Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([CH:18]=O)[CH:12]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][C:27]1[S:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.[OH-].[K+].CS(C)=O>O>[S:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[CH:26]=[CH:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:17]=[CH:16]2
Reactant: O=Cc1ccc2cc(N(c3ccccc3)c3ccccc3)ccc2c1
Reactant: Cc1nc2ccccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C(=Cc1nc2ccccc2s1)c1ccc2cc(N(c3ccccc3)c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A mixture of N,N-diphenyl-6-amino-2-naphthaldehyde (4.8 g, 0.015 mol.), 2-methyl benzothiazole (3.0 g, 0.020 mol.), powdered potassium hydroxide (18.0 g, 0.32 mol.) and DMSO (30 ml) was stirred at room temperature for 1 hour, poured into water, and the solids which separated were collected by filtration. These solids were purified by column chromatography on alumina using 1:3 toluene-heptane as the eluent, to give 3.6 g. of product (53% yield) m.p. 181.1-184.8° C. Recrystallization from 1:1 toluene-ethyl acetate raised the m. p. to 201.8-203.8° C. Mass Spec: m/z 454, (M+). Analysis calculated for C31H22N2S: C, 81.92; H, 4.88; N, 6.16; S, 7.04. Found: C, 81.82; H, 4.93; N; 6.04, and S; 6.91.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:45]2[CH:46]=[C:47]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:48]=[CH:49][CH:50]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[S:27]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:45]3[CH:46]=[C:47]([NH:51][S:52]([CH3:55])(=[O:53])=[O:54])[CH:48]=[CH:49][CH:50]=3)[CH:3]=[C:4]2[C:10]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH:15]=2)=[CH:9]1)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 100.9 %

Procedure:
Using similar reaction conditions as described in step 2 of example 1, 5-bromo-1-tosyl-3-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (165 mg, 0.28 mmol) was coupled with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methane sulfonamide (Intermediate 3) (119 mg, 0.401 mmol) in sodium carbonate (91 mg, 0.86 mmol), bis(triphenyl phosphine)palladium(ii) dichloride (10 mg, 0.014 mmol) and toluene/ethanol/water (15/6/2 ml) to afford 188 mg (98.4% yield) of the pure product after column purification using 60% ethyl acetate in hexane as eluent. MS: m/z=666.10 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[N:21]=[C:22]([CH3:24])[O:23][C:19]=4[CH:18]=[CH:17][C:16]4[CH:25]=[C:26]([O:29][Si](C(C)(C)C)(C)C)[CH:27]=[CH:28][C:15]3=4)[C:11](=[O:37])[NH:10][C:9]2=[O:38])[CH:5]=[CH:4][N:3]=1.[NH:39]1[CH2:42][CH:41]([C:43]([OH:45])=[O:44])[CH2:40]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:29][C:26]1[CH:27]=[CH:28][C:15]2[CH:14]([C:12]3[C:11](=[O:37])[NH:10][C:9](=[O:38])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:39]5[CH2:42][CH:41]([C:43]([OH:45])=[O:44])[CH2:40]5)[N:7]=4)[CH:13]=3)[C:20]3[N:21]=[C:22]([CH3:24])[O:23][C:19]=3[CH:18]=[CH:17][C:16]=2[CH:25]=1
Reactant: O=C(O)C1CNC1
Reactant: Cc1nc2c(o1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2c(o1)C=Cc1cc(O)ccc1C2c1cn(-c2ccnc(N3CC(C(=O)O)C3)n2)c(=O)[nH]c1=O

Procedure:
The product from step (ix) was treated with 3-azetidinecarboxylic acid (0.096 g) and N,N-diisopropylethylamine (0.445 ml) in N,N-dimethylformamide (10 ml) at 85° C. for 4 hours. The mixture was partitioned between 1N HCl and ethyl acetate. The aqueous layer was adjusted to pH 6 and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give a solid. Purification was by reverse phase chromatography eluting with 50% methanol in 0.1% aqueous ammonium acetate solution.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH:29]C(OC(C)(C)C)=O)=[CH:24][C:23]=1[CH3:37].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([CH3:37])[CH:24]=2)[N:29]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: Cc1cc(NNC(=O)OC(C)(C)C)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1Cl
Yield: 44921.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.0 g, 0.003 mmol), tert-butyl 2-(4-chloro-3-methylphenyl)hydrazinecarboxylate (Intermediate-105, 1.500 g), DCM (20 mL), and trifluoro acetic acid (5.0 mL) to afford 0.600 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 2.38 (s, 3H), 4.45 (d, J=5.4 Hz, 2H), 7.53 (d, J=9.3 Hz, 2H), 7.67 (s, 2H), 7.82 (d, J=8.1 Hz, 1H), 7.92 (s, 1H), 10.08 (t, 1H), 12.61 (s, 1H); MS (m/z): 445.31 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:27]([CH3:42])([CH3:41])[C:28](=[O:40])[C@H:29]([CH3:39])[C@@H:30]([OH:38])[C@@H:31]([CH3:37])[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH2:10][C:11]([O:13][C@@H:14]([CH2:24][CH:25]=[CH2:26])/[C:15](/[CH3:23])=[CH:16]/[C:17]1[N:18]=[C:19]([CH3:22])[S:20][CH:21]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Si:51](OS(C(F)(F)F)(=O)=O)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]>C(Cl)Cl>[Si:1]([O:8][C@H:9]([C:27]([CH3:41])([CH3:42])[C:28](=[O:40])[C@H:29]([CH3:39])[C@@H:30]([O:38][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[C@@H:31]([CH3:37])[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH2:10][C:11]([O:13][C@@H:14]([CH2:24][CH:25]=[CH2:26])/[C:15](/[CH3:23])=[CH:16]/[C:17]1[N:18]=[C:19]([CH3:22])[S:20][CH:21]=1)=[O:12])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)O[C@@H](CC=C)/C(C)=C/c1csc(C)n1)O[Si](C)(C)C(C)(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CCCC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)O[C@@H](CC=C)/C(C)=C/c1csc(C)n1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of (3S,6R,7S,8S)—(S,E)-2-methyl-1-(2-methylthiazol-4-yl)hexa-1,5-dien-3-yl 3-((tert-butyldimethylsilyl)oxy)-7-hydroxy-4,4,6,8-tetramethyl-5-oxotridec-12-enoate (Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960-7973) in DCM at −50° C. was treated with 2,6-lutidine (1.82 mL, 15.7 mmol) followed by TBSOTf (3.60 mL, 15.7 mmol). The reaction mixture was stirred at the same temperature for 0.5 h, quenched by NH4Cl (sat.) and extracted with DCM (3×). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. Purification by chromatography on SiO2 (hexanes:ethyl ether=100:2 to 10:1) followed by the second chromatography (hexanes: diethyl ether=100:4 to 100:6 to 10:1) afforded 0.281 g (73%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])(=[O:3])[CH3:2].[CH3:16][O:17][CH2:18][C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)=[O:20].N1CCCCC1.O>C(Cl)(Cl)Cl>[OH:10][C:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][C:5](=[O:15])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([NH:21][C:19](=[O:20])[CH2:18][O:17][CH3:16])[CH:23]=1
Reactant: CC(=O)c1c(O)c2ccccc2oc1=O
Reactant: COCC(=O)Nc1cccc(C=O)c1
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Solvent: O
Product: COCC(=O)Nc1cccc(C=CC(=O)c2c(O)c3ccccc3oc2=O)c1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
In 3 ml of chloroform were dissolved 0.18 g of 3-acetyl-4-hydroxy-2H-1-benzopyran-2-one, 0.17 g of 3-(methoxyacetylamino)benzaldehyde and 60 mg of piperidine, and the solution was heated under refluxing for 1 hour and 10 minutes while water was removed with a Soxhlet's extractor filled with a molecular sieve. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and fractions corresponding to Rf=0.3 were collected by thin layer chromatography (silica gel, chloroform (containing 2% methanol)), and concentrated to obtain 0.30 g of 4-hydroxy-3-[3-[3-(methoxyacetylamino)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (21d)].
Reaction SMILES: [C:1]([O:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12]C(C)=[CH:14][CH:15]=3)[C:10](=[O:21])[C:9]=2[CH:8]=[C:7]([O:22][C:23](=[O:25])[CH3:24])[CH:6]=1)(=O)[CH3:2].[OH2:26].[C:27]([OH:30])(=[O:29])[CH3:28]>C(OC(=O)C)(=O)C>[C:1]([O:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][C:28]([C:27]([OH:30])=[O:29])=[CH:14][CH:15]=3)[C:10](=[O:21])[C:9]=2[CH:8]=[C:7]([O:22][C:23](=[O:25])[CH3:24])[CH:6]=1)(=[O:26])[CH3:2]
Reactant: O
Reactant: CC(=O)O
Reactant: CC(=O)Oc1cc(OC(C)=O)c2c(c1)C(=O)c1cc(C)ccc1C2=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc(OC(C)=O)c2c(c1)C(=O)c1cc(C(=O)O)ccc1C2=O
Reaction time: 3 h

Procedure:
2.2 1, 3-Diacetoxy-6-methyl-anthraquinone (20 mg) (obtained in Example 2.1) was dissolved in a 1:1 mixture of acetic anhydride and acetic acid (16.6 ml) at 50° C. and added dropwise to a solution of CrO3 (135 mg) in aqueous 40% acetic acid (2.7 ml). The reaction mixture was then stirred for three hours, cooled and poured into 200 ml of water. After being left for two hours, the solution was extracted with ethyl acetate, washed with water and then extracted twice with saturated sodium bicarbonate solution. The aqueous phase was washed twice with methylene chloride, acidified with dilute HCl and extracted with ethyl acetate. The organic extract was evaporated to dryness yielding 18 mg of 1,3-diacetoxy-6-carboxy-anthraquinone (IV). UV-vis (EtOH) λmax353, 483, 530 sh, 564 nm (ε 22000, 30000, 20000, 15000)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[O:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=O.[BH4-].[Li+]>C1COCC1.C1(C)C=CC=CC=1>[OH:2][CH2:3][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([NH:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)=[O:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1nccc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c(CO)nccc12
Temperature: 60 °C
Yield: 12.2 %

Procedure:
N-[1-(Methoxycarbonyl)isoquinolin-5-yl]-N′-[4-(trifiluoromethyl)benzyl]urea (Example 116, 70 mg, 0.174 mmol) was suspended in a mixture of THF (5 ml) and toluene (5 ml). Lithium borohydride (50 mg, 2.27 mmol) was added and the reaction mixture heated at 60° C. for 1 hour. The reaction was cooled to room temperature and allowed to stand for 1 week. The crystalline product was collected by filtration, washed with toluene (2 ml), then triturated with 1:1 TBF-dichloromethane (2 ml), triturated again with THF (2 ml) and dried under vacuum to give the title compound (8 mg, 12%). m/z (ES+) 376 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][NH2:10]>COCCO>[CH3:8][N:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:10]
Reactant: CNN
Reactant: Clc1ccccn1
Solvent: COCCO
Product: CN(N)c1ccccn1

Procedure:
is obtained by boiling an admixture of 2-chloropyridine and methylhydrazine in 2-methoxyethanol under reflux.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:16][C:17]([CH3:21])([CH3:20])[CH:18]=O>C(Cl)Cl>[CH3:16][C:17]([CH3:21])([CH3:20])[CH:18]=[N:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]=[CH:16][C:17]([CH3:21])([CH3:20])[CH3:18]
Reactant: CC(C)(C)C=O
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C=NC1CCCCC1N=CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112 %

Procedure:
(+)-1,2-trans-Diaminocyclohexane (250 mg, 2.18 mmol) in CH2Cl2 (20 mL) was treated with Na2SO4 (923 mg, 6.50 mmol) and trimethylacetaldehyde (473 μL, 4.35 mmol). The mixture was stirred at ambient temperature under an atmosphere of N2 for 0.5 h then filtered. The filter was washed with CH2Cl2 (5 mL) and the combined organics were evaporated to give N,N′-bis-(2,2-dimethylpropylidene)-cyclohexane-1,2-diamine (610 mg, 98%) as an off-white semi solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:4][CH:3]=1.COC(OC)[N:21]([CH3:23])C.C(O)C.O.[NH2:30]N>>[Cl:16][C:12]1[N:11]=[C:10]([C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:30][NH:21][CH:23]=2)[CH:15]=[CH:14][N:13]=1
Reactant: NN
Reactant: O=C(Cc1ccnc(Cl)n1)c1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CCO
Product: Clc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
3.67 g (13.74 mMol) of 1-(4-Chloro-phenyl)-2-(2-chloro-pyrimidin-4-yl)-ethanone is suspended in 91.6 mL (50 Eq.) of N,N-dimethylformamid-dimethylacetal (Fluka puriss. 40271) and stirred for 2 h at 100° C. The dark brownish solution is freed from solvent under high vacuum at 30° C. The crude product, (Z)-1-(4-chloro-phenyl)-2-(2-chloro-pyrimidin-4-yl)-3-dimethylamino-propenone, is used for the next step without purification. To the solution of 5.42 g (14.2 mMol) of (Z)-1-(4-chloro-phenyl)-2-(2-chloro-pyrimidin-4-yl)-3-dimethylamino-propenone in 30 mL of ethanol 0.785 g (0.763 mL; 15.69 mMol, 1.1 Eq.) of hyrazine monohydrate (Fluka 53850) is added at rt. After stirring 45 min at rt, the yellow crystals are filtered off, washed with ethanol and dried at 60° C. under vacuum. The crude product is purified by recrystallization from methanol to obtain 2-chloro-4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidine as slightly yellowish crystals.
Reaction SMILES: [Cl-].[Li+].[CH3:3][Mg]Cl.[CH3:6]/[C:7](=[CH:22]\[CH2:23][CH3:24])/[C:8]([N:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][O:12][C:11]1=[O:21])=[O:9]>O.O1CCCC1.C(O)(=O)C>[CH3:6][C@H:7]([C@H:22]([CH3:3])[CH2:23][CH3:24])[C:8]([N:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][O:12][C:11]1=[O:21])=[O:9]
Reactant: CC/C=C(\C)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC[C@@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A 20 L jacketed reactor was fit with a gas inlet and a 2 L dripping funnel. A nitrogen sweep was begun over the reactor and maintained throughout the process. To the reactor was charged 392 g (9.26 mol) of lithium chloride, 1332 g (6.479 mol) of copper bromide dimethylsulfide complex and 11 L of tetrahydrofuran. The reaction was stirred for 30 minutes at room temperature and then cooled to −15° C. To the reaction mixture was added 4.268 L (12.80 mol) of 3.0M methyl magnesium chloride at a rate such that the reaction temperature did not exceed −10° C. Upon completion of the addition, the cuprate solution was allowed to stir at −5° C. overnight. To the cuprate solution was added 500 g (3.09 mol) of (S)-3-((E)-2-methyl-pent-2-enoyl)-4-phenyl-oxazolidin-2-one as a solid. The reaction was stirred at −3° C. for 2 hours. The reaction solution was charged to a 22 L round bottom flask containing 800 mL of acetic acid and 2 L of tetrahydrofuran at a rate such that the temperature of the quench solution did not exceed 25° C. To the quenched solution was added 6 L water. The resulting emulsion was filtered and the layers were separated. The organic layer was extracted with 9 L of 4.8 M NH4OH followed by 9 L of saturated NH4Cl. The organic layer was clarified through a plug of magnesol. The organic layer was concentrated to give 822 g of a crude solid. The crude solid was recrystallized from 8 L of 20% H2O in MeOH, filtered and dried in a vacuum oven to give 550 g of a white solid. The white solid was recrystallized from 5 L of 20% H2O in MeOH, filtered and dried in a vacuum oven to give 475 g of the titled compound: 1H-NMR (DMSO) 7.338-7.224 (m, 5H), 5.431-5.399 (q, 1H, J=4.288), 4.696-4.652 (t, 1H, J=8.773), 4.120-4.087 (m, 1H), 3.622-3.556 (m, 1H), 1.648-1.584 (m, 1H), 1.047-0.968 (m, 1H), 0.900-0.883 (d, 3H, J=6.823), 0.738-0.721 (d, 3H, J=6.628), 0.693-0.656 (t, 3H, J=7.408); Anal Calc'd for C16H21N1O3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.81; H, 7.61; N, 5.07; MS (Ion Mode: APCI) m/z=276 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(OCC)(=O)C>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:4]([CH2:5][CH2:6][NH:7][C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(/C=C/c1cccnc1)NCCc1cccc(O)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(CCNC(=O)/C=C/c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
(E)-N-(3-hydroxyphenethyl)-3-(3-pyridyl)-2-propenoic acid amide (600 mg, 2.24 mmol) obtained in Example 81 was dissolved in pyridine (4.0 ml) and acetic anhydride (0.40 ml, 4.24 mmol) was added under ice-cooling and stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction mixture and the mixture was washed with water and dried over magnesium sulfate. The solvent was distilled out under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:30) and recrystallized to yield the titled compound (574 mg, 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([CH3:26])([OH:25])[CH3:24])[C:20]([CH2:27][OH:28])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O>[C:35]([O:28][CH2:27][C:20]1[N:21]([CH2:22][C:23]([OH:25])([CH3:24])[CH3:26])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1)(=[O:37])[CH3:36]
Reactant: CC(C)(O)Cn1c(CO)nc2cnc3cc(OCc4ccccc4)ccc3c21
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-[7-benzyloxy-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (39.0 g, 0.133 mol), pyridine (390 mL), and acetic anhydride (195 mL) was heated at 35±5° C. for one hour in a reaction flask fitted with a calcium chloride drying tube. The reaction mixture was poured into a mixture of ice (2.5 kg) and deionized water and stirred for approximately 15 minutes. A precipitate formed and was isolated by filtration, washed with deionized water (500 mL), and dried under vacuum at 50° C. to provide 41.8 g of [7-benzyloxy-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)(O)[O-].[Na+]>CC(O)C>[CH3:15][C:2]1[N:16]=[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]2[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1
Reactant: Nc1ncccn1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc2ncccn2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In a thermally controlled reactor, stir a mixture of 2-bromo-1-[4-(trifluoromethyl)phenyl]propan-1-one (500 g, 1.78 mol, 1 equiv), IPA (5 L), 2-aminopyrimidine (205 g, 2.13 mol, 1.2 equiv), and sodium bicarbonate (298.8 g, 3.55 mol, 2 equiv) at 80° C. for 18 hours. Cool the suspension, and concentrate in vacuo. Dilute the resulting mixture in DCM (5 L), and wash with brine (2 L). Re-extract the brine wash with DCM (2.5 L); combine all the organic phases; and dry over MgSO4; filter; and collect the filtrate. Concentrate the filtrate to dryness under reduced pressure, and slurry the resulting red gum in Et2O (1.5 L). Collect the resulting solid by filtrate, and air dry for 45 min to give the title compound as a fine, off white solid (108 g, 22% yield). MS (m/z) 278 (M+1).
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.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)#[N:23]>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:33]4[CH2:32][CH2:31][N:30]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[C:22]#[N:23])[CH2:35][CH2:34]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: N#Cc1ccccc1N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: N#Cc1ccccc1N1CCN(C[C@@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-(2-cyanophenyl)piperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=473.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9](CC(C)(C)C)=[CH:10][CH:11]=2)[C:6]=1[OH:20])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:3][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:20]
Reactant: COC(=O)C1=C(O)c2cc(CC(C)(C)C)ccc2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2CCC1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To an ice-cooled solution of 7-(2,2-Dimethyl-propyl)-1-hydroxy-3,4-dihydro-naphthalene-2-carboxylic acid methyl ester (2.49 g, 9.07 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (1 M in tetrahydrofuran, 9 mL, 9 mmol). The reaction mixture was stirred at 0° C. for 2 h and then quenched with saturated ammonium chloride and ethyl acetate. The resulting emulsion was filtered through diatomaceous earth. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Flash column chromatography (silica gel, 10–20% ethyl acetate/hexanes) provided hydroxymethyl tetralone (1.55 g, 70%): 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=1.4 Hz, 1H), 7.27 (dd, J=7.8, 1.4 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 4.00–3.90 (m, 1H), 3.85–3.75 (m, 1H), 3.20–3.10 (m, 1H), 3.08–2.90 (m, 2H), 2.75–2.60 (m, 1H), 2.52 (s, 2H), 2.15–2.05 (m, 1H), 2.00–1.85 (m, 1H), 0.90 (s, 9H).