Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=[O:9])([CH3:3])[CH3:2].[I:15]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:15][C:10]1[CH:11]=[C:12]([O:13][CH3:14])[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: COc1ccc(C=O)cc1OC(C)C
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cc(I)c(C=O)cc1OC(C)C
Temperature: 61 °C
Yield: 92.8 %

Procedure:
Silver trifluoroacetate (12.3 g, 56.7 mmol) was added to a solution of isovanillin isopropyl ether (10.0 g, 51.5 mmol) in dry chloroform (120 mL) under nitrogen and the resultant slurry stirred and heated to 61° C. Iodine (14.4 g, 56.7 mmol) was then added portionwise (6 portions) over 0.6 h and the reaction allowed to reflux for a further 6.5 h. The reaction mixture was then cooled and filtered, rinsing with chloroform (50 mL). The filtrate was washed with Na2S2O5 (10% solution in water, 150 mL), NaHCO3 (sat. in water, 150 mL) and water (150 mL) dried (MgSO4) and concentrated under vacuum. The solid residue was suspended in hexane (200 mL) and stirred vigoursly for 1 h, cooled in an ice bath for 1 h and filtered rinsing with ice cold hexane (200 mL) to give the title compound as a cream solid (15.3 g, 93%) mp 75-6° C. IR (KBr disc, cm−1) 3072, 2978, 2932, 1673, 1581, 1503, 1438, 1385, 1332, 1260, 1215, 1174, 1157, 1133, 1105, 1024, 939. 1H NMR 300 MHz, CDCl3) δ9.77 (s, 1H), 7.34 (s, 1H), 7.24 (s, 1H), 4.57 (septet, J=6.0 Hz, 1H), 3.86 (s,3H), 1.31 (d, J=6.0 Hz, 6H). 13C NMR+APT (75.5 MH, CDCl3) δ194.7(−), 155.5(+), 47.9 (+), 128.2 (+), 122.2 (−), 114.1 (−), 110.8 (+), 92.4 (+), 71.3 (−), 56.4 (−), 21.77 (−), MS (70eV) m/z (%): 320 (M+•, 43), 278 (100), 249 (17), 207 (12), 150 (40). Anal. Calcd for C11H13O3I: C, 41.27; H, 4.09; I, 39.64. Found: C, 41.06; H, 3.80; I, 39.59.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.Cl.[NH2:13][CH2:14][CH2:15][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:13][CH2:14][CH2:15][CH:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(CCNc1ncc(Br)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Yield: 92.7 %

Procedure:
A procedure similar to the method described in step C.1 is carried out, starting from 2 g (8.42 mmol) of 5-bromo-2-chloro-3-nitropyridine, 3.14 g (10.11 mmol) of tert-butyl(S)-4-amino-2-tert-butoxycarbonylaminobutanoate hydrochloride and 2.31 g (16.85 mmol) of triethylamine in 30 ml of dioxane. This time the mixture is heated for 12 hours. This gives 3.71 g of the expected product, which is used as it is in the remainder of the synthesis.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][S:13][C:12]3=[N:15][CH:16]=[C:17]([C:18]([OH:20])=O)[N:11]23)=[CH:6][C:5]=1F)#[N:3].[Br:22][C:23]1[CH:36]=[CH:35][C:34]([O:37][Si:38]([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][C:24]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1=[O:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[Br:22][C:23]1[CH:36]=[CH:35][C:34]([O:37][Si:38]([C:51]([CH3:54])([CH3:53])[CH3:52])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:33][C:24]=1[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:18]([C:17]2[N:11]3[C:12]([S:13][CH2:14][CH:10]3[C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=3)=[N:15][CH:16]=2)=[O:20])[CH2:28][C:27]1=[O:32]
Reactant: CC(C)(C)[Si](Oc1ccc(Br)c(CN2CCNCC2=O)c1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(C2CSc3ncc(C(=O)O)n32)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](Oc1ccc(Br)c(CN2CCN(C(=O)c3cnc4n3C(c3ccc(C#N)cc3)CS4)CC2=O)c1)(c1ccccc1)c1ccccc1

Procedure:
The carboxylic acid from Step K (221 mg, 0.679 mmol), the piperazinone from Step E (390 mg, 0.679 mmol), EDC hydrochloride (156 mg, 0.814 mmol), HOBT (110 mg, 0.814 mmol), and N,N-diisopropylethylamine (0.591 mL, 3.39 mmol) were stirred together in dry, degassed DMF (5 mL) at 25° C. for 16 hours. The reaction was poured onto saturated aqueous sodium bicarbonate and extracted with methylene chloride (3×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow oil. The crude product was purified by column chromatography (3% methanol/methylene chloride) to provide the title compound as a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@H:15]([N:16]([CH3:33])[C:17](=[O:32])[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:34]([N:41]1[CH2:49][CH2:48][CH:44]([C:45](O)=[O:46])[CH2:43][CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O>[F:27][C:24]([F:25])([F:26])[C:22]1[CH:23]=[C:18]([C:17]([N:16]([CH3:33])[C@@H:15]2[CH2:14][CH2:13][N:12]([C:45]([CH:44]3[CH2:48][CH2:49][N:41]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:42][CH2:43]3)=[O:46])[CH2:11][C@H:10]2[C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=2)=[O:32])[CH:19]=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A mixture of N-[(3R*,4R*)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide monohydrochloride (0.90 g) obtained in Example 2, N-Boc-isonipecotic acid (1.52 g), WSC.HCl (0.82 mg) and HOBt (0.65 mg) was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50→100% ethyl acetate/hexane, then 0→10% methanol/ethyl acetate) to give the title compound (1.19 g, 59%) as a white powder.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[H][H]>CO.[Pd]>[NH2:1][C@@H:2]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCNC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Yield: 99.8 %

Procedure:
The compound obtained in (1) (650 mg) was dissolved in methanol (10 ml) and 10% Pd-C (118 mg) was added. The resulting mixture was vigorously stirred at room temperature under atmospheric pressure of hydrogen overnight. The catalyst was filtered off through Celite and the filtrate was concentrated under reduced pressure to give the product (450 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]([CH3:18])[C:14](OC)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C[O-].[Na+]>CO>[OH:28][NH:27][C:14](=[O:15])[CH:13]([N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18]
Reactant: COC(=O)C(C)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C(C)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(a) Methyl 2-[[4-methoxybenzenesulfonyl](benzyl)amino]propionate (2.1 g, 6.01 mmol) is dissolved in methanol (20.0 mL). To this solution is added hydroxylamine hydrochloride (0.84 g, 12.0 mmol), followed by the addition of sodium methoxide (7.0 mL of a 4.37M solution). The reaction is stirred overnight at room temperature. The reaction is worked up by first removing all the solvent, and partitioning between ethyl acetate/hexane (2/1) and saturated sodium bicarbonate. The aqueous phase is extracted well with ethyl acetate/hexane, the combined organic layers are dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (ethyl acetate) to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]propionamide, m.p. 149°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([NH2:11])[C:4]=1[C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.CO.[BH4-].[Na+].[H][H]>[Pd].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([NH2:11])[C:4]=1[C:12](=[O:22])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: COc1cc(N)c(C(=O)C=Cc2ccc(O)cc2)c(OC)c1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(N)c(C(=O)CCc2ccc(O)cc2)c(OC)c1

Procedure:
0.5 g of 1-(2,4-dimethoxy-6-aminophenyl)-3-(4-hydroxyphenyl)-prop-2-en-1-one, 20 mL methanol, and 1 g of palladium on carbon were mixed; and to the mixture was added 50 μL of sodium borohydride and placed under vacuum. The reaction was continued for 30 minutes or until hydrogen evolution ceased. The reaction mixture was diluted with 100 mL of water. Pale yellow to tan crystals of 1-(2,4-dimethoxy-6-aminophenyl)-3-(4-hydroxyphenyl)-propan-1-one formed. The crystals were obtained from the mixture via centrifugation at 1000×g for 10 minutes. The crystals were resuspended in water, and centrifugation was repeated.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.N#N>C1COCC1>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(OCc2ccccc2)cc1
Yield: 75.7 %

Procedure:
2-(5-Methyl-2-phenyloxazol-4-yl)ethanol [Hulin, et al., J. Med. Chem. (1992) 35(10), 1853-64] (7.42 g, 36.0 mmol), 4-benzyloxyphenol (7.3 g, 36.0 mmol) and triphenylphosphine (9.57 g, 36.0 mmol) were dissolved in anhydrous THF (500 mL) and treated with dropwise addition of diisopropyl azodicarboxylate (7.18 mL, 36.0 mmol). The reaction mixture was stirred at 20° C. for 18 h under a positive-pressure atmosphere of N2. The reaction was partitioned between EtOAc (100 mL) and 0.1 N NaOH (100 mL), and the organic phase washed with water (100 mL) and brine (100 mL). The organic layer was dried with Na2SO4 and concentrated to a residue which was purified by gradient column chromatography (silica column, 100% hexanes to 20% EtOAc/hexanes) to provide a white solid (10.5 g, 76%). Rf=0.3 (10% EtOAc/hexanes) 1H NMR (250 MHz, DMSO-d6) δ 7.86 (d, 2H), 7.41-7.48 (m, 3H), 7.22-7.38 (m, 5H), 6.86 (d, 2H), 6.80 (d, 2H), 4.97 (s, 2H), 4.07 (t, 2H), 2.84 (t, 2H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([OH:15])=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[N:18][CH:17]=2)[CH:3]=1.[Cl:22][C:23]1[C:24](F)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:31])=[O:30])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:22][C:23]1[C:24]([O:15][C:5]2[CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:2]([Cl:1])=[CH:3][C:4]=2[C:16]2[CH:21]=[CH:20][N:19]=[N:18][CH:17]=2)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:30])=[O:31])[CH:28]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1cc(-c2ccc(F)cc2)c(Cl)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4ccc(F)cc4)c(Cl)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.9 %

Procedure:
6-Chloro-4′-fluoro-4-(pyridazin-4-yl)biphenyl-3-ol (Preparation 102, 150 mg, 0.50 mmol), 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 345 mg, 0.75 mmol), and potassium carbonate (207 mg, 1.50 mmol) were suspended in dimethyl sulfoxide (2 mL). The reaction mixture was stirred for 18 hours at room temperature. Water (50 mL) was added and the suspension was extracted with ethyl acetate (2×50 mL) and dichloromethane (3×50 mL). The organic layers were combined, dried over MgSO4, filtered and evaporated. The residue was purified by semi preparative reverse phase HPLC (solvent A: 0.05% formic acid in acetonitrile; solvent B: 0.05% formic acid in water; flow rate: 15 mL/min; gradient 0 min 5% A, 2.5 min 5% A, 22.5 min 95% A, 32.5 min 95% A then return to initial conditions) to afford the title compound (100 mg, 27%) as a glass.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Mg].[CH:15]1[C:27]2[C:26](=[O:28])[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[N:18]=[CH:17][CH:16]=1>CCOCC.C1COCC1>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:26]1([OH:28])[C:27]2[C:19](=[N:18][CH:17]=[CH:16][CH:15]=2)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]12
Reactant: Ic1ccccc1-c1ccccc1
Reactant: O=C1c2cccnc2-c2ncccc21
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccccc2-c2ccccc2)c2cccnc2-c2ncccc21
Temperature: 25 °C
Yield: 93.6 %

Procedure:
Referring to scheme 6, under reflux, a flask containing with arylmagnesium iodide that was firstly prepared in advance from 2-iodo-biphenyl (11.2 g, 40 mmol) and magnesium (0.97 g, 40 mmol) in ether was added into 4,5-diazafluoren-9-one (3.64 g, 20 mmol) in THF. The mixture was refluxed for another 12 hours, then quenched with water after cooling to ambient temperature and extracted with CHCl3. The combined organic extracts were dried (MgSO4) and concentrated by rotary evaporation. The resulting crude solid was washed with n-hexane to give 5-biphenyl-2-yl-5H-cyclopenta[2,1-b;3,4-b′]dipyridin-5-ol (6.3 g, 93% yield) as a light brown solid, which was used for cyclization without further purification. 5-biphenyl-2-yl-5H-cyclopenta[2,1-b;3,4-b′]dipyridin-5-ol was heated to dissolve in 500 ml acetic acid. The solution was added 6 ml sulfuric acid as catalyst and refluxed for 24 hours. The reaction was quenched with cold water after cooling to room temperature and neutralized with NaOH(aq) to basic, then extracted with CHCl3 and dried with MgSO4. The combined organic solution was concentrated by rotary evaporation and washed with n-hexane to give 4,5-diaza-9,9′-spirobifluorene (4.3 g, 75%) as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: OB(O)c1ccccc1
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Product: CCCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (20% acetone in toluene to 60% acetone in toluene gradient) afforded 2-butyl-1-isobutyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. >250° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9]CC)=O.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([NH:13][NH2:14])=[O:9]
Reactant: NN
Reactant: CCOC(=O)c1nc[nH]c1C
Solvent: CCO
Solvent: O
Product: Cc1[nH]cnc1C(=O)NN
Yield: 86.6 %

Procedure:
To a hot solution of 154 g of 5-methyl-1H-imidazole-4-carboxylic acid, ethyl ester in 2 liters of absolute ethanol was added dropwise, but rapidly, 100 g of hydrazine hydrate. The solution was stirred at reflux temperature for 3 hours, then 150 ml of hydrazine hydrate was added and the solution was refluxed for 3 days. The mixture was partially evaporated, the solid collected, washed twice with absolute ethanol, then ether and dried, giving 121.3 g of 5-methyl-1H-imidazole-4-carboxylic acid hydrazide.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]2[O:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[O:12][C:7]=2[CH:6]=1)[C:2]#[CH:3].[C:19]([N:22]=[C:23]=[S:24])(=[O:21])[CH3:20]>C1COCC1>[CH2:3]=[C:2]1[S:24][C:23](=[N:22][C:19](=[O:21])[CH3:20])[N:4]([C:5]2[CH:18]=[CH:17][C:8]3[O:9][C:10]([F:15])([F:16])[C:11]([F:14])([F:13])[O:12][C:7]=3[CH:6]=2)[CH2:1]1
Reactant: C#CCNc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Reactant: CC(=O)N=C=S
Solvent: C1CCOC1
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)C(=NC(C)=O)S1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
An alternative procedure to prepare the titled compound follows. The propargylaniline (Example 22A, 31.08 g, ˜119 mmol) was dissolved into THF (300 mL) and treated with acetylisothiocyanate (11.5 mL, 131 mmol). After being stirred at room temperature briefly, it was heated to approximately 55° C. overnight, and at 60-65° C. for another 6 days. Then the mixture was concentrated and reconcentrated from CH2Cl2/hexanes to give a semi-solid which was mixed into 3:1 Et2O/hexanes and chromatographed on neutral alumina (40% Et2O/hexanes then 40% Et2O/CH2Cl2) to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([O:29]CC)=[O:28])=[CH:19][C:18]=2[CH:32]=1>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:15]1[C:14]([Cl:13])=[CH:32][C:18]3[CH:19]=[C:20]([C:27]([OH:29])=[O:28])[CH:21]([C:23]([F:25])([F:26])[F:24])[O:22][C:17]=3[CH:16]=1)[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Solvent: O
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc4cc(Br)ccc4c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 6-bromo-2-napthol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 252.6-254.8° C. 1H NMR (acetone-d6/300 MHz) 8.19 (s, 1H), 8.04 (d, 1H, J=9.1 Hz), 7.93 (s, 1H), 7.87 (d, 1H, J=8.9 Hz), 7.75 (s, 1H), 7.65 (d, 1H, J=8.8 Hz), 7.55 (s, 1H), 7.43 (d, 1H, J=9.1 Hz), 6.72 (s, 1H), 5.83 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz)−79.4 (d, J=6.5 Hz). FABLRMS m/z 497 (M−H). ESHRMS m/z 496.9421 (M−H, Calc'd 496.9403). Anal. Calc'd for C21H11BrClF3O4 with 1.75 wt % H2O: C, 49.60; H, 2.38; Br, 15.71; Cl, 6.97. Found: C, 49.55; H, 2.03; Br, 15.56; Cl, 7.22.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[C:17]3[S:21]C(=S)N[C:18]3=[O:23])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:24].[Na+].Cl>O>[C:1]1([C:7]2[C:15]([CH2:16][C:17](=[S:21])[C:18]([OH:23])=[O:24])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=S)SC1=Cc1c(-c2ccccc2)nn2ccccc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=S)Cc1c(-c2ccccc2)nn2ccccc12

Procedure:
A mixture of 5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)methylenerhodanine (13.0 g) and 15% aqueous solution of sodium hydroxide (50 ml) was refluxed for 3 hours. To the reaction mixture was added 10% hydrochloric acid (50 ml) and water (50 ml) and was stirred for an hour under ice-cooling. The precipitates were collected by filtration to give 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-thioxopropionic acid (7.85 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH:15](I)([CH3:17])[CH3:16]>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)Oc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepare a stirred mixture of ortho-bromo-phenol (25.951 g, 17.4 mL, 0.15 mole) and potassium carbonate (20.70 g, 0.16 mole) in 175 mL isopropanol at ambient temperature under argon. Slowly add isopropyl iodide (22.2 g, 16.00 mL), heat at reflux and stir the mixture overnight. Cool to ambient temperature then filter, condensing the filtrate on a rotary evaporator. Dissolve the residual oil in diethyl ether (300 mL) and twice extract with 100 mL 50% sodium hyroxide. Separate, wash with brine and concentrate on a rotary evaporator to give a pale yellow liquid. Distill on the Kugelrohr (0.05 mm, 100°-120° C.) to obtain the title compound as an oil. (24.21 g, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]2[C:12]([C:13]3[CH:25]=[CH:24][O:23][C:14]=3[CH2:15][O:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCOCC1.C(O)(=O)C.[Pd]>[C:29]([O:28][C:26]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]2[C:12]([C@H:13]3[CH2:25][CH2:24][O:23][C@H:14]3[CH2:15][O:16]2)=[CH:11][CH:10]=1)=[O:27])([CH3:31])([CH3:32])[CH3:30]
Reactant: [H][H]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1OCc1occc1-2
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1OC[C@@H]1OCC[C@H]21
Yield: 99.1 %

Procedure:
A solution of methyl 7-[bis-(tert-butoxycarbonyl)amino]-4H-furo[2,3-c]-chromene-6-carboxylate (Intermediate 3, 0.15 g) in a mixture of dioxane (15 mL) and acetic acid (1.5 mL) was treated under an atmosphere of nitrogen with palladium on carbon (10%, 0.02 g). The mixture was stirred and the nitrogen was replaced by hydrogen then the mixture was stirred under an atmosphere of hydrogen for 3 hours. The mixture was filtered through Celite, the pad was washed thoroughly with dioxane and the filtrate was evaporated to dryness to give methyl cis-(3aRS,9bRS)-7-[bis-(tert-butoxycarbonyl)amino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (0.15 g) as a gum.