Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1.O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:21]4=[O:45])=[CH:17][CH:16]=3)[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2cc(Br)cnc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Br)cnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.35 g of 6-bromo-2-hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 59), 2.60 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.39 ml of tributylphosphine, 1.41 g of 1,1'-(azodicarbonyl)dipiperidine and 35 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.43 g of the title compound, melting at 97-100° C. (softening).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[CH2:25]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:26][CH2:27][CH2:28][CH3:29]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: CCCCCNCCCCC
Solvent: CC(=O)CC(C)C
Product: CCCCCN(CCCCC)CCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 1.9 g N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 5.6 ml of dipentylamine, and 50 ml of methylisobutylketone, a reaction similar to that conducted in Example 142 was carried out. As a result, 2.97 g of N-(trans-4-methylcyclohexyl)-4-(2-dipentylaminoethoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1.O.Cl>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1CO
Temperature: 65 °C

Procedure:
A stirred solution of 2-amino-4-nitrobenzoic acid (Aldrich; 18.2 g, 100 mmol) in dry THF (500 mL) at 20° C., is treated with a solution of borane-THF complex (BH3-THF; Fluka; 100 mL of 1.0 M), dropwise over 45 min to regulate the gas evolution. The mixture is then heated at 65° C. for 2 h. The stirred mixture is then cooled to 0° C., treated with water (20 mL) and warmed to RT. Upon the cessation of gas evolution, hydrochloric acid (20 mL of 12 M) is added and the mixture is then heated at 65° C. for 30 min. The cooled mixture is then concentrated to a volume of circa 150 mL by rotary evaporation under reduced pressure to give a suspension. The suspension is filtered and the precipitate is redissolved in ethyl acetate (500 mL) and washed with saturated aqueous sodium hydrogen carbonate (2×150 mL). The solution is dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give the title compound as a yellow crystalline solid, m.p. 126-128° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:44])[CH:15]([C:35]2[CH:40]=[CH:39][C:38]3[O:41][CH2:42][O:43][C:37]=3[CH:36]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][O:24][Si](C(C)(C)C)(C)C)=[CH:19][C:18]=2[CH2:32][CH2:33][CH3:34])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:44])[CH:15]([C:35]2[CH:40]=[CH:39][C:38]3[O:41][CH2:42][O:43][C:37]=3[CH:36]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=2[CH2:32][CH2:33][CH3:34])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1cc(CO)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 26.2 %

Procedure:
To a solution of 3.20 g (5.01 mmol) of the product of Step D dissolved in 5.0 mL of anhydrous THF was added 5.06 mL (5.06 mmol) of a 1.0M solution of tetrabutylammonium fluoride in THF and the reaction mixture was stirred at room temperature under a nitrogen atmosphere. After 2.5 hours 1.0 mL additional tetrabutylammonium fluoride in THF was added and the reaction mixture was stirred for an additional 14 hours. The reaction mixture was then concentrated in vacuo and applied to a silica gel flash chromatography column and eluted with 60% EtOAc-hexane. Combination of the purified fractions and drying in vacuo afforded 0.691 g (26%) of the title compound as an amorphous powder.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[S:31][CH:32]=[CH:33][N:34]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30]1[S:31][CH:32]=[CH:33][N:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Reactant: Clc1nccs1
Product: CCc1nn(C2CCC2)c2cc(N3CCN(c4nccs4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 64 %

Procedure:
Prepared using the same procedure described in Example 413 from 6-((S)-3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole and 2-chlorothiazole to afford the title compound as a colorless solid (152 mg, 64%). LC/MS (Method B) 4.60 min, [M+1]+ 458.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C@@H:17]([OH:38])[CH2:18][NH:19][C:20]([CH3:37])([CH3:36])[CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][C:28]([C:32](OC)=[O:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].C(O)(C(F)(F)F)=O.[CH3:49][CH:50]([OH:52])[CH3:51]>>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C@@H:17]([OH:38])[CH2:18][NH:19][C:20]([CH3:36])([CH3:37])[CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][C:28]([C:32]([O:52][CH:50]([CH3:51])[CH3:49])=[O:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Reactant: CC(C)O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
240 mg (0.36 mmol) methyl 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylate (Example 5) are dissolved in 5 ml 2-propanol and combined with 19 mg (0.36 mmol) sodium methoxide. The mixture is stirred for 17 hours at ambient temperature and then acidified with TFA while cooling with ice. Then the solvent is eliminated in vacuo and the residue is chromatographed on Microsorb C18-reverse-phase [acetonitrile (0.1% TFA)/water (0.13% TFA)=10:90→100:0].
Reaction SMILES: [CH:1]1([C:4](O)=O)[CH2:3][CH2:2]1.[CH3:7][C:8]1([CH3:16])[O:15][C:13](=[O:14])[CH2:12][C:10](=[O:11])[O:9]1.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH:1]1([CH2:4][CH:12]2[C:13](=[O:14])[O:15][C:8]([CH3:16])([CH3:7])[O:9][C:10]2=[O:11])[CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC(=O)C(CC2CC2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
To a solution of cyclopropanecarboxylic acid (17.2 g) in methylene chloride (800 mL) were added Meldrum's acid (28.8 g), WSCI.HCl (42.2 g) and 4-dimethylaminopyridine (39.1 g), and the mixture was stirred at room temperature for 18 hr. Water and then hydrochloric acid were added to acidify the reaction mixture, and the aqueous layer was removed by partitioning. Under ice-cooling, acetic acid (114 mL) and then sodium borohydride (18.9 g) were added slowly to the organic layer, and the mixture was stirred at room temperature for 3 days. Water and then hydrochloric acid were added to the reaction mixture, and the aqueous layer was removed by partitioning. The organic layer was concentrated to give a yellow powder. This was washed with ether/hexane to give the title compound (25.8 g) as a yellow powder.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:25][C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH2:15][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6]2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CCl)Nc1cccc(F)c1
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(CC(=O)Nc2cccc(F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.9 %

Procedure:
A mixture of ethyl 4-nitro-1H-pyrazole-3-carboxylate (0.685 g, 3.7 mmol) and 2-chloro-N-(3-fluorophenyl) acetamide (0.694 g, 3.7 mmol) and potassium carbonate (0.613 g, 4.44 mmol) in dimethyl formamide (10 ml) was stirred at room temperature for 20 hours. The mixture was evaporated and the residue was purified by silica gel chromatography eluting with a 8 to 10% mixture of ethyl acetate in dichloromethane to give ethyl 1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-4-nitro-1H-pyrazole-3-carboxylate (0.920 g, 74% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([CH2:14][CH:15]([C:18]2[CH:19]=[N:20][C:21]([CH:24]([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:16][NH2:17])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([C:18]1[CH:19]=[N:20][C:21]([CH:24]([F:26])[F:25])=[CH:22][CH:23]=1)[CH2:14][CH:11]1[CH2:12][CH2:13]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)F)nc1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=365.1, tR (minutes, Method F)=2.97. [α]D20=+21.00 (c=3.00 mg/mL,CHCl3)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]CC2C=CC=CC=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of the product from step 1, in THF (11 ml), EtOH (25 ml), Pd—C (1.17 g, 10% wt) in a round bottom flask was charged with H2-balloon after flushing with hydrogen 3 times. The resulting solution was stirred overnight at rt. The reaction mixture was then filtered, washed with THF (30 ml), EtOH (25 ml) and dried over anhydrous MgSO4. After removal of the solvent in vacuo, the product was obtained as an orange oil (1.0 g, 95%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:38])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:38])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1

Procedure:
Starting materials: (2-{(E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamic acid tert-butyl ester (compound A7) (0.460 mmol), CH2Cl2 (50 ml), TFA (5 ml). Reaction conditions: room temperature, 18 hours.
Reaction SMILES: CS(O[CH2:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=2)[CH:8]=1)(=O)=O.[N:20]1([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]#[N:29])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:17][C:16]([F:19])([F:18])[C:12]1[CH:13]=[C:14]2[S:15][C:7]([CH2:6][N:23]3[CH2:22][CH2:21][N:20]([C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])[CH2:25][CH2:24]3)=[CH:8][C:9]2=[N:10][CH:11]=1
Reactant: CS(=O)(=O)OCc1cc2ncc(C(F)(F)F)cc2s1
Reactant: N#Cc1ccccc1N1CCNCC1
Product: N#Cc1ccccc1N1CCN(Cc2cc3ncc(C(F)(F)F)cc3s2)CC1

Procedure:
The solution from Example 25C (2 mL) and 2-(1-piperazinyl)benzonitrile (187 mg) were processed as described in Example 25D to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.81 (4H, t, J=4.8 Hz), 3.29 (4H, J=4.8 Hz), 4.00 (s, 2H), 7.03 (2H, m), 7.50 (2H, m), 7.59 (dd, 1H, J=7.5, 1.5 Hz), 8.39 (1H, m), 8.86 (1H, m). MS (DCI/NH3) m/z 403.1 (M+H)+. Anal. Calcd for C20H17N4F3S: C, 59.69; H, 4.26; N, 13.92. Found: C, 59.53; H, 4.12; N, 14.22.
Reaction SMILES: C([NH:8][C:9]([NH:11][C:12]1([CH2:33][O:34][SiH3:35])[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:13]1[F:32])=[O:10])C1C=CC=CC=1>CC(O)=O.[Pd]>[C:28]([CH:14]1[C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([CH2:33][O:34][SiH3:35])([NH:11][C:9](=[O:10])[NH2:8])[CH:13]1[F:32])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)C1C(F)C(CO[SiH3])(NC(=O)NCc2ccccc2)C1(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)C1C(F)C(CO[SiH3])(NC(N)=O)C1(c1ccccc1)c1ccccc1
Reaction time: 96 h

Procedure:
In the Parr Hydrogenator flask with 1 mL AcOH and 10% Pd/C 0.15 g inside, 1-benzyl-3-(3-tert-butyl-diphenyl-siloxymethyl-2-fluoro-cyclobutyl)-urea in 5 mL AcOH was added. This was hydrogenolysed at 50 psi for 4 d, after which the crude mixture was filtered through celite and was purified by silica gel flash chromatography (CH2Cl2:MeOH=40:1) to give 0.15 g (63.3%, Rf=0.44 (CH2Cl2: MeOH=20:1) the desired product. IR (neat) νmax 3425, 3339, 2931, 2858, 1656, 1608, 1560, 1111, 701.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[O:30][N:29]=[CH:28][C:27]=1[C:31](Cl)=[O:32]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:31]([C:27]5[CH:28]=[N:29][O:30][C:26]=5[CH3:25])=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1oncc1C(=O)Cl
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cnoc1C
Yield: 80.5 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (162 mg, 0.50 mmol), N-methylpyrrolidone (5 mL) and 5-methylisoxazole-4-carbonyl chloride (146 mg, 1.0 mmol), and in the same manner as in Example 162, the title compound (174 mg, yield 80%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[N:12]=[N+]=[N-]>C(O)(=O)C>[CH:5]1[C:4]2[C:3](=[N:12][O:10][N+:9]=2[O-:11])[C:2]([Cl:1])=[CH:7][C:6]=1[Cl:8]
Reactant: [N-]=[N+]=Nc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: [O-][n+]1onc2c(Cl)cc(Cl)cc21

Procedure:
The compound 2,4-dichloro-6-nitroazidobenzene is dissolved in glacial acetic acid then refluxed for several hours to yield 4,6-dichlorobenzofuroxan. This step is similar to that described in Boulton et al., J. Chem. Soc. B., p. 909 (1967) except that the present invention uses a longer reflux time.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([CH2:20][OH:21])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C(Cl)Cl>[NH:1]([C:8]1[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([CH2:20][O:21][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(CO)c(F)cc12
Reactant: COc1ccc(O)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(OCc2nc3c(cc2F)c(=O)cc(Nc2ccccc2)n3-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
2-anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (62 mg, 0.175 mmol) was dissolved in CH2Cl2 (1.2 mL). 4-methoxyphenol (22 mg, 0.175 mmol) was added followed by Ph3P (91.8 mg, 0.35 mmol), and ADDP (88.31 mg, 0.35 mmol). The reaction was left to stir overnight at room temperature under argon. Hexanes (5 mL) were added and the reaction was filtered. The filtrate was concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 7:3 to 9:1 EtOAc:Hex provided 2-anilino-6-fluoro-7-[(4-methoxyphenoxy)methyl]-1-phenyl-1,8-naphthyridin-4(1H)-one (30.0 mg, 37%) as a white solid: LCMS RT 2.87 min, MH+: 464.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=O)[CH:5]=[CH:6][CH:7]=1.[Cl-].[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH:23]=[CH:10][CH:9]=[CH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=CC=Cc1cccc(Cl)c1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Clc1cccc(C=CC=Cc2ccccc2OCc2ccccc2)c1
Yield: 94 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, the whole of this 3-(3-chlorophenyl)-2-propenal was reacted with 6.9 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 2.89 g of 1,8-diazabicyclo[5,4,0]undec-7-ene in 100 ml of acetonitrile. The crude product, extracted as described in the first part of Preparation 3, was purified as described in the first part of Preparation 3, to give 4.13 g (yield 94%) of 1-(2-benzyloxyphenyl)-4-(3-chlorophenyl)butadiene as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:22]=[CH:21][C:10]3[C@:11]4([CH3:20])[C@@H:16]([CH2:17][CH2:18][C:9]=3[CH:8]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]4)[S:5][CH:6]=1.[C:23](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:23][N:15]1[C@H:16]2[C@@:11]([CH3:20])([C:10]3[CH:21]=[CH:22][C:7]([C:4]4[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=4)=[CH:8][C:9]=3[CH2:18][CH2:17]2)[CH2:12][CH2:13][C:14]1=[O:19]
Reactant: Cc1csc(-c2ccc3c(c2)CC[C@H]2NC(=O)CC[C@]32C)c1
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: Cc1csc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-methylthiophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (20 mg, 0.06 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (20 mg, 0.18 mmol). Methyl iodide (0.011 mL, 0.18 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 15 mg (72%) of the title compound as a white solid. mp 115°-117°. FDMS: m/e=351.
Reaction SMILES: [C:1]([N:4]([O:42][CH3:43])[C:5]1([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36])(=[O:3])[CH3:2].Cl.C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>O1CCOCC1>[OH:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([N:4]([O:42][CH3:43])[C:1](=[O:3])[CH3:2])([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:6](=[O:36])[C:7]=1[C:16]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([NH:26][S:53]([CH3:52])(=[O:55])=[O:54])=[CH:25][C:19]=2[S:18](=[O:34])(=[O:35])[N:17]=1
Reactant: CON(C(C)=O)C1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CON(C(C)=O)C1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
A mixture of the product of Example 39A (16 mg, 0.026 mmol) and 4 N HCl in dioxane (0.26 mL) was stirred at room temperature for 4 h and then concentrated in vacuo. The resulting residue was taken up in dichloromethane (1 mL) and triethylamine (36 μL, 0.3 mmol) and methanesulfonyl chloride (10μL, 0.13 mmol) were then added. The reaction solution was stirred at room temperature for 2 h. The solution was then washed with aqueous 1 N HCl (2×0.5 mL), dried (Na2SO4), and concentrated in vacuo. The residue was then dissolved in methanol (1 mL) and treated with excess of K2CO3 for 30 min. The mixture was diluted with ethyl acetate (3 mL) and filtered. The filtrate was washed with aqueous 1 N HCl (2×1 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (1%→3%→5% methanol/dichloromethane) afforded the title compound as a yellow solid (8 mg, 53%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.38-0.56 (m, 1H), 0.60-0.73 (m, 6H), 0.91-1.09 (m, 1H), 1.17-1.39 (m, 2H), 2.01 (s, 3H), 2.11-2.32 (m, 1H), 3.03 (s, 3H), 4.05 (s, 3H), 7.32-7.62 (m, 7H), 8.05 (d, J=7.72 Hz, 1H), 10.05 (s, 1H), 14.46 (s, 1H); MS m/z 591.1 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.OC1C=C[N:25]=CC=1>>[C:17]([O:16][C:14]([N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:8][O:1][C:2]1[CH:7]=[CH:6][N:25]=[CH:4][CH:3]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Reactant: Oc1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccncc1
Yield: 47 %

Procedure:
2-(Pyridin-4-yl-oxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (22) was prepared according to the same procedure for compound 9, except using 4-hydroxypyridine. The crude product was purified with ethyl acetate to afford 1.31 g (47%) of 22 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.42 (m, 2H), 6.87 (m, 2H), 4.15 (m, 3H), 3.43 (m, 2H), 1.98 (m, 4H), 1.50 (s, 9H).