Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][NH2:10])[CH:7]=[N:6][CH:5]=[N:4]1.[OH-].[Na+].[Cl:13][C:14]1[C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[S:17][C:18]=1[C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:13][C:14]1[C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[S:17][C:18]=1[C:19]([NH:10][CH2:9][CH2:8][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)=[O:20]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: NCCn1cncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCn1cncn1)c1sc2ccccc2c1Cl
Reaction time: 16 h

Procedure:
A mixture of about 1.85 g of 1H-1,2,4-triazole-1ethanamine dihydrochloride, about 50 ml of methylene chloride, about 30 ml of 1N sodium hydroxide and about 2.3 g of 3-chlorobenzo-[b]thiophene carbonyl chloride was stirred for about 16 hours. A 50 ml portion of methylene chloride and about 5 ml of 1N sodium hydroxide were added and the layers were separated. The organic layer was washed twice with water dried and concentrated, giving the desired compound, mp 151°-152° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.BrCC1CCCCO1.[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]1([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]1)[C:21](=[O:27])[NH:22]2.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]1([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]1)[C:21](=[O:27])[N:22]2[CH2:7][C:4]1[S:3][C:2]([Cl:1])=[CH:6][CH:5]=1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: ClCc1ccc(Cl)s1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(Cl)s2)c2cccc(Br)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-chloro-5-(chloromethyl)thiophene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-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, 4′-bromo-1′-[1(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 85-87° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.19-7.11 (m, 2H), 6.88-6.85 (m, 2H), 6.76 (d, J=3.8 Hz, 1H), 6.47 (s, 1H), 6.06 (s, 1H), 5.87 (d, J=5.8 Hz, 2H), 4.97 (ABq, 2H), 4.91 (d, J=9.2 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.9, 157.2, 156.9, 149.3, 143.3, 142.1, 136.3, 130.3, 129.8, 127.7, 126.3, 126.0, 120.2, 116.1, 107.9, 102.6, 101.6, 93.3, 77.2, 59.5, 39.4; MS (ES+) m/z 490.3 (M+1), 488.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C>ClCCl>[N+:18]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[NH:1][CH2:2][C:3]([CH3:5])([NH2:6])[CH3:4])=[N:16][CH:15]=[CH:14][CH:13]=2)([O-:20])=[O:19]
Reactant: CC(C)(N)CN
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cccnc12
Reaction time: 8 h
Yield: 97.4 %

Procedure:
1,2-Diamino-2-methylpropane (8.4 mL, 80.0 mmol) was added to a chilled (0° C.) solution of 4-chloro-3-nitro[1,5]naphthyridine (15.2 g, 72.7 mmol) and triethylamine (20.2 mL, 145 mmol) in dichloromethane (350 mL). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was combined with water (300 mL) and heated at reflux with stirring for 1 hour. The reaction mixture was cooled and filtered. The isolated solid was washed with water and then dried under high vacuum to provide 18.5 g of N1-(3-nitro[1,5]naphthyridin-4-yl)-2-methylpropane-1,2-diamine as a bright yellow powder.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c1
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A154) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=1)[CH:19]=O>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH2:19][C:10]2[S:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH:21]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Fc1cccc(-c2cccs2)c1
Product: Fc1cccc(-c2ccc(Cc3cc(Br)ccc3F)s2)c1

Procedure:
2-(3-Fluorophenyl)thiophene obtained in Reference Example 75-(1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])(C)(C)C.CC1(C)O[C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=[O:38])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:28]([C:30]4[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=4)[C:33]#[N:34])[CH2:27][C:26](=[O:38])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccc(Cl)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (3-amino-4′-chloro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G12) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow powder (79 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:3]([N:2]([CH3:1])[C:12](=[O:13])[CH2:11][Cl:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)CCl
Reactant: CNCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C(=O)CCl
Yield: 63.2 %

Procedure:
To a vigorously stirred suspension of N-methylbenzylamine (0.260 mL, 2 mmol) in EtOAc (3 mL) and 3 mL of saturated NaHCO3 solution was added chloroacetyl chloride (0.160 mL, 2 mmol). Effervescence was observed. Once gas production had ceased, the reaction mixture was diluted with hexanes (10 mL). The phases were separated and the organic phase was washed with brine (5 mL), dried and concentrated to yield ˜0.250 g of the title compound as an oil. The crude material was used in the subsequent step without further purification.
Reaction SMILES: C(O[K])(C)(C)C.C1OCCOCCOCCOCCOCCOC1.[CH3:25][N:26]([CH2:28][CH2:29][C@H:30]([O:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)[C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[CH3:27]>S1(CCCC1)(=O)=O>[CH3:25][N:26]([CH2:28][CH2:29][CH:30]([O:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)[C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[CH3:27]
Reactant: CN(C)CC[C@H](Oc1cccc2ccccc12)c1cccs1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)O[K]
Solvent: O=S1(=O)CCCC1
Product: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Temperature: 110 °C

Procedure:
tBuOK (16.8 g), and 18-crown-6 (0.25 g) are added to a solution of (S)-N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine (31 g) in sulfolane (100 ml), bubbled with a moderate stream of nitrogen, and the mixture is stirred and heated at 110° C. for 2 hours. After cooling down to lab temperature, the mixture is diluted with water (300 ml) and the racemic product is extracted with toluene. After evaporation, 25 g (81%) of RS)-N-methyl-3-(naphthyloxy)-3-(2-thienyl)propylamine is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7](=[O:9])[CH3:8])[CH2:2]1.C(N(CC)CC)C.[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[C:7]([CH:3]1[O:4][CH2:5][CH2:6][N:1]([C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[CH2:2]1)(=[O:9])[CH3:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)C1CNCCO1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)C1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a solution of 1-(morpholin-2-yl)ethanone (3.9 g, 30.0 mmol) in DCM (60 mL) was added triethylamine (1.0 g, 10 mmol) to adjust pH 9. Then benzyl carbonochloridate (5.6 g, 33.0 mmol) and triethylamine (3.0 g, 30.0 mmol) were added and the mixture was stirred at room temperature for 16 hr. The reaction solution was added H2O (20 mL) and extracted by DCM (100 mL*3). The organic layer was concentrated and purified by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=20/1-15/1-10/1) to give benzyl 2-acetylmorpholine-4-carboxylate (5.0 g, 63%).
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C>[C:1]1([C:11]2[O:12][C:15]3[CH:16]=[C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:19][C:14]=3[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Reactant: O=Cc1nccc2ccccc12
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)Cc1ccc2nc(-c3nccc4ccccc34)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
In ethanol (5 ml), 1-isoquinolinecarbaldehyde (252 mg, 1.60 mmol) and methyl 4-amino-3-hydroxyphenylacetate (349 mg, 1.93 mmol) were stirred at room temperature for 12 hours. Iodobenzene diacetate (619 mg, 1.92 mmol) was added and the reaction mixture was stirred further at room temperature for 15 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (4:1 to 3:1, v/v) eluate fractions, methyl (2-(1-isoquinolinyl)-6-benzoxazolyl)acetate (166 mg, 33%) was obtained as a yellow amorphous substance.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[C:27]([O:31][C:32](=[O:41])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]O)([CH3:30])([CH3:29])[CH3:28]>O.ClCCl>[C:27]([O:31][C:32](=[O:41])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][I:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)CCCCCCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCCCI
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Imidazole (2.10 g, 30.9 mmol), triphenylphosphine (8.10 g, 30.9 mmol), and iodine (6.27 g, 24.7 mmol) were successively added to a dichloromethane solution (100 mL) of t-butyl-8-hydroxyoctanoate (4) (4.45 g, 20.6 mmol) at 0° C. under the argon atmosphere, and the temperature of the reaction solution was raised to room temperature, followed by stirring for 2 hours. Thereafter, water (5 mL) was added to the reaction solution, and the mixture was washed successively with a 0.1 N aqueous sodium periodate solution (50 mL), 30% aqueous hydrogen peroxide (50 mL), and saturated brine (50 mL), dried over magnesium sulfate, and concentrated. The resulting brown oily crude product (21 g) was separated and purified by silica gel column chromatography (hexane:ethyl acetate 50:1) to obtain t-butyl-8-iodooctanoate (5) as a colorless liquid substance (5.53 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42](=[O:52])[N:43]([CH2:48][CH2:49][CH2:50][CH3:51])[CH2:44][CH2:45][CH2:46][CH3:47])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:41])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[C:25]([O:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)[CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].[CH2:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:56][C@@H:55]([CH2:63][N:64]2[CH2:69][CH2:68][O:67][CH2:66][CH2:65]2)[NH:54]1>>[CH2:48]([N:43]([CH2:44][CH2:45][CH2:46][CH3:47])[C:42]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:41])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[C:25]([O:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)[CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10]([N:54]2[C@H:55]([CH2:63][N:64]3[CH2:69][CH2:68][O:67][CH2:66][CH2:65]3)[CH2:56][C:57]3[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:53]2)=[O:11])[N:4]=1)=[O:52])[CH2:49][CH2:50][CH3:51]
Reactant: c1ccc2c(c1)CN[C@H](CN1CCOCC1)C2
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN2CCOCC2)c(C)c1Cl
Yield: 72.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 91, 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(8-(2-morpholinoethoxy) naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 183B, 15 mg, 0.020 mmol) and (S)-4-((1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)morpholine (Intermediate 109, 18 mg, 0.080 mmol) were converted to the title compound (14 mg, 62%). 1H NMR (CD3OD, mixture of amide rotamers) δ 9.19-9.04 (m, 1H), 8.26-7.93 (m, 4H), 7.79-7.53 (m, 3H), 7.36-7.09 (m, 4H), 6.99 (d, J=7.7 Hz, 1H), 5.37-5.16 (m, 1H), 4.75-4.41 (m, 3.5H), 4.22-2.52 (m, 27.5H), 2.37-2.16 (m, 3H), 1.75-0.48 (m, 14H); MS(ESI+) m/z 968.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH:6]=[N:7][OH:8].[Cl:14]N1C(=O)CCC1=O>>[OH:8][N:7]=[C:6]([Cl:14])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1
Reactant: ON=Cc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Cl
Product: ON=C(Cl)c1cccc(C(F)(F)F)c1
Yield: 95.3 %

Procedure:
In a similar manner as described in Preparation Example 9, by using 3-(trifluoromethyl)benzaldehydeoxime (30.0 g, 158.60 mmol), dimethylformimide (300 mL) and N-chlorosuccinimide (23.31 g, 174.46 mmol), a pale yellow solid required compound (33.81 g, 151.22 mmol, 95%) was obtained.
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.CN1C=CC(N)=N1.C[O:33][C:34]1[CH:35]=[C:36]([C:40]2[C:41]3[CH2:54][CH2:53][N:52]([C:55]4[CH:59]=[CH:58][N:57]([CH3:60])[N:56]=4)[C:42]=3[N:43]=[C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[N:45]=2)[CH:37]=[CH:38][CH:39]=1>>[CH3:60][N:57]1[CH:58]=[CH:59][C:55]([N:52]2[C:42]3[N:43]=[C:44]([N:46]4[CH2:47][CH2:48][O:49][CH2:50][CH2:51]4)[N:45]=[C:40]([C:36]4[CH:35]=[C:34]([OH:33])[CH:39]=[CH:38][CH:37]=4)[C:41]=3[CH2:54][CH2:53]2)=[N:56]1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccn(C)n2)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Agent: Cn1ccc(N)n1
Product: Cn1ccc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)n1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 1-methyl-1H-pyrazol-3-ylamine, 4-(3-methoxy-phenyl)-7-(1-methyl-1H-pyrazol-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:21]C=2C=1.N1C2C=CC=CC=2N=C1CN(C1C2N=CC=CC=2CCC1)CCCCN>CN(C=O)C.O.C(OCC)(=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:21])=[O:7])=[CH:4][N:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(O)nc1
Agent: NCCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-hydroxynicotinic acid (0.049 g, 0.35 mmoles) in DMF (2.7 mL) was added EDC (0.083 g, 0.43 mmoles), HOBT (0.056 g, 0.41 mmoles) and N1-(1H-Benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (0.1 g, 0.29 mmoles) and the reaction stirred overnight at room temperature. Ethyl acetate (40 mL) and water (25 mL) were added and the organic layer was washed with brine (30 mL) and saturated aqueous NaHCO3 (30 mL). The aqueous layers were extracted with ethyl acetate (3×30 mL) and the combined organic extracts dried with Na2SO4 and concentrated. The crude product was purified by radial chromatography on silica gel (1 mm plate, 2% MeOH/1% NH4OH/CH2Cl2, then 10% MeOH/1% NH4OH/CH2Cl2) to give N-{4-[1H-benzolimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-6-hydroxynicotinamide as an offwhite foam (30 mg, 16%).
Reaction SMILES: [N+:1]([CH2:4][CH:5]([CH2:11][CH2:12][CH3:13])[CH2:6][C:7](OC)=[O:8])([O-])=O>C(O)C.[Pt]=O>[CH2:11]([CH:5]1[CH2:4][NH:1][C:7](=[O:8])[CH2:6]1)[CH2:12][CH3:13]
Reactant: CCCC(CC(=O)OC)C[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: CCCC1CNC(=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
Platinum oxide (0.4 g) was added to a solution of methyl 3-(nitromethyl)hexanoate (3.64 g, 19.2 mmol) in ethanol (20 ml) was added and the mixture was stirred at room temperature for 18 hours under a hydrogen stream. The reaction mixture was filtered through celite, and then the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate, ethyl acetate: methanol) to yield the title compound (1.63 g) as a light yellow oil. 1H-NMR (CDCl3) δ(ppm) 0.92 (3H, t, J=7.2 Hz), 1.27-1.53 (4H, m), 1.93-2.05 (1H, m), 2.37-2.53 (2H, m), 3.01 (1H, dd, J=9.2 Hz, 6.4 Hz), 3.48 (1H, dd, J=9.2 Hz, 9.2 Hz), 5.67-5.97 (1H, m)
Reaction SMILES: OO.[C:3]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([OH:31])[C:25]([CH3:33])([CH3:32])[CH2:24]1)(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].S([O-])([O-])=O.[Na+].[Na+].[C:40]([OH:44])([CH3:43])([CH3:42])[CH3:41]>>[C:3]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH2:41][C:40]([CH3:43])([OH:44])[CH2:42][O:31][N:26]2[C:27]([CH3:29])([CH3:30])[CH2:28][CH:23]([O:22][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:24][C:25]2([CH3:32])[CH3:33])[C:25]([CH3:32])([CH3:33])[CH2:24]1)(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC(C)(C)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OCC(C)(O)CON2C(C)(C)CC(OC(=O)CCCCCCCCCCCCCCCCC)CC2(C)C)C(C)(C)C1

Procedure:
Aqueous hydrogen peroxide is added to a mixture of 4-octadecanoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqueous sodium sulfite solution. The organic layer is concentrated to obtain a mixture which includes 1-(2-hydroxy-2-methylpropoxy)-4-octa-decanoyloxy-2,2,6,6-tetramethylpiperidine and the title compound. The title compound is separated from the mixture by high pressure liquid chromatography.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[N:14]=[C:13](S(C)(=O)=O)[N:12]=[C:11]([NH:19][CH:20]([CH3:22])[CH3:21])[C:10]=1[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30]>CN(C=O)C>[Cl:8][C:9]1[N:14]=[C:13]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[N:12]=[C:11]([NH:19][CH:20]([CH3:22])[CH3:21])[C:10]=1[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30]
Reactant: c1cn[nH]c1
Reactant: CC(C)Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Nc1nc(-n2cccn2)nc(Cl)c1-c1c(F)cccc1Cl
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A solution of 180 mg (2.64 mmol) of pyrazole in 4 ml of anhydrous DMF was treated with 106 mg (2.64 mmol) of NaH (60% suspension in mineral oil), with ice-cooling. After the mixture had been stirred for one hour, 500 mg (1.32 mmol) of the product of step d were added and the mixture was stirred for approximately 14 hours at 20 to 25° C. The product was precipitated by adding water. Filtration, washing with water and drying gave 450 mg of the title compound as colorless crystals of m.p. 185-187° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([OH:7])[CH2:5][OH:6].[CH3:8][C:9]1([CH3:34])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([C:21]3[N:26]=[C:25]([N:27]4[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]4)[CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2.Cl>>[CH3:8][C:9]1([CH3:34])[CH2:18][CH2:17][C:16]([CH3:19])([CH3:20])[C:15]2[CH:14]=[C:13]([C:21]3[N:26]=[C:25]([N:27]4[CH2:32][CH2:31][CH:30]([NH:1][CH2:2][CH2:3][C@H:4]([OH:7])[CH2:5][OH:6])[CH2:29][CH2:28]4)[CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: NCC[C@H](O)CO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(=O)CC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(NCC[C@H](O)CO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS1008 starting from 21 mg (0.199 mmol) of (S)-4-aminobutane-1,2-diol and 80 mg (0.199 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=2)[C:22]#[N:23])[CH:5]=[CH:4][N:3]=1.Cl.Cl.[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37].Cl.C([O-])(O)=O.[Na+]>C(O)C(F)(F)F>[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([NH:37][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=3)[C:22]#[N:23])[CH:5]=[CH:4][N:3]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C#N
Reactant: CN(C)CCOc1cccc(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCC(F)(F)F
Product: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cccc(OCCN(C)C)c3)n2)cc1C#N
Temperature: 84 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-2-(methyloxy)benzonitrile (Intermediate Example 4) (2.02 g, 5.57 mmol) and 3-{[2-(dimethylamino)ethyl]-oxy}aniline dihydrochloride (1.67 g, 6.58 mmol) in trifluoroethanol (20 mL) was added HCl (0.700 mL, 4M in dioxane, 2.8 mmol). The reaction was stirred at 84° C. for 2 days. The reaction was poured into half saturated NaHCO3, extracted with DCM and EtOAc, dried (MgSO4), concentrated and triturated with diethyl ether to provide the title compound (2.63 g, 5.18 mmol, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.17 (s, 6H), 2.57 (t, J=5.7 Hz, 2H), 3.96 (s, 5H), 6.55 (d, J=8.4 Hz, 1H), 6.63 (d, J=5.1 Hz, 1H), 7.07 (t, J=7.0 Hz, 1H), 7.16 (t, J=8.1 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.33 (d, J=9.2 Hz, 1H), 7.45-7.53 (m, 2H), 7.74 (d, J=9.2 Hz, 1H), 7.92 (dd, J=9.0, 2.0 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H), 8.39 (d, J=5.1 Hz, 1H), 9.49 (d, J=6.2 Hz, 1H), 9.77 (s, 1H).