Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]([O:21][C:22]([F:39])([F:38])[C:23]([F:37])([F:36])[O:24][C:25]([F:35])([F:34])[C:26]([F:33])([F:32])[O:27][C:28]([F:31])([F:30])[F:29])([F:20])[F:19])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:40]([O:44][CH2:45][CH2:46][CH2:47][CH2:48]Cl)[CH2:41][CH2:42][CH3:43]>>[CH3:43][CH2:42][CH2:41][CH2:40][O:44][CH2:45][CH2:46][CH2:47][CH2:48][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]([O:21][C:22]([F:39])([F:38])[C:23]([F:36])([F:37])[O:24][C:25]([F:34])([F:35])[C:26]([F:32])([F:33])[O:27][C:28]([F:29])([F:30])[F:31])([F:20])[F:19])=[CH:10][CH:9]=2)=[N:4][CH:3]=1
Reactant: Oc1cnc(-c2ccc(CCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Reactant: CCCCOCCCCCl
Product: CCCCOCCCCOc1cnc(-c2ccc(CCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 12 by combining 5-hydroxy-2-[4-(2-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)ethyl)phenyl]pyrimidine (2.0 g, 3.5 mmol) with 4-butoxybutyl chloride (7.0 g, 4.2 mmol). The reaction mixture was quenched with water, and the resulting crude product was further purified by recrystallization from ethanol, followed by Kugelrohr distillation (210-15° C. at 0.15 torr), to provide a yield of 1.39 g.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1>O1CCCC1>[NH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCN)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)ccc3OCCCN)ccc21
Yield: 59.3 %

Procedure:
In a manner similar to that of Example 2a, by reaction of 140 mg (3.5 mmol) of sodium hydroxide with 170 mg (0.35 mmol) of ethyl 4′-(3-aminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (Example 17b) in 30 ml of tetrahydrofuran. 95 mg of 4′-(3-aminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid are obtained in the form of a white solid (m.p.=243° C., yield=49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19]OS(C)(=O)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: C1CCNCC1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Solvent: CCO
Product: Cc1cc(-c2cc(CN3CCCCC3)c(=O)n(CC(C)C)n2)ccc1F
Temperature: 80 °C

Procedure:
6-(4-Fluoro-3-methylphenyl)-2-isobutyl-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one (80 mg, 0.22 mmol) and piperidine (55 mg, 0.65 mmol) were dissolved in ethanol (0.5 mL), and the mixture was heated at 80° C. for 1 hour under stirring. The solvent was distilled off. The residue was purified by preparative thin-layer chromatography on silica gel [developing solvent: chloroform/methanol (10/1)] to yield the title compound as a slightly yellow oil (73 mg, 94.0%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][CH2:20][S:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:23][O:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[O:24][CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][CH2:20][S:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Cl
Solvent: Cc1ccccc1
Product: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1OC
Temperature: 55 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(3-methylthiopropoxy)quinoline (0.95 g, 2.97 mmol) and 2-methoxyaniline (1.46 g, 11.8 mmol) in toluene was heated to 55° C. and stirred overnight. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated. The residue was chromatographed (SiO2 ; CH2Cl2 :MeOH 95:5) yielding 0.90 g (71%) of the desired product.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[N:22][CH:23]=[C:18]([S:17][CH3:16])[CH:19]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CSc1cncc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (600 mg, 2.419 mmol), 5-(methylthio)pyridin-3-ylboronic acid (429 mg, 2.54 mmol), PdCl2(PPh3)2 (170 mg, 0.242 mmol), sodium carbonate (769 mg, 7.26 mmol), 1,4-dioxane (6.5 mL), and water (1.6 mL) at 95° C. for 2 h. Purification by column chromatography (silica gel, 0-30% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-3-methyl-2-(5-(methylthio)pyridin-3-yl)quinoline. Mass Spectrum (ESI) m/e=337.0 (M+1).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[C:22]1(B(O)O)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: OB(O)c1cccc2ccccc12
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3cccc4ccccc34)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), naphthalene-1-boronic acid (99 mg, 0.575 mmol) and potassium carbonate (120 mg, 0.87 mmol) in mixture of 1,2-dimethoxyethane (4 mL)-water (2 mL) was purged with nitrogen followed by addition of Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(naphthalen-1-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (DMSO, TFA salt) δ (ppm): 8.0 (d, 1H), 7.8 (d, 1H), 7.79 (d, 1H), 7.3-7.5 (m, 5H), 7.1 (s, 1H), 6.9 (d, 1H), 4.21 (m, 2H), 3.4 (m, 2H), 2.77-3.0 (m, 9H), 2.3 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:39]2[CH:40]=[C:41]3[O:45][CH2:44][CH2:43][C:42]3=[C:46]([CH:48]=[O:49])[CH:47]=2)O1>O1CCOCC1.O.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:39]4[CH:47]=[C:46]([CH:48]=[O:49])[C:42]5[CH2:43][CH2:44][O:45][C:41]=5[CH:40]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(C=O)c3c(c2)OCC3)OC1(C)C
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: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)c5c(c4)OCC5)cc23)CC1
Temperature: 120 °C
Yield: 90.9 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (113 mg, 0.274 mmol) in dioxane (9.0 mL) and H2O (3.0 mL) was added sodium carbonate (174 mg, 1.64 mmol), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-4-carbaldehyde (150 mg, 0.547 mmol). The reaction mixture was flushed under Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0) (16 mg, 0.014 mmol). The reaction was heated in a microwave at 120° C. for 30 min. All solvent was then concentrated and purified by flash chromatography using DCM and MeOH to give 120 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2,3-dihydro-1-benzofuran-6-yl)-1H-indole-7-carboxamide (91%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:41][C@@H:42]2[O:44][CH2:43]2)(=O)=O)=CC=1>CC(N(C)C)=O>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:41][C@H:42]5[CH2:43][O:44]5)=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
Nitrogen was bubbled through a mixture of 7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (3.07 g, 10 mmol), (prepared as described for the starting material in Example 107), potassium carbonate (4.14 g, 30 mmol) and (2R)-(−)-glycidyl tosylate (4.57 g, 20 mmol) in DMA (35 ml) for 5 minutes. The mixture was then stirred at 60° C. for 2 hours under an atmosphere of nitrogen and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica by gradient elution with dichloromethane/methanol (100/0 to 95/5), to give (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline as a yellow solid (1.92 g, 53%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>>[CH3:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: COCCCCN
Product: COCCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 75.5-76.8° C. and MS: m/e=298 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and 4-methoxy-butylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[C:29]([F:30])=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[C:19]([F:31])[CH:18]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:13][C:12]([F:15])([F:14])[CH2:11]1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[C:29]([F:30])=[CH:28][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:31])[CH:18]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][C:12]([F:14])([F:15])[CH2:13]1
Reactant: CC(C)(C)OC(=O)c1cc(F)c(Oc2cnc(OCC3CC(F)(F)C3)c(Cl)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(F)c(Oc2cnc(OCC3CC(F)(F)C3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
tert-Butyl 4-({5-chloro-6-[(3,3-difluorocyclobutyl)methoxy]pyridin-3-yl}oxy)-2,5-difluorobenzoate (Preparation 7, 0.400 g, 0.87 mmol) was dissolved in THF (5.0 mL) and methanol (5.0 mL). Then an aqueous solution of sodium hydroxide was added (3.0 M, 5.0 mL) and the mixture was stirred at room temperature under nitrogen for 3 hours. Aqueous solution of HCl (1.0 M, 75.0 mL) was added and the mixture was extracted with EtOAc (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (trilution method) to afford the title compound (0.31 g, 88%):
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:18])=[CH:13][O:14][C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[C:25]1([CH2:31]CC(Cl)=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.CCOCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:18])=[CH:13][O:14][C:15](=[O:17])[CH2:16][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=COC(=O)CCc1ccccc1)Cc1ccc(C(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 83.5 %

Procedure:
A solution of 65.8 g acetic acid 3-(4-tert-butyl-phenyl)-2-methyl-propenyl ester in 200 ml of THF was cooled to −70° C. A solution of 42.3 g potassium-tert-butoxide in 200 ml of THF was added at −70° C. during 20 min. and the resulting reaction mixture was stirred for 90 min. at the same temperature. 53.5 g 3-phenyl-propionyl chloride was dropped in and the reaction mixture was stirred for another 3 hours at −70° C. Then the reaction mixture was diluted with ether, washed with saturated NaHCO3 and brine. The organic phase was dried, filtered and evaporated to dryness. The residue was thin-layer distilled to yield 75.0 g of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[C:39]([Zn]C#N)#[N:40].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CN(C=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:39]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:26][CH2:27]3)[CH:20]=[N:19][CH:18]=1)#[N:40]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C#N)cc34)n2)C1
Temperature: 100 °C
Yield: 91.5 %

Procedure:
(4R)-tert-Butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (124 mg, 0.212 mmol), dicyanozinc (Aldrich, St. Louis, Mo.; 32.4 mg, 0.276 mmol), Pd2(dba)3 (Aldrich, St. Louis, Mo.; 9.71 mg, 10.61 μmol), and XPhos (Strem, Newburyport, Mass.; 10.11 mg, 0.021 mmol) in a mixture of DMF (2.0 mL) and water (0.020 mL) was heated at 100° C. for 19 h. The mixture was concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-60% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(5-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (102.8 mg, 0.194 mmol, 91% yield) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.04 (1 H, s), 8.74 (1 H, br. s.), 8.25 (1 H, br. s.), 8.02 (1 H, s), 7.78 (1 H, s), 7.64 (1 H, s), 5.84 (1 H, d, J=6.8 Hz), 4.63 (1 H, br. s.), 4.35-4.44 (1 H, m), 4.21-4.33 (1 H, m), 3.90-4.10 (2 H, m), 3.73-3.85 (2 H, m), 3.34 (2 H, d, J=14.1 Hz), 2.53-2.70 (2 H, m), 2.45 (1 H, m), 2.09-2.30 (2 H, m), 1.68-1.90 (4 H, m), 1.14 (9 H, br. s.). MS (ESI, pos. ion) m/z: 531.3 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([F:11])=[C:9](Cl)[N:8]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[C:6]=1[Cl:17])(=[O:3])[CH3:2].NC1C(F)=C([Br:26])N=C(C(OC)=O)C=1Cl>>[C:1]([NH:4][C:5]1[C:10]([F:11])=[C:9]([Br:26])[N:8]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[C:6]=1[Cl:17])(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(Cl)c(F)c(NC(C)=O)c1Cl
Reactant: COC(=O)c1nc(Br)c(F)c(N)c1Cl
Product: COC(=O)c1nc(Br)c(F)c(NC(C)=O)c1Cl

Procedure:
Methyl 4-(acetylamino)-6-bromo-3-chloro-5-fluoro-picolinate was prepared in analogous fashion to methyl 4-(acetylamino)-3,6-dichloro-5-fluoro-picolinate in Example 8 except that methyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate was used in place of methyl 4-amino-3,6-dichloro-5-fluoropicolinate: mp=190-192° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.5 (s, 1H), 3.93 (s, 3H), 2.16 (s, 3H); 13C NMR (100.6 MHz, DMSO-d6) δ 168.0, 162.8, 153.1, 150.5, 143.7 (d, JF-C=24 Hz), 134.1 (d, JF-C=56 Hz), 127.3 (d, JF-C=96 Hz), 53.2, 22.5; 19F NMR (376.5 MHz, DMSO-d6) δ −108.3; MS Calcd. for C9H7BrCl2FN2O3: 323.93. Found: 289, 226.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH:13][C:14]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)=[O:15])[CH:7]=1.CO.[OH-].[Na+]>C1COCC1>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:27])=[O:2])=[CH:7][C:8]=1[NH:13][C:14]([C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:15]
Reactant: COC(=O)C=Cc1ccc(F)c(NC(=O)c2ccc(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C=Cc1ccc(F)c(NC(=O)c2ccc(-c3ccccc3)o2)c1
Reaction time: 1 h

Procedure:
The ester (44) (18 mg, 0.049 mmol) was hydrolysed using Method C, except that MeOH (1 mL), THF (1 mL) and 1M NaOH (2 mL) were used, and the reaction was stirred for 1 hour. Yield: 3 mg, 17%; LC-MS tr 1.44 min; HPLC Purity: 91%; MS (ES+) m/z 352 (M+H); 1H NMR (400 MHz; MeOH): δ 6.50 (d, 1H), 7.05 (d, 1H), 7.25-7.60 (m, 6H), 7.70 (d, 1H), 7.95 (d, 2H), 8.15 (d, 1H)
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(OCC)C.[CH2:14]([C:16]1[C:30]([O:31][CH3:32])=[CH:29][C:19]2[C@@H:20]3[C@H:24]([CH2:25][C:26](=[O:27])[C:18]=2[C:17]=1[OH:33])[CH2:23][N:22]([CH3:28])[CH2:21]3)[CH3:15]>C(O)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH2:14]([C:16]1[C:30]([O:31][CH3:32])=[CH:29][C:19]2[CH:20]3[CH:24]([CH2:25][C:26](=[O:27])[C:18]=2[C:17]=1[OH:33])[CH2:23][N:22]([CH3:28])[CH2:21]3)[CH3:15]
Reactant: CCc1c(OC)cc2c(c1O)C(=O)C[C@@H]1CN(C)C[C@H]21
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CCO
Product: CCc1c(OC)cc2c(c1O)C(=O)CC1CN(C)CC21
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.9 %

Procedure:
168 mg (1.45 mmol) of fumaric acid and 50 ml of diethyl ether were added while stirring to a solution of 0.4 g (1.45 mmol) of cis-7-ethyl-6-hydroxy-8-methoxy-2-methyl-1,2,3,3a,4,9b-hexahydro-benzo[e]isoindol-5-one in 0.5 ml of ethanol. The mixture was stirred at room temperature for a further 17 hours and the solid was subsequently filtered off. 0.55 g (97%) of 7-ethyl-6-hydroxy-8-methoxy-2-methyl-1,2,3,3a,4,9b-hexahydro-benzo[e]isoindol-5-one fumarate (1:1) was obtained as a white solid with m.p. 195°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([OH:30])[CH:29]=1>C(OCCO)C>[OH:30][C:28]1[CH:29]=[C:24]([NH:23][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:25]=[CH:26][C:27]=1[O:31][CH3:32]
Reactant: COc1ccc(N)cc1O
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1ccc(Nc2c(C#N)cnc3c(OC)cccc23)cc1O
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 200.0 mg (0.92 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 105.7 mg (0.92 mmol) of pyridine hydrochloride and 140.6 mg (1.0 mmol) of 5-amino-2-methoxy-phenol in 10 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. The work up gave 261.6 mg (89.0%) of the product as a deep yellow solid, m.p. 138-140° C. (dec.), mass spectrum (electrospray, m/e): M+H 321.9.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>ClCCCl.ClC(Cl)C>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccccc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: Oc1ccccc1Oc1ccccc1
Yield: 82.3 %

Procedure:
A solution of 23.4 g (74.9 mmol) of boron tribromide-dimethyl sulfide complex in 150 mL of 1,2-dichloroethane was added dropwise to 3.00 g (15.0 mmol) of 2-methoxyphenyl phenyl ether in 50 mL dichloroethane at room temperature. The mixture was stirred at reflux overnight. 50 mL 3M NaOH was added to quench the reaction. After separation of layers, the organic layer was extracted with 3×100 mL 3M NaOH. The combined aqueous layer was acidified with conc. HCl, and the precipitated product was extracted with 3×150 mL ethyl ether. After washing with brine solution, drying over MgSO4, and filtering, solvents were evaporated under reduced pressure to give 2.30 g (82.4%) of an off-white solid, which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 5.57 (s, 1H); 6.81-6.90 (m, 2H); 7.01-7.07 (m, 4H); 7.12 (t, 1H, J=7.3 Hz); 7.31-7.38 (m, 2H). ##STR105##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:30].[Cu](C#N)[C:32]#[N:33].C(OCC)(=O)C>CN(C)C=O>[Cl:30][C:3]1[CH:4]=[C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:32]#[N:33]
Reactant: N#C[Cu]C#N
Reactant: O=S(=O)(c1ccc(Br)c(Cl)c1)N1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1Cl
Temperature: 200 °C
Yield: 42.1 %

Procedure:
2.48 g 1-(4-bromo-3-chloro-benzenesulfonyl)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole were dissolved in 10 ml dimethylformamide. 2.15 g copper cyanide were added and the resulting mixture stirred under microwave irradiation at 200° C. for thirty minutes. The mixture was diluted by addition of 100 ml ethyl acetate and washed five times with portions of 50 ml saturated ammonium chloride solution. The organic layer was dried over MgSO4 then the solvent was removed in vacuo to obtain 935 mg crude 2-chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile. This material was used without further purification.