Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18](O)=[O:19]>>[CH3:27][O:26][C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([O:14][CH3:13])[C:23]=1[O:24][CH3:25])[C:18]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([OH:12])[CH2:11][CH:2]1[CH3:1])=[O:19]
Reactant: CC1CC(O)c2ccccc2N1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Product: COc1cc(C(=O)N2c3ccccc3C(O)CC2C)cc(OC)c1OC
Yield: 33.4 %

Procedure:
Starting with 2-methyl-1,2,3,4-tetrahydro-4-quinolinol (3.00 g, 18.3 mmol) synthesized in the published manner and 3,4,5-trimethoxybenzoic acid (2.0 g, 10.9 mmol), the same procedure as shown in Reference Example 19 was repeated to give the titled compound (1.30 g, yield: 33%) as a white crystal. (cis:trans=1:1)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[C:12]1(=[O:29])[N:16]([CH:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[C:15](=[O:24])[C:14]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:13]12>C(O)C>[C:15]1(=[O:24])[N:16]([CH:17]2[CH2:18][C:19]3[C:8]4[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:9]=4)[NH:10][C:20]=3[CH2:21][CH2:22]2)[C:12](=[O:29])[C:13]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:14]12
Reactant: COc1ccc(NN)cc1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: Cl
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)CC3
Yield: 93.5 %

Procedure:
Reaction of 4-methoxyphenyl hydrazine hydrochloride (0.87 g, 5.0 mmol) with 4-phthalimido-cyclohexanone (1.22 g, 5.0 mmol) in ethanol (20 ml) heated under reflux for 2 hr, followed by cooling and removal of the precipitated solid by filtration gave 3-phthalimido-6-methoxy-1,2,3,4-tetrahydrocarbazole (1.62 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([OH:19])=[C:14](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([OH:19])=[C:14]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:15]=1
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Oc1ccc(Cl)cc1-c1ccnc(Cl)n1
Temperature: 0 °C
Yield: 7.7 %

Procedure:
A mixture of 2,4-dichloropyrimidine (0.765 g, 5.03 mmol), (5-chloro-2-hydroxyphenyl)boronic acid (0.568 g, 3.30 mmol), 2.0 M aqueous sodium carbonate (2.82 mL, 5.64 mmol), and 1,2-dimethoxyethane (8 mL) was sparged for 10 minutes with argon. Tetrakis(triphenylphosphine)palladium(0) (0.217 g, 0.19 mmol) was added, and the resultant mixture was heated for 4 hours at 85° C. The reaction mixture mixture was cooled to 0° C., quenched with saturated aqueous ammonium chloride solution, and extracted with dichloromethane (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by automated silica gel flash chromatography (hexanes to ethyl acetate gradient elution) to afford the title compound as a yellow solid (61.5 mg, 7%).
Reaction SMILES: [CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:36])[N:13]([CH2:21][C:22]([N:24]([CH:33]([CH3:35])[CH3:34])[C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[O:23])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1>>[CH:1]1([C:7]2[N:16]3[C:10]([C:11](=[CH:46][C:39]4[C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[NH:37][CH:38]=4)[C:12](=[O:36])[N:13]([CH2:21][C:22]([N:24]([CH:33]([CH3:34])[CH3:35])[C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[O:23])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(C4CCCCC4)n3-c3ccccc32)C(C)C)cn1
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4ccccc34)c3nnc(C4CCCCC4)n3-c3ccccc32)C(C)C)cn1
Yield: 64 %

Procedure:
Following the procedure described for Example 1(A), Step A, 2-(1-cyclohexyl-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (Preparation 8(A)) (90 mg, 0.184 mmol) was condensed with 1H-indole-3-carbaldehyde (32 mg, 0.221 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (10% EtOAc in hexanes to 100% EtOAc) yielded 72.5 mg of 2-[1-cyclohexyl-4-(1H-indol-3-ylmethylene)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CDCl3) δ 8.63 (s, 1H), 8.16 (m, 1H), 7.88-7.96 (m, 1H), 7.45-7.76 (m, 2H), 7.12-7.44 (m, 1H) 6.83 (m, 1H), 5.10 (m, 1H), 4.11-4.35 (m, 1H), 3.94 (t, 2H), 3.84 (dd, 1H), 2.94 (m, 1H), 2.25 (m, 1H), 1.99 (m, 2H), 1.70 (m, 6H), 1.35 (m, 3H), 1.15 (m, 6H); MS 616.4 (M+1), 614.3 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:16])([F:15])[CH2:12][O:13][CH3:14])=[N:9][N:10]=2)[CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)#[CH:18]>C1COCC1.[Cu]I>[F:15][C:11]([C:8]1[N:6]2[CH:7]=[C:2]([C:18]#[C:17][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([F:16])[CH2:12][O:13][CH3:14]
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: COCC(F)(F)c1nnc2ccc(Br)cn12
Agent: [Cu]I
Solvent: C1CCOC1
Product: COCC(F)(F)c1nnc2ccc(C#Cc3ccc(C(F)(F)F)cc3)cn12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-bromo-3-(1,1-difluoro-2-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyridine (46 mg, 0.16 mmol) in THF (5 mL) was added catalytic amount of dichlorobis(triphenylphosphine) palladium(II) (11 mg) and copper(I) iodide (3 mg), followed by 1-ethynyl-4-(trifluoromethyl)benzene (41 mg, 0.24 mmol). The resulting mixture was flushed with N2 and Et3N (2 mL) was added. The reaction mixture was stirred at 70° C. overnight and purified by prep-TLC (EtOAc: hexanes=2:3) followed by HPLC to give 3-(1,1-difluoro-2-methoxyethyl)-6-((4-(trifluoromethyl)phenyl)ethynyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: C(OC([NH:8][C:9]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)([CH3:22])[CH2:10][NH:11][C:12]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=O)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:8][C:9]([C:23]1[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=1)([CH3:22])[CH2:10][NH:11][C:12]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)C1(NCC(C)(NC(=O)OC(C)(C)C)c2cc(F)cc(F)c2)CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)C1(NCC(C)(N)c2cc(F)cc(F)c2)CCCCC1
Reaction time: 0.5 h

Procedure:
A solution of methyl 1-{[2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propyl]amino}cyclohexanecarboxylate from Step E (280 mg, 0.657 mmol) in EtOAc (5 mL) at 0° C. was saturated with HCl (g). The reaction mixture was aged at 0° C. for 30 min, then poured carefully into saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=327 (M+1).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1Cl>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
6.5 g of pulverised potassium hydroxide and 20 g of methyl 4-hydroxy-α-phenoxypropionate in 250 ml of dry dimethyl sulphoxide are charged at 0° C into a three-necked flask. With stirring, and at a temperature between 0° and 5° C, 19.5 g of 3,4-dichloro-nitrobenzene are added by small amounts and stirring is continued for 12 hours at room temperature. Thereafter the reaction mixture is poured into ice-water and extracted with ethyl acetate. The extract is dried over sodium sulphate and the solvent distilled off to yield an oily product which is then subjected to high vacuum distillation. The resultant substance, viz. methyl 4-(2'-chloro-4'-nitrophenoxy)-α-phenoxypropionate (yield 27 g), boils at 194° C/0.01 Torr (compound 1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[C:23]([Cl:24])=[CH:22][N:21]=[C:20]2[O:25][CH2:26][O:27][C:19]=12>>[Cl:24][C:23]1[C:18]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[C:19]2[O:27][CH2:26][O:25][C:20]2=[N:21][CH:22]=1
Reactant: ClCCCOc1ccc2c(Cl)ncnc2c1
Reactant: Nc1c(Cl)cnc2c1OCO2
Product: ClCCCOc1ccc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2c1
Yield: 89 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-7-(3-chloropropoxy)quinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 89% yield; NMR Spectrum: (DMSOd6 and CF3CO2D) 2.25 (m, 2H), 3.8 (t, 2H), 4.35 (t, 2H), 6.25 (s, 2H), 7.35 (s, 1H), 7.6 (d, 1H), 7.9 (s, 1H), 8.7 (d, 1H), 9.0 (s, 1H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26])[NH:13][C:12]=2[CH:11]=1.[OH-].[K+]>C(C(C)=O)C>[CH2:2]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:29])(=[O:28])[N:25]([CH3:26])[CH3:27])[NH:13][C:12]=2[CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCI
Reactant: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: CCCCCCCOc1ccc2c(c1)Nc1cccc(S(=O)(=O)N(C)C)c1S2
Yield: 149.8 %

Procedure:
2-Heptyloxy-6-dimethylsulphamoylphenothiazine (m.p. 160°-162°C.; 23.4 g.) is prepared by reacting 1-iodoheptane (8.4 g.) with 2-hydroxy-6-dimethylsulphamoylphenothiazine (76.8 g.) in the presence of powdered potassium hydroxide (41.4 g.) in methyl ethyl ketone (600 cc.).
Reaction SMILES: Cl.[C:2]([CH2:5][CH2:6][CH2:7][CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH2:11][CH2:10][N:9]1[CH2:21][CH3:22])([OH:4])=[O:3].C(=O)(O)[O-].[Na+].[CH2:28](O)[CH3:29]>>[CH2:28]([O:3][C:2]([CH2:5][CH2:6][CH2:7][CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH2:11][CH2:10][N:9]1[CH2:21][CH3:22])=[O:4])[CH3:29]
Reactant: CCN1CCc2c([nH]c3ccccc23)C1CCCC(=O)O
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CCCC1c2[nH]c3ccccc3c2CCN1CC
Yield: 85 %

Procedure:
15 ml of ethanol and 3 ml of 10% ethanolic hydrogen chloride were added to 2.86 g of 1,2,3,4-tetrahydro-1-(3-carboxypropyl)-2-ethyl-β-carboline, and the mixture was refluxed for 2 hours. After the reaction was completed, the mixture was evaporated under reduced pressure to remove solvent. The residue thus obtained was alkalified with an aqueous saturated sodium bicarbonate solution and then extracted with ethyl acetate. The extract was washed with water, dried and evaporated to remove solvent. 2.67 g of 1,2,3,4-tetrahydro-1-(3-ethoxycarbonylpropyl)-2-ethyl-β-carboline were obtained. Yield: 85.0%.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([CH2:30][CH2:31][S:32][C:33]1[CH:34]=[C:35]([C:39]([C:41]2[N:42]=[CH:43][N:44]3[CH:48]=[C:47]([Sn](CCCC)(CCCC)CCCC)[S:46][C:45]=23)=[O:40])[CH:36]=[N:37][CH:38]=1)=[N+:28]=[N-:29]>>[N:27]([CH2:30][CH2:31][S:32][C:33]1[CH:34]=[C:35]([C:39]([C:41]2[N:42]=[CH:43][N:44]3[CH:48]=[C:47]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]5[C:7]=4[C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=4)=[O:13])[S:46][C:45]=23)=[O:40])[CH:36]=[N:37][CH:38]=1)=[N+:28]=[N-:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(SCCN=[N+]=[N-])c3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(SCCN=[N+]=[N-])c5)c4s3)[C@H](C)[C@H]12
Yield: 41 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-[5-(2-azidoethylthio)pyridin-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (370 mg) was prepared in the same manner as in step a) of Example 1, except that 485 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 857 mg of 7-[5-(2-azidoethylthio)pyridin-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [CH2:1]([C:8]1([C:17]([O:19]C)=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH2:1]([C:8]1([C:17]([OH:19])=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Cc2ccccc2)CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(Cc2ccccc2)CCc2ccccc21
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
Methyl 1-benzylindane-1-carboxylate (2.5 g, 9.4 mmol) from Step B was dissolved in a solution of 23 mL methanol and 23 mL water. Sodium hydroxide (0.940 g, 23.5 mmol) was added to the reaction. The reaction was refluxed and stirred for 90 minutes and then quenched with 100 mL of 1N HCl and extracted with diethyl ether (3×50 mL). The combined organic washings were dried over MgSO4 and evaporated to furnish 1-benzylindane-1-carboxylic acid (2.4 g, 100%) as a yellow oil that was pure enough to be used in the next step.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[CH:30]1(O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[F:29][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:25]=[C:24]([C:26]([O:28][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: O=C(O)c1cccc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Reactant: OC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(OC1CCCCC1)c1cccc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-pyridine-2-carboxylic acid (157 mg) in dichloromethane (5 ml) are added, at room temperature, cyclohexanol (42 mg), 4-dimethylaminopyridine (4.6 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (80 mg). The mixture is stirred at room temperature overnight, and then water is added. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives cyclohexyl 6-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)pyridine-2-carboxylate (87 mg).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[CH:25][C:26]([N:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[N:23]([C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)[CH:22]=2)=[CH:17][CH:16]=1.O>CN(C=O)C>[CH3:6][N:5]([CH3:7])[CH2:4][CH2:3][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:29]3[C:24](=[CH:25][C:26]([N:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)=[CH:27][CH:28]=3)[N:23]([C:43]3[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=3)[CH:22]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(-c4ccc(O)cc4)cn(-c4ccncc4)c3c2)CC1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Chloro-N,N-dimethylethylamine hydrochloride (7.3 mg, 0.051 mmol) and cesium carbonate (33 mg, 0.101 mmol) were added to a mixture solution of tert-butyl 4-(3-(4-hydroxyphenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate (12 mg, 0.025 mmol) in DMF (1 mL). After room temperature stirring at room temperature for 16 hours, followed by addition of water, the mixture was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The target compound was obtained as white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:29]=[CH:28][C:27]2[N:26]([CH2:30][O:31][CH3:32])[C:25]3[C:33](=[O:45])[N:34]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:35]=[C:36]([CH2:37]O)[C:24]=3[C:23]=2[CH:22]=1.[Br:46]C(Br)(Br)Br.C1CCCCC1>ClCCl>[Br:46][CH2:37][C:36]1[C:24]2[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[N:26]([CH2:30][O:31][CH3:32])[C:25]=2[C:33](=[O:45])[N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:35]=1
Reactant: COCn1c2ccc(F)cc2c2c(CO)nn(-c3ccccc3)c(=O)c21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: COCn1c2ccc(F)cc2c2c(CBr)nn(-c3ccccc3)c(=O)c21
Reaction time: 2 h
Yield: 77.8 %

Procedure:
4.5 g (17.1 mmol) of triphenylphosphine are added to a solution of 3.2 g (9 mmol) of 8-fluoro-1-(hydroxymethyl)-5-(methoxymethyl)-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one and of 6.3 g (19 mmol) of tetrabromomethane in 200 ml of dichloromethane. The mixture is stirred for 2 h, 50 ml of cyclohexane are added and the precipitate is collected by filtration and dried under reduced pressure. 2.9 g (7 mmol) of solid are isolated, which solid is used as is in the following stage.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(N(CC)CC)C.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>CN(C)C=O>[N:10]1[C:2]([NH:1][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:3]2[C:7]([N:6]=[CH:5][NH:4]2)=[N:8][CH:9]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CNc1ncnc2nc[nH]c12)C(=O)OCC
Yield: 75.4 %

Procedure:
A mixture of 6-aminopurine (13.5 g), triethylamine (10.1 g) and 2-ethoxy-1,1-bis(ethoxycarbonyl)ethene (21.6 g) in dimethylformamide (100 ml) was heated at reflux for 16 hours. It was then cooled and the product which separated was crystallised from dimethylformamide and washed with diethyl ether, to give 2-(purin-6-ylamino)-1,1-bis(ethoxycarbonyl)ethene (23 g), in the form of colourless, fluffy crystals, m.p. 234° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7]
Reactant: Cc1ccccc1C=CC(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)/C=C\c1ccccc1CBr

Procedure:
A mixture of 2 g (12.34 mmol) of (E) 2-methyl cinnamic acid, 2.19 g (12.34 mmol) of N-bromosuccinimide (NBS) and a catalytic amount of benzoyl peroxide in 6 ml of CCl4 are heated under reflux for hours. The residue is filtered and washed with ether. The organic phase is successively washed with a 1N HCl aqueous solution then with water. It is dried on MgSO4, filtered and evaporated to dryness.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1)(=[O:17])[CH3:16]
Reactant: NC(=O)NC1CCC(O)c2sccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CCC(NC(N)=O)c2ccsc21

Procedure:
Two g (9.43 mm) of 4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylurea is stirred for 2 days at room temperature with acetic anhydride (5 ml) and pyridine (10 ml). The excess reagents are removed in vacuo, the resulting gum dissolved in methylene chloride (50 ml), the solution washed with water (50 ml), the water wash counter extracted with methylene chloride (25 ml), the combined methylene chloride layers dried with sodium sulfate and evaporated. The resulting gum is treated with ethyl acetate (≈5 ml) to afford a first crop (1.15 g, 48% Y) of the title compound, m.p. 168° C-170° C, dec. and a second crop (0.58 g, 24% Y) m.p. 166° C-172° C, dec. The analytical sample crystallized from ethyl acetate has m.p. 165° C-168° C dec. The isomeric compound prepared in the same manner melts at 182° C-184° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10]1.C1C(=O)N([Br:35])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:35])[NH:12][C:11]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2ncccc2Cl)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2ncccc2Cl)=NC1c1ccc(F)cc1Br
Yield: 49.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(3-chloropyridin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (6.07 g, 13.4 mmol) (The compound was synthesized according to the procedure as described in WO0058302) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.5 g, 49%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]([OH:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(O)c1cc2cccc(Cl)c2nc1Cl
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2cccc(Cl)c2nc1Cl
Yield: 89.3 %

Procedure:
A mixture of 1-(2,8-dichloroquinolin-3-yl)ethanol (5.0 g, 21 mmol) and MnO2 (18 g, 10 eq) in toluene (200 mL) were heated to reflux for 2 h. Filtration followed with removal of solvent gave a white solid as 1-(2,8-dichloroquinolin-3-yl)-ethanone (4.5 g, 91%). A solution of this solid (5.0 g, 21 mmol) in THF (50 mL) was added to a solution of (+)-DIP-Cl (14.7 g, 2.2 eq) in THF (150 mL) at −78° C. dropwise. The reaction was slowly warmed up to rt over night. The reaction was then quenched with acetone (23 mL) and stirred at 0° C. for 1 h before addition of EtOAc. The reaction was warmed up to rt and washed with 10% Na2CO3 and water. Chiral HPLC on IA column (isopropanol in hexane, 10%) showed a ratio of 19:1 for two enantiomers. The combined crude products were concentrated under high vacuum and purified by column chromatography on silica gel (EtOAc/hexane, 1/3) to give a white solid which is recrystallized from a mixture of EtOAc (30 mL) and Hexane (210 mL). A white needle was obtained. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 5.40 (q, J=8.0 Hz, 1H), 1.63 (d, J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=242 (M+1).