Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Cl:40][C:41]1[N:45]([CH3:46])[N:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[C:42]=1[C:51](O)=O.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:51]([C:42]2[C:43]([C:47]([F:50])([F:48])[F:49])=[N:44][N:45]([CH3:46])[C:41]=2[Cl:40])[O:16][N:15]=1
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Reactant: Cn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2c(C(F)(F)F)nn(C)c2Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.023 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.31 (s, 1H), 4.99 (s, 2H), 3.95 (s, 3H), 2.87 (t, 2H), 1.80-1.58 (m, 2H), 1.01 (t, 3H); MS (ES) m/z 484 (M+1).
Reaction SMILES: [C:1]([C:4]1([CH2:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:33]([O:40][C:41](=[O:47])[C@H:42]([CH:44]([CH3:46])[CH3:45])[NH2:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>O1CCCC1>[C:16]([S:15][CH2:14][C:4]1([C:1]([NH:43][C@H:42]([C:41]([O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:47])[CH:44]([CH3:46])[CH3:45])=[O:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)SCC1(C(=O)O)CCc2ccccc2C1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (278 mg, 1.0 mmol) in anhydrous tetrahydrofuran (10 mL). Add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (230 mg, 1.2 mmol), L-valine benzyl ester hydrochloride (244 mg, 1.00 mmol) and triethylamine (0.132 mL, 1.00 mmol). Stir at room temperature under an argon atmosphere overnight. Partition between ethyl ether and 5% sulfuric acid. Separate the organic phase and wash with water, saturated sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (20% ethyl acetate/hexane) to give the title compound as a clear yellow oil (256 mg, 55%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:25])[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([OH:25])[CH:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1ccc(-c2coc3cc(OC(C)=O)ccc3c2=O)cc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2COc3cc(OC(C)=O)ccc3C2O)cc1OC
Yield: 98.8 %

Procedure:
In a similar manner to Example 4.1, 7-acetoxy-3-(3,4-dimethoxyphenyl)chromen-4-one (1.4 g) and 5% Pd—C (0.24 g) were suspended in absolute ethanol (200 mL) and hydrogen was introduced to the system for 55 h until the reaction was complete. Filtration and evaporation gave a cis- and trans-mixture of 7-acetoxy-3-(3,4-dimethoxyphenyl)chroman-4-ol (1.4 g, 100%). This mixture was used in the next step without any further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[CH2:8]=O.Br.Br.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[NH:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:15][CH:14]=1>O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[NH2:29])=[CH:17][CH:18]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[NH:29][CH:30]2[CH2:31][CH2:32][N:33]([CH2:8][C:5]3[O:1][C:2]([CH2:6][OH:7])=[CH:3][CH:4]=3)[CH2:34][CH2:35]2)=[CH:15][CH:14]=1
Reactant: OCc1ccco1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: C=O
Agent: Br
Solvent: O
Product: Nc1nc2ccccc2n1Cc1ccc(F)cc1
Product: OCc1ccc(CN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)o1
Temperature: 3 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
A mixture of 30 parts of 2-furanmethanol, 300 parts of a formaldehyde solution 4% in water and 145 parts of 1-[(4-fluorophenyl)-methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide was stirred at 3° C. The mixture was allowed to reach slowly room temperature and stirring was continued for 3 days at room temperature. The reaction mixture was alkalized and extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using first trichloromethane and then a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the (E)-2-butenedioate salt and the free base was liberated again in the conventional manner. It was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 57 parts (44%) of 5-[[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimdazol-2-yl]amino]-1-piperidinyl]methyl]-2-furanmethanol; mp. 148.8° C. (compound 47).
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:8]=1)[CH2:2][CH3:3].C([Li])CCC.CN([CH:25]=[O:26])C>C1COCC1>[CH2:1]([C:4]1[S:5][C:6]([CH:25]=[O:26])=[C:7]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:8]=1)[CH2:2][CH3:3]
Reactant: CN(C)C=O
Reactant: CCCc1nc(COC2CCCCO2)cs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1nc(COC2CCCCO2)c(C=O)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
A solution of 2-propyl-4-((2-tetrahydropyranyloxy)methyl)thiazole (12.0 g, 49.8 mmol), from step 548 above, in 120 mL of THF was cooled to -78° C. and treated with n-butyllithium (20.0 mL, 2.5M solution in hexanes). The reaction mixture was stirred at -78° C. for 30 minutes, and 5.46 g (74.7 mmol) of DMF was added. The reaction mixture was stirred at -78° C. for 1.5 hours, then warmed to room temperature and quenched with satd NH4Cl solution. The mixture was partitioned between water and ethyl acetate. The organic extract was washed with water and brine, dried over MgSO4, and concentrated to afford 13.6 g of the title product as a viscous oil, which was taken to the next step without further purification. NMR (CDCl3) δ:10.32 (s, 1H), 5.15 (d, J=12 Hz, 1H), 4.88 (d, J=12 Hz, 1H), 4.81 (t, J=3 Hz, 1H), 3.92-3.82 (m, 1H), 3.61-3.47 (m, 1H), 2.99 (t, J=7 Hz, 2H), 1.9-1.5 (m, 8H), 1.03 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].[CH3:17][NH:18][CH2:19][CH2:20][CH3:21].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([N:18]([CH3:17])[CH2:19][CH2:20][CH3:21])=[O:10])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Reactant: CCCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Yield: 40.5 %

Procedure:
Stir a solution of 5-hydroxymethyl-isophthalic acid monoethyl ester (1.9 g, 8.4 mmol), N-methylpropylamine (947 μl, 9.2 mmol), 1-hydroxybenzotriazole (1.24 g, 9.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.77 g, 9.2 mmol) in a mixture of dichloromethane (12 mL) and DMF (12 mL) at room temperature for 1.5 h. Concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (950 mg, 40% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16]CC)=O)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:16])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)nc2)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(Cl)nc2)sc1C(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
A mixture of ethyl 2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazole-5-carboxylate i98 (0.47 g, 1 eq, 1.84 mmol), morpholine (0.19 g, 1.2 eq, 2.21 mmol) and triethylamine (0.5 ml, 2 eq, 3.68 mmol) in dichloromethane (15 ml) is cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.39 g, 1.1 eq, 2.02 mmol) and 1-hydroxybenzotriazole (0.05 g, 0.2 eq, 0.37 mmol) are then added to the solution and the mixture is stirred 24 h at room temperature. The mixture is then washed with water and a saturated solution of aqueous ammonium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to give 0.53 g of 4-{[2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]carbonyl}morpholine i99.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N+:15](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-:16]>S(Cl)(Cl)=O>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[N+:15]=[N-:16])[C:4]([C:3]1[C:2]([Cl:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=1)=[O:6])[CH3:22]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1ccc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
2-Chloro-6-trifluoromethylnicotinic acid (10.0 g, 44.3 mmol) was suspended in thionyl chloride (85 ml) and heated under reflux for 2 h. The mixture was allowed to cool to ambient temperature, the solvent was removed in vacuo, toluene (50 ml) was added and the solution concentrated to afford a brown residue. This residue was cooled to −10° C. before ethyl diazoacetate (12.7 g, 110 mmol) was added dropwise over 30 min (maintaining the internal temperature below −5° C.). On complete addition the mixture was allowed to stir at 0° C. for 1 h then heated at 55° C. for 18 h. The mixture was allowed to cool to ambient temperature then evaporated. The residue was purified by dry flash chromatography on silica eluting with isohexane on a gradient of ethyl acetate (10–30%). Collecting the appropriate fractions gave 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-2-diazo-3-oxo-propionic acid ethyl ester (13.7 g, 96%) as a yellow oil: δH (400 MHz, CDCl3) 1.17 (3H, t, J7), 4.15 (2H, q, J7), 7.68 (1H, d, J8), 7.78 (1H, d, J8), CHN2 absent.
Reaction SMILES: C(OC(N[C@H](C([N:18]([CH3:35])[C@@H:19]([C@@H:31]([CH3:34])CC)[C@H:20]([O:29][CH3:30])[CH2:21][C:22]([O:24]C(C)(C)C)=O)=O)C(C)C)=O)C1C=CC=CC=1.[CH:36]1(NC2CCCCC2)CCCCC1.[NH2:49][C@@:50]1([C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])[CH2:52][C@@H:51]1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(OC(N[C@@]1(C(O)=O)C[C@@H]1C1C=CC=CC=1)=O)(C)(C)C.C(O)C1C=CC=CC=1.[F:97][C:98]([F:103])([F:102])[C:99]([OH:101])=[O:100]>>[F:97][C:98]([F:103])([F:102])[C:99]([OH:101])=[O:100].[CH3:30][O:29][C@@H:20]([C@@H:19]1[CH2:31][CH2:34][CH2:35][NH:18]1)[C@@H:21]([CH3:36])[C:22]([NH:49][C@@:50]1([C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])[CH2:52][C@@H:51]1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:24]
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: N[C@@]1(C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)C[C@@H]1c1ccccc1
Solvent: OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)N[C@@]1(C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1

Procedure:
The title compound was prepared in analogy to the synthesis of Intermediate 18, proceeding from (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-3-methoxy-2-methylpropanoic acid (Starting Compound 1), which was released from the dicyclohexylamine salt, and benzyl(1S,2R)-1-amino-2-phenylcyclopropanecarboxylate. Benzyl (1S,2R)-1-amino-2-phenylcyclopropanecarboxylate had been prepared beforehand by standard methods, by esterifying commercially available (1S,2R)-1-[(tert-butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylic acid with benzyl alcohol and subsequent Boc detachment with trifluoroacetic acid.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:30])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]23[CH2:29][CH:24]4[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]4)[CH2:21]2)[CH2:27]3)=[CH:16][CH:15]=1.Cl.C(OCC)(=O)C>O1CCOCC1.O>[C:20]12([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:31])=[O:2])=[O:30])=[CH:15][CH:16]=3)[CH2:29][CH:24]3[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]3)[CH2:27]1)[CH2:21]2
Reactant: COC(=O)c1ccccc1NC(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1ccccc1C(=O)O
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A solution of 2-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid methyl ester (30.5 mg, 0.07 mmol) in 1,4-dioxane/H2O (3:1, 3 mL) added LiOHH2O (8.4 mg, 0.2 mmol) at room temperature. The resulting mixture was stirred overnight, and then acidified with 10% HCl to PH 2. Ethyl acetate was added and the organic layer was separated. The organic layer was washed with water, and dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:EtOAc:MeOH=6:3:1) to gave 2-[2-(4-Adamant-1-yl-phenoxy)-acetylamino]-benzoic acid as a white solid (18.5 mg, 62.5% yield).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: NCC1CCN(CCCC(F)(F)F)CC1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: O[C@@H](CNCC1CCN(CCCC(F)(F)F)CC1)COc1cccc2[nH]c3ccccc3c12
Yield: 45.6 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.125 g, 0.52 mmol) and 4-aminomethyl-1-(4,4,4-trifluorobutyl)-piperidine (0.224 g, 1.0 mmol) according to the procedure used for Example 2 to give 0.110 g of the title compound as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][F:39]>C(#N)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:37][CH2:38][F:39])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=2)[CH2:16][CH2:15]1
Reactant: Fc1ccc(O[C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)nc1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FCCN1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](Oc3ccc(F)cn3)CC2)C1
Temperature: 70 °C

Procedure:
A mixture of trans-8-chloro-1-[4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (0.10 g, 0.24 mmol) and potassium carbonate (67 mg, 0.48 mmol) in acetonitrile (1.2 ml) was treated with 1-bromo-2-fluoroethane (37 mg, 0.29 mmol) at 0° C. The cooling bath was removed and the reaction mixture was heated at 70° C. over night. The mixture was filtered and concentrated in vacuo. Purification by flash column chromatography gave the title compound (17 mg, 15%) as white solid. MS m/e: 460 (M+H+)
Reaction SMILES: C1(CN(C2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)CCC2C=CC(O)=CC=2)CC1.Cl.ClCCN1CCCC1.[CH:44]1([CH2:47][N:48]([C:65]2[CH:70]=[C:69]([O:71]C)[CH:68]=[CH:67][C:66]=2[CH:73]2[CH2:82][CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[C:78]([O:83]C)[CH:79]=3)[CH2:74]2)[CH2:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH2:59][N:60]3[CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:53][CH:52]=2)[CH2:46][CH2:45]1>>[CH:44]1([CH2:47][N:48]([CH2:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH2:59][N:60]3[CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:53][CH:52]=2)[C:65]2[CH:70]=[C:69]([OH:71])[CH:68]=[CH:67][C:66]=2[CH:73]2[CH2:82][CH2:81][C:80]3[CH:79]=[C:78]([OH:83])[CH:77]=[CH:76][C:75]=3[CH2:74]2)[CH2:45][CH2:46]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(OCCN3CCCC3)cc1)CC1CC1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(O)cc1)CC1CC1)C2
Agent: Cl
Agent: ClCCN1CCCC1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1N(CCc1ccc(OCCN3CCCC3)cc1)CC1CC1)C2
Yield: 89.4 %

Procedure:
Synthesized from 4-{2-{cyclopropylmethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol and 1-(2-chloroethyl)pyrrolidine hydrochloride according to an analogous synthetic method to Preparation Example 40, cyclopropylmethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]{2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]ethyl}amine (284 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (241 mg).
Reaction SMILES: [C:1]([C:3]1[O:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:8][C:9]1[S:10][C:11]([CH3:20])=[C:12]([CH3:19])[C:13]=1[C:14](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:14]1[C:13]2[C:12]([CH3:19])=[C:11]([CH3:20])[S:10][C:9]=2[N:8]=[C:1]([C:3]2[O:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Reactant: N#Cc1ccno1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C

Procedure:
With the procedure of Example 477, the reaction of 5-cyanoisoxazole and 2-amino-4,5-dimethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:19]=[CH:18][C:17]([CH3:21])([CH3:20])[C:16]2[C:9]=1[CH:10]=[C:11]1[C:15]=2[CH:14]=[N:13][N:12]1[CH2:22][C@H:23](O)[CH3:24].C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:33]([C@@H:23]([CH3:24])[CH2:22][N:12]1[C:11]2=[CH:10][C:9]3[C:16]([C:17]([CH3:21])([CH3:20])[CH:18]=[CH:19][C:8]=3[O:7][CH3:6])=[C:15]2[CH:14]=[N:13]1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=C2C=c3c(cnn3C[C@@H](C)O)=C2C(C)(C)C=C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2C(C)(C)C=C1
Yield: 89.2 %

Procedure:
0.8 ml (10.2 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.41 g (5.2 mmol) of (R)-1-(7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 2.9 ml (20.4 mmol) of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time arid the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.76 g (11.4 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.38 g (89%) of (S)-1-(2-azido-propyl)-7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a yellow oil.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Br[C:7]1[N:11]([C@H:12]2[O:24][C@@H:23]([CH2:25][O:26]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@@H:13]2[O:14]C(=O)C)[C:10]2[CH:30]=[C:31]([Cl:35])[C:32]([Cl:34])=[CH:33][C:9]=2[N:8]=1.C(O)C>CN(C=O)C>[Cl:34][C:32]1[C:31]([Cl:35])=[CH:30][C:10]2[N:11]([C@H:12]3[O:24][C@@H:23]([CH2:25][OH:26])[C@H:18]([OH:19])[C@@H:13]3[OH:14])[C:7]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[N:8][C:9]=2[CH:33]=1
Reactant: CC(C)CN
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)CNc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 75 °C
Reaction time: 24 h

Procedure:
Isobutylamine (10 ml ) and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.6 g, 1.1 mmol) were combined with absolute ethanol (50 mL) and stirred at 75° C. for 24 h. The reaction mixture was concentrated and purified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:20 methanol:dichloromethane (500 mL), then 1:9 methanol:dichloromethane to give a tan solid (0.39 g, 1.0 mmol. 90%); m.p. 136° C.; [a]20D =(-) 28.4 (c=0.5 DMF).
Reaction SMILES: C(O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:12]([CH2:24][CH3:25])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:14]=1)[CH3:11].[C:26]([O:29][C:30](=[O:32])[CH3:31])(=O)[CH3:27]>CO>[CH2:20]([N:19]([CH2:22][CH3:23])[C:15]1[CH:14]=[C:13]([N:12]([CH2:10][CH3:11])[CH2:24][CH3:25])[CH:18]=[CH:17][C:16]=1[C:26]1([C:5]2[CH:4]=[CH:3][C:2]([N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])=[CH:7][CH:6]=2)[C:27]2[C:31](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:30](=[O:32])[O:29]1)[CH3:21]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: O=C(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)cc1
Temperature: 70 °C

Procedure:
A mixture of 2-(4-diethylamino)benzoyl)benzoic acid (5.94 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (4.84 g.) and acetic anhydride (3 ml.) was heated at 70° C. Addition of methanol (20 ml.) afforded 3-(2,4-bis(diethylamino)phenyl)-3-(4-(diethylamino)phenyl)phthalide (I: X = Y4 = (CH3CH2)2N, Y2 = Z4 = Z5 = Z6 = Z7 = H) (7.1 g., 135°-137° C.).