Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[CH2:16][CH3:17])/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.O[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[C:10](\[CH2:16][CH3:17])/[CH:11]=[CH:12]/[C:13]([N:26]2[CH2:27][CH2:28][CH2:23][CH2:24][CH2:25]2)=[O:15])=[CH:7][CH:8]=1
Reactant: CCC(/C=C/C(=O)O)=C\c1ccc(OC)cc1
Reactant: OC1CCNCC1
Solvent: O=S(Cl)Cl
Product: CCC(/C=C/C(=O)N1CCCCC1)=C\c1ccc(OC)cc1

Procedure:
The title compound was prepared from 4-methoxybenzaldehyde (5.2 g, 38 mmol) by subjecting it to Grignard's reaction with 1-n-bromopropane by the method described in example 1(i) to give 1-(4-methoxyphenyl)-n-butanol of formula 3 (6.7 g, yield 98%). The secondary alcohol (5.55 g, 30 mmol) was subjected to Vilsmeier reaction with dimethyl formamide-phosphorous oxychloride as described in example 1 (ii) to furnish 2-formyl-1-(4-methoxyphenyl)-1-butene of formula 4 (4.0 g, 70%). The resulting aldehyde (3.8 g, 20 mmol) was subjected to Wittig reaction as described in example 1 (iii) followed by saponification to produce 5-(4-methoxyphenyl)-4-ethyl-2E,4E-pentadienoic acid of formula 6(3.0 g, 65%). The pentadienoic acid (1.0 g, 4.3 mmol) after acid chloride formation with thionyl chloride, and reaction with 4-hydroxypiperidine was purified by column chromatography on silica gel to give 5-(4-methoxyphenyl)-4-ethyl-2E,4E-pentadienoic acid piperidide of formula 1a (0.84 g, 60%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[S:20]1[CH:24]=[CH:23][C:22]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)=[CH:21]1
Reactant: OB(O)c1ccsc1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2ccsc2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 2 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and thiophene-3-boronic acid. The title compound (118 mg) was obtained as a pale solid, m/z 347 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:15]=3)[CH:8]=[C:7]([OH:20])[C:6]=12.CS(O[C@H:26]([C@@H:28]1[CH2:32][C:31](=[O:33])[N:30]([C@@H:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH3:35])[CH2:29]1)[CH3:27])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([C:16]([CH3:17])([CH3:19])[CH3:18])[CH:15]=3)[CH:8]=[C:7]([O:20][C@@H:26]([C@H:28]3[CH2:29][N:30]([C@@H:34]([C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[CH3:35])[C:31](=[O:33])[CH2:32]3)[CH3:27])[C:6]=12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)OS(C)(=O)=O)CC2=O)cc1
Reactant: CC(C)(C)n1cc(-c2cc(O)c3c(Br)cnn3c2)cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4cnn(C(C)(C)C)c4)cn4ncc(Br)c34)CC2=O)cc1
Temperature: 90 °C

Procedure:
To an appropriate sized microwave vial, 3-bromo-6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (60 mg, 0.18 mmol), (S)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethyl methanesulfonate 1.30 (73 mg, 0.21 mmol), cesium carbonate (82 mg, 0.25 mmol) and DMF were added. The mixture was heated at 90° C. for 2 h. After cooling to room temperature, the mixture was poured into a saturated aqueous solution of NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford (R)-4-((R)-1-(3-bromo-6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.30.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[BH4-].[Na+].Cl>COCCOC.O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(Oc2cccc(C=O)c2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1cccc(Oc2cccc(CO)c2)c1
Reaction time: 4 h
Yield: 82.6 %

Procedure:
3-(3-Methylphenoxy)benzaldehyde (5.80 g, 27.3 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (30 mL) and tetrahydrofuran (30 mL), sodium borohydride (0.567 g, 15.0 mmol) was added under ice-cooling and the mixture was stirred at the same temperature for 4 hrs. Dil. hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound (4.83 g, yield 83%) as a pale-yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[CH:23]=[CH:22][C:16]([C:17](OCC)=[O:18])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1>C(OCC)C>[F:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[CH:23]=[CH:22][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
Lithium aluminum hydride (0.25 g, 6.69 mmol) was slurried in 20 ml of dry diethyl ether and cooled in an ice bath. The ethyl 4-(4-fluorophenoxy)benzoate (2.32 g, 8.91 mmol) in 5 ml of dry diethyl ether was added dropwise and the reaction was stirred at room temperature overnight. More lithium aluminum hydride (0.25 g) was added and the reaction was stirred for four hours. The reaction was carefully quenched by sequential addition of 0.5 ml of water, 0.5 ml of 15% NaOH solution in water, and 1.5 ml of water. The resulting white precipitate was filtered using celite and washed with diethyl ether and discarded. The filtrate and washings were combined and concentrated to afford 1.92 g (99%) of the subtitle compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33])=[CH:25][CH:24]=3)[C@@H:14]([CH3:36])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:37][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:35])[C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][CH2:31][C:32]([OH:34])([CH3:37])[CH3:33])=[CH:27][CH:28]=3)[C@@H:14]([CH3:36])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCCC(C)(C)O)cc2)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of N-(4-chlorophenyl)-N-((2S,4R)-2-methyl-1-(4-(4-oxopentyl)benzoyl)-1,2,3,4-tetrahydroquinolin-4-yl)acetamide (40 mg, 0.079 mmol) in THF (2 mL), was added MeMgBr (68 uL, 0.095 mmol, 1.4 M solution in THF) at 0° C. The mixture was stirred at 0° C. for 2 h. After quenching with sat. NH4Cl solution, the mixture was extracted with EtOAc. The combined organic phases were dried over MgSO4 and concentrated. The residue was purified by column chromatography (EtOAc) to give 16 mg of desired product as a white solid (40% yield).
Reaction SMILES: [C:1]([CH:3]=[C:4]([C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([NH:21][C:22](=[O:24])[CH3:23])[CH:20]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)#[N:2].N[C:28]1C=C(C(C2C=CC(OC)=C(OCC)C=2)=CC#N)C=CC=1OC.C(Cl)(=O)C>CCCCCC>[C:1]([CH:3]=[C:4]([C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([NH:21][C:22](=[O:24])[CH3:23])[CH:20]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:14][CH3:28])[CH:6]=1)#[N:2]
Reactant: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1NC(C)=O
Reactant: CCOc1cc(C(=CC#N)c2ccc(OC)c(N)c2)ccc1OC
Solvent: CCCCCC
Solvent: CC(=O)Cl
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(NC(C)=O)c2)ccc1OC
Yield: 41 %

Procedure:
N-{5-[2-Cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide (E and Z isomers) were prepared analogously to N-{5-[2-cyano-1-(3,4-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide using 3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.4 g, 1.1 mmol) and acetyl chloride (1.1 mL). The crude product was slurried with hexane to give N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide (0.2 g, 41%) as a white solid: mp 155-157° C.; 1H NMR (CDCl3) δ 9.25 (d, J=2 Hz, 1H), 7.90 (d, 13.5 Hz, 1H), 7.17-6.90 (m, 3H), 6.75 (d, J=1 Hz, 1H), 6.13 (s, 1H), 5.97 (s, 1H), 4.02-3.97 (m, 2H), 3.94-3.97 (m, 6H), 2.07 (d, J=7 Hz, 3H), 1.70 (t, 3H); 13C NMR (CDCl3) δ 161.29, 151.18, 150.02, 147.76, 147.32, 130.47, 130.23, 129.18, 128.91, 127.26, 127.22, 122.40, 122.18, 118.77, 118.70, 113.81, 122.20, 111.43, 111.34, 111.04, 110.77, 92.73, 92.45, 63.76, 63.71, 55.87, 55.41, 23.80, 23.68, 14.57; Anal Calcd for C21H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C, 68.94, 5.93; N, 7.53.
Reaction SMILES: BrC[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].C(N(CC)CC)C.Cl>O1CCCC1>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[C:5]1[CH:14]=[CH:15][CH:16]=[CH:3][CH:4]=1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 1374.3 %

Procedure:
The free base of 2-isopropoxyphenyl piperazine was prepared by treatment of the fumarate salt with aqueous bicarbonate followed by extraction into chloroform, to provide a brown oil (7.28 g, 33.0 mmol) which was dissolved in 75 mL of tetrahydrofuran. To this solution was added a solution of 3-(bromomethyl)benzophenone (10.0 g, 3.63 mmol) in 75 mL of tetrahydrofuran followed by triethylamine (5.53 mL, 39.6 mmol). The reaction mixture was refluxed for 19 h. After cooling to ambient temperature the reaction mixture was poured into 1N HCl solution. After washing with ether, the aqueous solution was basified with solid K2CO3 and extracted with chloroform. The chloroform extracts were combined, dried (Na2SO4), and concentrated to provide a dark brown oil which was purified on a Waters 500A Prep LC apparatus (1% hexanes-chloroform) to afford 9.09 g of pure benzophenone intermediate as a brown oil. The oil was dissolved in acetone and treated with concentrated HBr (2.5 mL). When diethyl ether was added, a fine white precipitate fell out of solution. This solid was recrystallized from acetone/ether to provide 4.59 g of a white solid. A second crop of crystals was also collected. These were combined to provide 7.94 g (46%) of aryl piperazine benzophenone intermediate, mp 193°-197° C. The 1H NMR in CD3OD supported the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17](C(O)=O)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:25][CH3:26])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:62]([O:64][C:65]([C:67]1[CH:68]=[C:69]2[N:75]=[C:74](C3C=C4C(=CC=3)N=C(C3C=CC=CC=3Br)C=C4)[N:73]([CH:93]3[CH2:98][CH2:97][CH2:96][CH2:95][CH2:94]3)[C:70]2=[N:71][CH:72]=1)=[O:66])[CH3:63]>CN(C=O)C.CC(O)=O>[CH2:62]([O:64][C:65]([C:67]1[CH:68]=[C:69]2[N:75]=[C:74]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[N:13]=[C:12]([C:11]3[C:6]([C:5]5[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=5)=[CH:7][CH:8]=[C:9]([O:25][CH3:26])[CH:10]=3)[CH:21]=[CH:20]4)[N:73]([CH:93]3[CH2:98][CH2:97][CH2:96][CH2:95][CH2:94]3)[C:70]2=[N:71][CH:72]=1)=[O:66])[CH3:63]
Reactant: CCOC(=O)c1cnc2c(c1)nc(-c1ccc3nc(-c4ccccc4Br)ccc3c1)n2C1CCCCC1
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(C(=O)O)ccc3n2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Yield: 40 %

Procedure:
The amine was reacted with Compound 525c (0.314 g, 0.805 mmol) in the presence of HBTU (0.32 g, 0.844 mmol) and DIEA (0.47 mL, 2.68 mmol) in DMF (10 mL), followed cyclization in AcOH (10 mL) according to procedure (2) and (3) in the preparation of Compound 477d. Separation by RP HPLC (from 20% of buffer B to 99% of buffer B) gave the title intermediate (0.19 g, 40%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[CH:19]=[CH:20][C:5]([O:4][CH2:3][CH2:2][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:6][C:7]=3[S:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1COCCN1
Product: Brc1ccc(-c2nsc3cc(OCCN4CCOCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and morpholine were converted to yield 3-(4-Bromo-phenyl)-6-(2-morpholin-4-yl-ethoxy)-benzo[d]isothiazole, MS: 420 (MH+, 1Br).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:31][CH2:32][C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)C(CCC)=C(C(OC)=O)C(C2C=CC(C(F)(F)F)=CC=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])[CH2:2][CH3:3].NCCC1SC=CC=1.C(CC(OC)=O)(=O)CCC>>[S:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[CH2:32][CH2:31][NH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CCCC1=C(C(=O)OC)C(c2ccc(C(F)(F)F)cc2)C(C(=O)OC)=C(CCC)N1CCc1cccs1
Agent: CCCC(=O)CC(=O)OC
Agent: NCCc1cccs1
Product: CCCC(=CC(=O)OC)NCCc1cccs1

Procedure:
In a manner similar to that described in the preceding examples, dimethyl 2,6-di-(n-propyl)-4-(4-trifluoromethylphenyl)-1-[2-(2-thienyl)ethyl]-1,4-dihydropyridine-3,5-dicarboxylate is prepared by the reaction of (a) 2-(2-aminoethyl)thiophene and methyl butyrylacetate to obtain methyl 3-[2-(2-thienyl)ethyl]amino-2-hexenoate and (b) reacting the ester so obtained with 4-trifluoromethylbenzaldehyde in the presence of 2-(2-aminoethyl)thiophene and titanium tetrachloride.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Cl.[C:13]([N:17]1[CH:21]=[C:20]([CH2:22]Cl)[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14].O>CN(C)C=O>[C:13]([N:17]1[CH:21]=[C:20]([CH2:22][CH:2]([C:1]#[N:5])[C:3]#[N:4])[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: N#CCC#N
Reactant: CC(C)(C)n1cc(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1cc(CC(C#N)C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
5.95 g of malononitrile was dissolved in 30 ml of N,N-dimethylformamide, and 12.44 g of potassium carbonate was then added under ice-cooling. Thereto a solution of 6.27 g of 1-t-butyl-4-(chloromethyl)-1H-pyrazole hydrochloride in 30 ml of N,N-dimethylformamide was added dropwise over 1 hour. After completion of the addition, the mixture was stirred at room temperature for 8 hours. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 4.12 g of [(1-t-butyl-1H-pyrazol-4-yl)methyl]malononitrile.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[N+:14]([O-])=O)C.CCO>C1COCC1.[Ni]>[Br:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]2[C:8]=1[NH:14][C:4](=[O:3])[CH2:5][NH:6]2
Reactant: CCOC(=O)CNc1cccc(Br)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1CNc2cccc(Br)c2N1

Procedure:
10.33 g (ca. 25.9 mmol) (3-Bromo-2-nitro-phenylamino)-acetic acid ethyl ester is hydrogenated in the presence of 2.84 g Ra—Ni (B113W EtOH, Degussa) in 340 ml of THF:EtOH=1:1 for 20 h. The reaction mixture is filtered on hyflo and the filtrate is concentrated in vacuo. A mixture of the title compound with uncyclized (2-Amino-3-bromo-phenylamino)-acetic acid ethyl ester is obtained and used as obtained in the next synthetic step.
Reaction SMILES: FC1C=C(F)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:37]2[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:36]=2[F:35])=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: O=C(N=C=S)c1ccc(F)cc1F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4F)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
2,4-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-difluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (50 mg, yield 63%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:20][O:21]C(Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.Cl>ClCCl.O>[CH:20]([C:5]1[C:6]([OH:8])=[CH:7][C:2]([OH:1])=[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:21]
Reactant: COC(Cl)Cl
Reactant: COC(=O)Cc1cc(O)cc(O)c1-c1ccccc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1c(C=O)c(O)cc(O)c1-c1ccccc1
Temperature: 4 °C
Reaction time: 0.08 h
Yield: 75.6 %

Procedure:
Compound 1 (0.25 g, 0.97 mmol) obtained in Example 1 was dissolved in dichloromethane (10 mL), and the solution was cooled to 4° C., and then dichloromethyl methyl ether (0.13 mL, 1.4 mmol) and tin(IV) chloride (0.17 g, 1.5 mmol) were added thereto and stirred at 4° C. for 5 minutes. Water (10 mL) and 3 mol/L hydrochloric acid (10 mL) were added to the reaction mixture, and extracted with chloroform (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The residue was purified through preparative thin-layer chromatography (n-hexane/ethyl acetate=1/2) and crystallized (n-hexane/ethyl acetate=1/2) to obtain Compound 55 (0.21 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)[C:6]([N+:16]([O-])=O)=[CH:5][C:4]=1[NH:19][C:20]1[N:25]=[C:24]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=23)[CH:23]=[CH:22][N:21]=1.[NH4+].[Cl-]>[Fe].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)[C:6]([NH2:16])=[CH:5][C:4]=1[NH:19][C:20]1[N:25]=[C:24]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=23)[CH:23]=[CH:22][N:21]=1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Yield: 76.4 %

Procedure:
A mixture of N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 151, 285 mg, 0.56 mmol), iron (188 mg, 3.36 mmol), NH4Cl (21 mg, 0.39 mmol) ethanol (10.5 mL) and water (3.5 mL) was heated at reflux for 1.5 h. The reaction was judged to be incomplete so further NH4Cl (21 mg, 0.39 mmol) and iron (188 mg, 3.36 mmol) were added and the mixture was heated at reflux for a further 1.5 h. After cooling, the mixture was filtered and concentrated in vacuo. Purification by FCC, eluting with 2-10% 7N methanolic ammonia in CH2Cl2 gave the title compound (183 mg, 69%) as an orange gum which was used without further purification; 1H NMR: 2.30 (3H, s), 2.36-2.45 (2H, m), 2.60 (2H, t), 2.98-3.06 (2H, m), 3.74 (3H, s), 4.34 (2H, s), 5.73 (1H, s), 6.64 (1H, s), 7.09 (1H, m), 7.26 (1H, d), 7.38-7.49 (2H, m), 8.00 (1H, s), 8.35 (1H, d), 8.58 (1H, d), 8.80 (2H, m); m/z: ES+ MH+ 427.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(CN[C@H]2CCCc3ccccc32)cc1Cl

Procedure:
3,4-Dichlorobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH:26][C:27]([NH2:29])=[NH:28])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>CO.O>[NH:26]([O:25][CH2:24][CH2:23][O:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[N:13]([CH:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:5][C:4]([OH:30])=[O:3])[CH:14]=[CH:15]2)[C:27]([NH2:29])=[NH:28]
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCONC(=N)N)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N=C(N)NOCCOc1ccc2c(ccn2C(CC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
3-(5-{2-[guanidino-oxy]-ethoxy}-indol-1-yl)-3-phenyl-propionic acid ethyl ester (0.30 gg, 0.71 mmol) was dissolved in 70% methanol/water (4 mL) and lithium hydroxide monohydratate (0.70 g , 4.67 mmol) was added. The reaction was stirred for 16 h at room temperature under an argon atmosphere. The solution was neutralized with 1.0 N HCl (4.67 mL) and the solvent was evaporated under vacuum. The crude mixture was purified via column chromatography with silica gel, eluting with 10% methanol/dichloromethane to afford the title compound (80% yield). 1H NMR (CD3OD-d4) δ 7.34 (d, 1H, J=3.2 Hz). 7.06–7.15 (m, 6H), 6.97 (d, 1H, J=2.3 Hz), 6.65 (dd, 1H, J=2.5, 9.0 Hz), 6.31 (d, 1H, J=3.2 Hz), 5.93 (t, 1H, J=7.0 Hz), 4.01 (m, 4H), 3.07 (m, 2H).