Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[S:10]([CH:13]1[CH2:17][CH2:16][O:15]C1=O)(=[O:12])=[O:11].[Si]([O:26][CH2:27][C@H:28]([CH3:46])[O:29][C:30]1[CH:31]=[C:32]([CH:42]=[C:43]([OH:45])[CH:44]=1)[C:33]([NH:35][C:36]1[CH:40]=[CH:39][N:38]([CH3:41])[N:37]=1)=[O:34])(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:9][C:5]1[C:6]([O:45][C:43]2[CH:42]=[C:32]([CH:31]=[C:30]([O:29][C@@H:28]([CH3:46])[CH2:27][OH:26])[CH:44]=2)[C:33]([NH:35][C:36]2[CH:40]=[CH:39][N:38]([CH3:41])[N:37]=2)=[O:34])=[CH:7][C:2]2[O:15][CH2:16][CH2:17][CH2:13][S:10](=[O:11])(=[O:12])[C:3]=2[CH:4]=1
Reactant: O=C1OCCC1S(=O)(=O)c1cc(F)c(F)cc1F
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(Oc2cc3c(cc2F)S(=O)(=O)CCCO3)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 150 °C
Yield: 34.3 %

Procedure:
A solution of 3-[(2,4,5-trifluorophenyl)sulfonyl]dihydrofuran-2(3H)-one (126 mg, 0.45 mmol) and 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (203 mg, 0.50 mmol) in acetonitrile (3.5 mL) was treated with caesium carbonate (650 mg, 2.0 mmol) and heated in a microwave reactor at 150° C. for 1.5 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was then chromatographed on silica, eluting with a gradient of 0 to 10% methanol in ethyl acetate, to afford the title compound (78 mg).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:34])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(3-Chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.BrCC1CCCCO1.[CH3:22][C:23]1[C:27]2[CH:28]=[C:29]3[C:34]4([C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[NH:36][C:35]4=[O:43])[CH2:33][O:32][C:30]3=[CH:31][C:26]=2[O:25][N:24]=1>>[O:13]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:36]3[C:37]4[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:34]4([C:29]5[C:30](=[CH:31][C:26]6[O:25][N:24]=[C:23]([CH3:22])[C:27]=6[CH:28]=5)[O:32][CH2:33]4)[C:35]3=[O:43])=[CH:4][CH:5]=2)=[CH:10][CH:11]=[N:12]1
Reactant: BrCc1ccc(-c2ccno2)cc1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(-c3ccno3)cc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-(4-(bromomethyl)phenyl)isoxazole (0.20 g, 0.84 mmol) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(4-isoxazol-5-ylbenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one was obtained (60%) as a colorless solid: mp 192-194° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.25 (d, J=1.8 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.6 Hz, 1H), 7.27-7.09 (m, 2H), 7.02-6.95 (m, 2H), 6.75 (d, J=7.8 Hz, 1H), 6.50 (d, J=1.8 Hz, 1H), 5.32 (d, J=16.2 Hz, 1H), 5.15 (d, J=9.1 Hz, 1H), 4.89 (d, J=9.1 Hz, 1H), 4.83 (d, J=16.2 Hz, 1H), 2.45 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 169.0, 164.0, 158.2, 155.0, 150.8, 141.9, 137.4, 130.5, 129.4, 127.8, 126.8, 123.8, 123.7, 123.1, 118.0, 109.7, 108.9, 108.0, 98.9, 81.4, 56.4, 53.5, 44.1, 9.8; MS (ES+) m/z 449.9 (M+1).
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:16](=[O:19])(=[O:18])[NH2:17])[C:14]=1[Cl:15])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl.[CH2:21](O)[CH3:22]>>[CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:16](=[O:18])(=[O:19])[NH2:17])[C:14]=1[Cl:15])[C:9]([O:11][CH2:21][CH3:22])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cl
Reactant: CCO
Agent: Cl
Product: CCCCSc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Cl

Procedure:
3-Butylthio-4-chloro-5-sulfamylbenzoic acid (1.8 g) in a saturated solution of hydrogen chloride in ethanol (40 ml) is stirred for 18 hours. The precipitate is collected by filtration and washed with ethanol and petroleum ether to yield ethyl 3-butylthio-4-chloro-5-sulfamylbenzoate with a melting point of 160° - 162°C.
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[C:9]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)O)=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2>N1C=CC=CC=1>[CH3:1][N:2]1[S:3](=[O:5])(=[O:4])[NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[CH:11]=[CH:10][C:9]=2[CH:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(O)c2ccccc2)ccc2cccnc12
Solvent: c1ccncc1
Product: CN1C(c2ccccc2)c2ccc3cccnc3c2NS1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.7 %

Procedure:
N-Methylsulfamoyl chloride (414 mg, 3.2 mmol) was added to a suspension of (8-amino-quinolin-7-yl)-phenyl-methanol (Intermediate 215) (200 mg, 0.8 mmol) in pyridine (5 ml) and the reaction was stirred at room temperature for 16 h. The solution was concentrated in vacuo. The crude residue was purified by column chromatography, with heptane/EtOAc (90:10-50:50) gradient elution to give the title compound (20 mg, 8%).
Reaction SMILES: Br[C:2]1([Cl:14])[CH2:7][CH:6]=[CH:5][CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.CCCCCC.CON(C)[C:29]([C@@H:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]1)=[O:30]>C1COCC1>[C:40]([O:39][C:37]([N:33]1[CH2:34][CH2:35][CH2:36][C@@H:31]([C:29](=[O:30])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:14])[CH2:32]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: ClC1(Br)CC=CC=C1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2-c2ccccc2Cl)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a solution of 2-bromo-2-chloro-biphenyl (5.34 g, 20 mmol) in anhydrous THF (50 mL) cooled to −78° C. was added dropwise a solution of 1.6 M n-BuLi in hexane (12.5 mL, 20 mmol). The reaction mixture was stirred at −78° C. for 1 h and a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)-piperidine-1-carboxylate (5.44 g, 20 mmol) in anhydrous THF (50 mL) was added. The mixture was allowed to warm to rt and stirred overnight. The mixture was quenched with sat'd aq NH4Cl (100 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, which was purified by flash column chromatography to afford (3R)-1-(tert-butoxycarbonyl)-3-((2-(2-chlorophenyl))benzoyl)piperidine (4.43 g, 55%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[N:22]1([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:25]4[CH2:26][CH2:27][N:22]([C:28]5[N:29]=[CH:30][CH:31]=[CH:32][N:33]=5)[CH2:23][CH2:24]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ncccn2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-piperazin-1-yl-pyrimidine in ethanol, essentially as described above in Example 70. Purity by LC/MS=-100%, [M+H]+=450.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:46]1[CH2:51][CH2:50][CH2:49][C@@H:48]([NH:52][C:53]2[CH:58]=[N:57][CH:56]=[C:55]([C:59]3[CH:60]=[N:61][N:62]4[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=34)[N:54]=2)[CH2:47]1>CN(C=O)C>[O:12]=[C:10]([N:46]1[CH2:51][CH2:50][CH2:49][C@@H:48]([NH:52][C:53]2[CH:58]=[N:57][CH:56]=[C:55]([C:59]3[CH:60]=[N:61][N:62]4[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=34)[N:54]=2)[CH2:47]1)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccn2ncc(-c3cncc(N[C@@H]4CCCNC4)n3)c2c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
[(Tert-Butoxycarbonyl)amino]acetic acid (65 mg, 0.37 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (142 mg, 0.37 mmol) and diisopropylethylamine (65 mL, 0.37 mmol) were added to a solution of (R)—N-(piperidin-3-yl)-6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-amine (Preparation 28b, 100 mg, 0.34 mmol) in N,N′-dimethylformamide (2 mL) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water and the organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by reverse phase chromatography (C-18 silica from Waters, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to yield the title compound (88 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ncccn1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ncccn2)cn1
Yield: 58 %

Procedure:
As described for Example 46, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (97 mg, 0.4 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (75 mg, 58%) as a light yellow solid. MS: m/e=322.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.CCO>[Pd].C(OCC)(=O)C>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1ccc(O)c(N)c1
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A mixture of 4-hydroxy-3-nitrobenzonitrile (100 mg, 0.61 mmol), palladium on charcoal (10 mg, 10%), EtOH (0.67 mL) and ethyl acetate (0.33 mL) was hydrogenated at rt for 2 h. Then the mixture was filtered and concentrated to give 3-amino-4-hydroxybenzonitrile 60 mg (73%) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:10][C:11]([NH:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][N:15]=1)=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].CC#N>C(Cl)Cl>[CH3:21][O:20][C:18]1[C:17]([O:22][CH3:23])=[CH:16][N:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[N:19]=1
Reactant: COc1cnc(NC(=O)CCl)nc1OC
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cnc(NC(=O)Cn2cc([N+](=O)[O-])cn2)nc1OC
Temperature: 80 °C

Procedure:
A flask was charged with 4-nitro-1H-pyrazole (A) (317 mg, 2.8 mmol), 2-chloro-N-(4,5-dimethoxypyrimidin-2-yl)acetamide (2.26 mmol), Cs2CO3 (1.0 g, 3.09 mmol) and MeCN (9.0 mL). The resulting reaction mixture was stirred at reflux (80° C.) for 1 h, then allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM. The filtercake was redisolved in DCM and water, the org. layer was separated and the aq. layer was extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4), filtered and concentrated to yield N-(4,5-dimethoxypyrimidin-2-yl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide as a crude which was used in the next step without further purification. LC-MS conditions B: tR=0.46 min, [M+H]+=309.10.
Reaction SMILES: [Li]C(CC)C.CN(CCN(C)C)C.[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]2[C:20]([CH3:24])([CH3:23])[CH2:21][O:22][C:18]=2[CH:17]=1.[Li].[B:28](OC)([O:31]C)[O:29]C>C1COCC1>[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]2[C:20]([CH3:24])([CH3:23])[CH2:21][O:22][C:18]=2[C:17]=1[B:28]([OH:31])[OH:29]
Reactant: COc1ccc2c(c1)OCC2(C)C
Reactant: COB(OC)OC
Agent: CN(C)CCN(C)C
Agent: [Li]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1B(O)O)OCC2(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
s-BuLi (35 mL, 1.3M in cyclohexane) was added to TMEDA (6.6 mL) at −78° C. drop wise within 30 min, 20 mL of THF was added to keep stirring. After 20 min, 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran (5.4 g, 30.3 mmol) in THF (30 mL) was added into the lithium solution slowly. The solution was stirred at −78° C. for 1.5 h and trimethyl borate (18 mL) was added. The mixture was warmed to room temperature and stirred at room temperature overnight. The solution was acidified to pH=5-6 and extracted with ethyl acetate. The organic layer was concentrated and the resulted residue was purified on column chromatography (silica gel, dichloromethane/petroleum ether=3/1) to give the crude product, which was sonicated with petroleum ether. The white precipitate was filtered and dried to give 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-ylboronic acid (3.55 g, 53%) as a white solid.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>CN(C)C=O>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(Cc3cnc(N)nc3N)CC2)cc1
Temperature: 25 °C
Reaction time: 110 h
Yield: 51.1 %

Procedure:
A solution of 0.87 g (0.00493 mol) of 1-p-tolyl-piperazine in 30 ml of dimethylformamide was treated with 1.37 ml (0.00986 mol) of triethylamine and 0.60 g (0.00164 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 110 hours. The mixture was completely freed from the solvents. The residue was chromatographed over silica gel with methanol as the eluent, digested in dichloromethane/water 1:1 and subsequently filtered off under suction. 0.25 g (51%) of 5-(4-p-tolyl-piperazin-1-ylmethyl)-pyrimidine-2,4-diamine was obtained as beige crystals; m.p. 248°-250°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([I:31])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[Se](=O)=[O:33]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:33])[C:5]2[C:9]([I:31])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: O=[Se]=O
Reactant: Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 53.1 %

Procedure:
6-Chloro-3-iodo-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (20 g, 37.3 mmol) was dissolved in dioxane (400 mL) and selenium dioxide (12.43 g, 112 mmol) was added. The reaction mixture was stirred at 100° C. for 6 hrs. Selenium dioxide (4.14 g, 37.3 mmol) was added and the reaction mixture continued stirring at 100° C. overnight. The reaction was filtered over celite, rinsed with DCM, and concentrated in vacuo. The residue was dissolved in DCM (1.0 L) and filtered over celite. The material was concentrated in vacuo while loading on silica gel. Purification by flash chromatography (0-5% DCM/EtOAc) gave 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (10.88 g, 19.79 mmol, 53.0%). 1H NMR (ppm, 500 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.39-7.35 (m, 10H), 7.17-7.11 (m, 5H), 6.29 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:19].[Na+:20]>>[NH2:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:19])=[O:1].[Na+:20]
Reactant: [OH-]
Reactant: O=C1Cc2cccc(Oc3ccccc3Cl)c2N1
Agent: [Na+]
Product: Nc1c(CC(=O)[O-])cccc1Oc1ccccc1Cl

Procedure:
Thus obtained 2-oxo-7-(2-chlorophenoxy)indoline was treated successively with sodium hydroxide in a similar manner to that of Example 29 to give sodium 2-[2-amino-3-(2-chlorophenoxy)phenyl]acetate, which was identified with the crop obtained in Example 5-(2) by I.R. and N.M.R. spectra.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C.[CH3:24][O:25][CH2:26]Cl>O1CCCC1>[CH3:24][O:25][CH2:26][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: CC(C)=CCc1cc(C=O)ccc1O
Reactant: COCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C=O)cc1CC=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Then, 7.0 g of the so-obtained 4-hydroxy-3-(3-methyl-2-butenyl)benzaldehyde was dissolved in 70 ml of tetrahydrofuran, and 19.25 g of N,N-diisopropylethylamine was added to the solution and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction liquid was cooled to 0° C. and 7.0 ml of chloromethyl methyl ether was dropped into the reaction liquid, and the mixture was stirred at room temperature overnight. Then, the reaction liquid was poured into ice water, and the organic layer was extracted with ether, washed with water, dried with anhydrous sodium sulfate, and filtered. The obtained residue was subjected to the column chromatography (260 g of 200-400 mesh Kieselgel 60, hexane/ethyl acetate=6/1, 0.4 kg/cm2), fractions of 50 ml were recovered in sequence, and the 14th to 24th fractions were combined to obtain 7.85 g (yield=91.1%) of 4-methoxymethoxy-3-(3-methyl-2-butenyl)benzaldehyde in the form of a colorless liquid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][S:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]([CH2:39][C@H:40]([OH:50])[C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-])=O)=[CH:43][CH:42]=3)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:25][CH:24]=2)=[CH:19][C:18]=1[O:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)=[O:16])(=[O:13])=[O:12])C1C=CC=CC=1.C([O-])=O.[NH4+].CO>[Pd].O>[NH2:47][C:44]1[CH:45]=[CH:46][C:41]([C@@H:40]([OH:50])[CH2:39][N:31]([CH2:30][CH2:29][C:26]2[CH:27]=[CH:28][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:15]([NH:14][S:11]([CH2:10][CH2:9][OH:8])(=[O:13])=[O:12])=[O:16])=[C:18]([O:51][CH:52]4[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]4)[CH:19]=3)=[CH:24][CH:25]=2)[C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCOCc3ccccc3)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCO)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccc(N)cc1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
A mixture of tert-butyl [2-[4′-[[[[2-(benzyloxy)-ethyl]sulfonyl]amino]carbonyl]-3′-(cyclohexyloxy)-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-(4-nitrophenyl)ethyl]-carbamate (215 mg), 10% palladium on activated carbon (50% wet, 645 mg), ammonium formate (845 mg), methanol (6.45 ml) and water (0.65 ml) was refluxed for 20 minutes. After cooling to room temperature, the catalyst was removed by filtration and washed with methanol. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give tert-butyl [(2R)-2-(4-aminophenyl)-2-hydroxyethyl][2-[3′-(cyclohexyloxy)-4′-[[[(2-hydroxyethyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl]-carbamate (123 mg) as a pale-yellow solid.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]2[C:19]([C:20]=1[CH2:21][C:22]([NH2:24])=O)=[CH:18][CH:17]=[CH:16][CH:15]=2)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[C:2]1([C:1]2[N:13]3[C:14]4[C:19]([C:20]([CH2:21][C:22]#[N:24])=[C:12]3[CH2:11][CH2:10][N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1c(CCNC(=O)c2ccccc2)[nH]c2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCc1c2n(c3ccccc13)C(c1ccccc1)=NCC2

Procedure:
1.6 g (0.005 mol) of 2-(benzoylamino-ethyl)-indole-3-acetamide is heated under reflux for 2 hours in 16 ml of phosphorus oxychloride. Excess phosphorus oxychloride is distilled off, the oily residue is taken up in water and by-products of the reaction are removed by extracting with ether. Concentrated ammonia is added to the aqueous phase, while cooling, and extraction with ether is carried out. After washing and drying the ether phase and concentrating it by evaporation, 1-phenyl-3,4-dihydro-pyrimido[1,6-a]indole-5-acetonitrile is obtained as a yellowish oil which, by dissolving in methanol and adding ethereal hydrochloric acid, can be converted into a crystalline hydrochloride having a melting point of 195°-205°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[O:11][N:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]=1[CH2:7][CH2:6]2)=C.C[N+]1([O-])CC[O:24]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.[Os](=O)(=O)(=O)=O.O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[O:11][N:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]=1[CH2:7][CH2:6]2)=[O:24]
Reactant: C=Cc1ccc2c(c1)CCc1c(C(=O)OC)noc1-2
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1noc2c1CCc1cc(C=O)ccc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of methyl 7-vinyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (Preparation 45B, 65 mg, 0.255 mmol) in THF (4 mL) were sequentially added N-methylmorpholine-N-oxide in water (0.084 mL, 0.407 mmol) and osmium tetroxide in water (0.062 mL, 10.19 μmol) at room temperature. The solution was stirred vigorously at room temperature overnight. Sodium periodate (109 mg, 0.509 mmol) in water (1 mL) was added and the mixture was stirred at room temperature under nitrogen for two hours. Water (2 mL) was then added and the mixture was concentrated to remove THF. The resulting solid was filtered, washed with water (2×2 mL), and dried to give 72 mg of product as a yellow solid. The compound had an HPLC ret. time=0.88/2.0 min. (condition E).