH2:20]([NH:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C:17]#[CH:18])[C:12]([Br:19])=[CH:11][N:10]=2)=[CH:4][CH:3]=1)=[S:25])[CH:21]=[CH2:22]
Reactant: C=CCN=C=S
Reactant: C#CCNc1nc(Nc2ccc(N)cc2)ncc1Br
Solvent: CC#N
Product: C#CCNc1nc(Nc2ccc(NC(=S)NCC=C)cc2)ncc1Br

Procedure:
N2-(4-Amino-phenyl)-5-bromo-N4-prop-2-ynyl-pyrimidine-2,4-diamine (100 mg, 0.3 mmole, prepared in analogy procedure 21) was dissolved in acetonitrile (10 ml) and allyl isothiocyanate (1 ml) was added at room temperature. The reaction mixture was heated under reflux for 3 hours, the solvent removed under reduced pressure and 1-Allyl-3[4-(5-bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]-thiourea was crystallized from acetone/ethyl acetate/hexanes. Yield 37 mg. ESI-MS: 418.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])[N:3]=1.[Na]>CO>[CH2:2]([O:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])[N:3]=1)[C:10]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Cn2nc(O)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: [Na]
Solvent: CO
Product: COC(=O)c1ccc(Cn2nc(OCc3ccccc3)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 120.8 %

Procedure:
Methyl 4-(3-hydroxy-6-nitroindazol-1-ylmethyl)-3-methoxybenzoate (T) (35.7 g.) was added to a mixture of sodium (2.3 g.) and methanol (200 ml.). The mixture was stirred for 18 hours, and evaporated. The residue was dissolved in N,N-dimethylformamide (100 ml.) , cooled to 0° C., and benzyl bromide (15.5 ml.) added. After 18 hours at ambient temperature, ethyl acetate and 1N sodium hydroxide solution were added. The precipitate was isolated by filtration, washed with ether, and chromatographed by HPLC on silica gel, eluting with dichloromethane, to give methyl 4-(3-benzyloxy-6-nitroindazol-1-ylmethyl)-3-methoxybenzoate (CC) (27 g., 60%) as a solid; NMR (250 MHz, DMSO-d6): 3.84(s,3H, OMe); 3.86(s,3H, OMe); 5.38(s,2H, NCH2); 5.65(s,2H, OCH2); 6.95(d,1H); 7.36 (m,3H); 7.46(m,5H); 7.86(m,2H); 8.66(s,1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[H-].[Na+].[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl.O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([O:9][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(O)c(C(C)(C)C)cc1Br
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCOc1cc(C)c(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-2-t-butyl-5-methylphenol from Example YY (32.8 g, 135 mmol) in THF (150 mL) was treated portionwise with NaH (6.5 g of a 60% dispersion in oil, 162 mmol), and the mixture was stirred at room temperature for 1 hour. To the suspension was added 2-methoxyethoxymethyl chloride (18 mL, 158 mmol) all at once, and the resulting mixture was stirred at room temperature overnight. H2O (200 mL) was added slowly, followed by EtOAc (200 mL). The organic layer was separated, washed with H2O, and dried (MgSO4). Concentration gave the title compound. 1H NMR (CDCl3) δ 1.31 (s, 9 H), 2.29 (s, 3 H), 3.36 (s, 3 H), 3.55 (m, 2 H), 3.78 (m, 2 H), 5.25 (s, 2 H), 7.02 (s, 1 H), 7.33 (s, 1 H).
Reaction SMILES: [CH2:1](N(CC)CC)C.Cl.[OH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[NH:15])=[CH:12][CH:11]=1.[N:19]1[CH:24]=[CH:23][CH:22]=CC=1>>[C:24]([C:23]1[CH:1]=[N:15][C:14]([C:13]2[CH:17]=[CH:18][C:10]([OH:9])=[CH:11][CH:12]=2)=[N:16][CH:22]=1)#[N:19]
Reactant: N=C(N)c1ccc(O)cc1
Reactant: CCN(CC)CC
Reactant: c1ccncc1
Agent: Cl
Product: N#Cc1cnc(-c2ccc(O)cc2)nc1

Procedure:
50 ml abs. triethylamine, 50 ml abs. pyridine, 17.3 g (0.1 mol) 4-hydroxybenzamidine-hydrochloride and 11 g (0.1 mol) α-cyano-β-dimethylamino-acroleine are heated upon stirring for 6 hours to 80° C. Dark brown colored reaction mixture is poured on ice/concentrated H2SO4 (500 g/50 ml), the precipitate is removed by suction, washed thoroughly with water and recrystallized from methanol/activated carbon. The yield is 12.8 g (65% of the theoretical value). m.p.: 160-262 (sublimed).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]([NH:12][C:13](=[O:16])[CH2:14]Cl)([CH3:11])[CH2:9][OH:10])[CH:7]=1.[K].CCSC([N:24]([CH2:29][CH:30]([CH3:32])[CH3:31])CC(C)C)=O>[Pd]>[C:29](=[N:24][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH3:11])[NH:12][C:13](=[O:16])[CH2:14][O:10][CH2:9]2)[CH:7]=1)([C:30]1[CH:31]=[CH:11][CH:8]=[CH:9][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCSC(=O)N(CC(C)C)CC(C)C
Reactant: CC(CO)(NC(=O)CCl)c1cc(Br)ccc1F
Agent: [Pd]
Agent: [K]
Product: CC1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(=O)N1

Procedure:
In a reaction sequence analogous to that described for the preparation of the optically active Building block H, the cyclization of the (RS)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide with potassium tent-butylate, followed by the palladium-catalyzed amination yielded the (RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one. Its reaction with Lawesson's reagent and the following treatment with hydrochloric acid yielded the title compound as a light yellow solid. Mass (calculated) C11H13FN2OS.ClH [276.762]; (found) [M+H]+=241.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=1>>[Br:15][C:10]1[CH:11]=[CH:12][C:13]([OH:14])=[C:8]([C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:9]=1
Reactant: C=C1CCCCC1
Reactant: Oc1ccc(Br)cc1
Product: CC1(c2cc(Br)ccc2O)CCCCC1
Temperature: 80 °C
Yield: 18.6 %

Procedure:
A mixture of methylene cyclohexane (0.96 g, 10 mmoles), p-bromophenol (1.73 g, 10 mmoles) and acid resin (Dowex 50×12--150 mg) is heated at 80° C. for 16 hours. The residue is purified by silica gel chromatography (eluant: 50/50 mixture of CH2Cl2 /hexane). On evaporation of the solvents 0.50 g (19% yield) of 4-bromo-2-(1-methylcyclohexyl) phenol in the form of a yellowish oil is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:41].[NH2:42][CH:43]1[CH2:48][CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45][CH2:44]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:41]
Reactant: Cc1cc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3ccc(=O)n4-c3c(F)cccc3F)c2)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1cc(C(=O)Nc2ccc(C)c(-c3nc(NC4CCNCC4)nc4c3ccc(=O)n4-c3c(F)cccc3F)c2)ccc1F

Procedure:
The title compound was prepared as described in Example 2 from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-4-fluoro-3-methylbenzamide and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate: LC-MS m/z 599 (M+H)+, 1.98 min (ret time).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH3:42][C:43]1([CH3:52])[CH2:48][CH:47]([NH2:49])[CH2:46][C:45]([CH3:51])([CH3:50])[NH:44]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:49][CH:47]5[CH2:48][C:43]([CH3:52])([CH3:42])[NH:44][C:45]([CH3:51])([CH3:50])[CH2:46]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CC(C)(C)NC(C)(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.12 mL (0.66 mmole) of ethyldiisopropyl amine and 0.039 g (0.25 mmole) of 2,2,6,6-tetramethyl-piperidin-4-ylamine in 2.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 0.065 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2,2,6,6-tetramethyl-piperidin-4-yl)-benzamide (I-65) as a white solid.