Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)O.C(OC[CH2:13][CH2:14][NH2:15])=C.C=O>C1(C)C=CC=CC=1>[O:6]1[C:5]2[CH:4]=[CH:3][CH:1]=[CH:8][C:7]=2[CH:13]=[CH:14][NH:15]1
Reactant: Oc1ccc(O)cc1
Reactant: C=COCCCN
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1

Procedure:
Hydroquinone (8.23 grams, 75 mmole), 3-amino-1-propanol vinyl ether (15.1 grams, 150 mmole), and toluene (100 mL) were placed in a 250 mL round bottom flask. Paraformaldehyde (9.0 grams, equivalent to 300 mmole of formaldehyde) was then added to the flask. The flask was then equipped with a magnetic stir bar, a Dean-Stark trap, and condenser. The mixture was stirred and heated to reflux under an argon blanket. A total of 5.2 milliliters (96% of theory) of water was collected in the trap after two hours reflux. The reaction mixture had turned black by this point. The toluene reaction solution was washed with two 50 mL aliquots of 5% aqueous sodium hydroxide, followed by one 50 mL aliquot of water. The toluene solution was passed over a bed of neutral alumina and then evaporated to yield 3.8 grams (14% of theory) of a viscous, light brown liquid.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[CH:9][CH:8]=1.[Cl:15][CH2:16][C:17]([CH3:19])=[CH2:18]>O>[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[C:9]([C:17]([CH3:19])([CH3:18])[CH2:16][Cl:15])[CH:8]=1
Reactant: C=C(C)CCl
Reactant: Cc1cc(O)ccc1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(O)c(C(C)(C)CCl)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
Concentrated sulfuric acid (1.75 g, 17.8 mmol) was added drop wise to a cooled (ice bath) mixture of 4-bromo-5-methyl-phenol (Compound 45, 10 g, 53.46 mmol) and 3-chloro-2-methyl-propene (5.28 mL, 53.46 mmol). The dark reaction mixture was allowed to warm to ambient temperature and stirred a total of 2 hours. The reaction mixture was diluted with water, and extracted with diethylether. The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Flash column chromatography using 3% ethyl acetate in hexanes as the eluent afforded the title compound (6.2 g, 48%) as a green solid; 4-bromo-5-methyl-phenol was recovered. 1H NMR (300 MHz, CDCl3): δ 7.35 (s, 1H), 6.54 (s, 1H), 5.02 (s, 1H), 3.96 (s, 2H), 2.28 (s, 3H), 1.44 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH2:25][OH:26])[CH:5]=[CH:6][CH:7]=1.[Cl:27][C:28]1[C:29](B2OC(C)(C)C(C)(C)O2)=[C:30]2[CH:36]=[CH:35][N:34]([Si](C(C)C)(C(C)C)C(C)C)[C:31]2=[N:32][CH:33]=1.C([O-])([O-])=O.[Cs+].[Cs+]>ClCCl.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1COCC1>[Cl:27][C:28]1[C:29]([C:2]2[CH:3]=[C:4]([N:8]3[CH:13]=[C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:11](=[O:24])[CH:10]=[C:9]3[CH2:25][OH:26])[CH:5]=[CH:6][CH:7]=2)=[C:30]2[CH:36]=[CH:35][NH:34][C:31]2=[N:32][CH:33]=1
Reactant: COc1ccc(COc2cn(-c3cccc(Br)c3)c(CO)cc2=O)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(B3OC(C)(C)C(C)(C)O3)c(Cl)cnc21
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(COc2cn(-c3cccc(-c4c(Cl)cnc5[nH]ccc45)c3)c(CO)cc2=O)cc1
Temperature: 150 °C

Procedure:
To each of three 20 mL microwave tubes was added 0.5 g (1.2 mmol) 1-(3-bromo-phenyl)-2-hydroxymethyl-5-(4-methoxy-benzyloxy)-1H-pyridin-4-one, 0.33 g (0.45 mmol) dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloromethane adduct, 0.51 g (1.44 mmol) 5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine, 3.6 mL (3.6 mmol) 1 M aq. Cs2CO3, and 10 mL THF. The vials were then capped and heated by microwave to 150° C. for 12 minutes each. After cooling, the aqueous layer was removed and the organics were concentrated in vacuo. Purification by automated flash chromatography (40 g silica gel cartridge 0-10% MeOH/EtOAc over 30 min) afforded 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-phenyl]-2-hydroxymethyl-5-(4-methoxy-benzyloxy)-1H-pyridin-4-one. LCMS (M+H)+ 488.4.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].O.Cl.[NH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[N:12]=[C:13]([C:16]([N:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)=[O:17])[S:14][CH:15]=1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC(=O)CC3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (160 mg; 0.53 mmol; 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 4-Piperidone hydrochloride monohydrate (Aldrich) (97.7 mg; 0.64 mmol; 1.20 eq.) and triethylamine (0.22 ml; 1.59 mmol; 3 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (42) as a pale yellow powder (39.2 mg; 20%). 1H NMR (DMSO-d6, 300 MHz) δ 2.14 (s, 3H), 2.49 (s, 3H), 2.53 (m, 4H), 3.94 (m, 2H), 4.53 (m, 2H), 8.03 (s, 1H), 12.17 (s, 1H). M− (ESI): 363.09; M+ (ESI): 365.04. HPLC (method A), Rt: 2.44 min (purity: 95.3%).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[NH2:33][C:34]([CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38])([CH3:36])[CH3:35]>O1CCCC1>[OH:38][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34]([NH:33][C:12](=[O:14])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)([CH3:36])[CH3:35]
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: CC(C)(N)C(O)c1ccccc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: CC(C)(NC(=O)Cc1cccc2ccccc12)C(O)c1ccccc1
Temperature: 65 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
A solution of 74.5 g. (0.4 mole) of 1-naphthyl acetic acid, 111.0 g. (0.45 mole) of EEDQ and 66.0 g. (0.4 mole) of α-(1-amino-1-methylethyl)benzenemethanol in 1 l. tetrahydrofuran is stirred and heated for 2 hours at 65° C. and then allowed to stand for 20 hours at room temperature. THF is evaporated in vacuo, and the residue is taken up with ice and 10% aqueous H2SO4 solution to pH 2. The resulting amide is extracted twice with 750 ml. ethyl acetate. The combined organic extracts are washed with 500 ml. dilute NaHCO3, dried (Na2SO4) and evaporated to dryness in vacuo. The oil is dissolved in 1 l. hot isopropyl ether and on standing at 25° C. gives 101.0 g. (77% yield) of N-(2-hydroxy-1,1-dimethyl-2-phenylethyl)-1-naphthaleneacetamide as an off-white crystalline solid of analytical purity, m.p. 106°-107° C.
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][N:14]([O:27]CC3C=CC=CC=3)[C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:16])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2>>[C:2]12([CH2:12][CH2:13][N:14]([OH:27])[C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:16])[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2
Reactant: O=C(NCCCc1ccncc1)N(CCC12CC3CC(CC(C3)C1)C2)OCc1ccccc1
Agent: Cl
Product: O=C(NCCCc1ccncc1)N(O)CCC12CC3CC(CC(C3)C1)C2
Reaction time: 72 h
Yield: 34 %

Procedure:
2 N Hydrochloric acid (4.0 ml) was added to a solution of 1-[2-(1-adamantyl)ethyl]-1-benzyloxy-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-28) (438 mg, 0.978 mmol) in methanol (9.78 ml), and a nitrogen gas was bubbled through the mixture. To the mixture was added 10% palladium on carbon (43 mg), and the whole was stirred under hydrogen at 1 atm for three days. The palladium on carbon was filtered out, the filtrate was concentrated under reduced pressure, and the concentrate was diluted with diethyl ether (30 ml). The whole was washed with a saturated aqueous sodium hydrogencarbonate solution (30 ml) and a saturated aqueous sodium chloride solution (30 ml) successively, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 119 mg (34%) of the titled compound.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:23]#[N:24])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:21][OH:22])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH:10]=2)[NH:5][CH:4]=1)=[O:2].CC(=CC)C.Cl([O-])=[O:31].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-].[NH4+]>O1CCCC1.C(O)(C)(C)C.O.CO>[C:23]([C:8]1[CH:7]=[C:6]2[C:11]([C:3]([C:1]([OH:31])=[O:2])=[CH:4][NH:5]2)=[CH:10][C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]2([CH2:21][OH:22])[CH2:19][CH2:20]2)=[CH:16][CH:17]=1)#[N:24]
Reactant: N#Cc1cc2[nH]cc(C=O)c2cc1-c1ccc(C2(CO)CC2)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: N#Cc1cc2[nH]cc(C(=O)O)c2cc1-c1ccc(C2(CO)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
A partial solution/suspension of 3-formyl-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-6-carbonitrile (236 mg, 0.746 mmol) in tetrahydrofuran/t-butanol (6 mL/6 mL) was treated with 2-methyl-2-butene (4 mL, 40 mmol) followed by a solution of sodium chlorite (942 mg, 11 mmol) and sodium phosphate (monobasic and monohydrate, 1585 mg, 11.48 mmol) in water (4 mL) via glass pipet. The reaction was stoppered and allowed to stir overnight at room temperature. After 16 hours, the reaction mixture was poured into half-diluted saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 346 mg of the crude desired product. The crude material was diluted with methanol (25 mL) and the mixture was heated to reflux. The resulting solution was allowed to cool to room temperature slowly. As the solution was cooling, the sides of the flask were scratched with a glass pipette and stirred at room temperature for 4 hours resulting in a precipitate. The precipitate showed birefringence under the microscope and the mixture was allowed to stir overnight at room temperature (18 hours). After 18 hours, the mixture was filtered and the filter cake was washed with methanol (2 mL) and dried under high vacuum for 40 minutes yielding 127 mg (51%) of desired product as a crystalline solid. The melting point range was determined by a starting temperature of 250° C. and a gradient of 2° C./minute which produced a melting point of 270.9-271.6° C. (determined by the Buchi Melting Point B-545). MS (ES+) 331.4 (M−H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35 (br. s, 1H), 12.33 (br. s, 1H), 8.29 (d, J=2.3 Hz, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 4.73 (t, J=5.7 Hz, 1H), 3.60 (d, J=5.7 Hz, 2H), 0.86-0.93 (m, 2H), 0.78-0.85 (m, 2H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[N:4]=[C:3]1[NH:10][NH2:11].[CH:12](OCC)(OCC)OCC>C(O)CCC>[NH2:11][N:10]1[C:3]2=[N:4][C:5]([CH3:9])=[CH:6][C:7](=[O:8])[N:2]2[N:1]=[CH:12]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1cc(=O)n(N)c(NN)n1
Solvent: CCCCO
Product: Cc1cc(=O)n2ncn(N)c2n1

Procedure:
A 2.4 g portion of 3-amino-2-hydrazino-6-methyl-4(3H)-pyrimidinone was dissolved in 100 ml of n-butanol by heating to the boiling point. A 20 ml portion of triethyl orthoformate was added and the solution was refluxed for 45 minutes. The solid was collected while the solution was hot, washed with ether and dried, giving 1.45 g of the desired intermediate, mp 202°-204°.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[NH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[C:6]([C:7]1[C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[NH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1c[nH]c2ncncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1c[nH]c2ncncc12
Yield: 86.7 %

Procedure:
5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine (0.320 g, 1.49 mmol) and potassium carbonate (0.513 g, 3.72 mmol) were stirred in MeOH (6 mL) for 18 hours. The mixture was diluted with EtOAc, washed with saturated ammonium chloride, brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound as an orange solid (0.185 g, 87%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]([NH:5][C@@H:6]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]([NH:9][C@H:10]([B:16]1[O:20][C@@H:19]2[CH2:21][C@@H:22]3[CH2:25][C@H:24]([C@:18]2([CH3:28])[O:17]1)[C:23]3([CH3:27])[CH3:26])[CH2:11][CH:12]1[CH2:15][CH2:14][CH2:13]1)=[O:8])=[O:4].Cl.C(#N)C.[C:48](OC(=O)C)(=[O:50])[CH3:49].C(N(CC)C(C)C)(C)C>>[C:48]([NH:1][C@@H:2]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]([NH:5][C@@H:6]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]([NH:9][C@H:10]([B:16]1[O:20][C@@H:19]2[CH2:21][C@@H:22]3[CH2:25][C@H:24]([C@:18]2([CH3:28])[O:17]1)[C:23]3([CH3:26])[CH3:27])[CH2:11][CH:12]1[CH2:15][CH2:14][CH2:13]1)=[O:8])=[O:4])(=[O:50])[CH3:49]
Reactant: CC1(C)[C@@H]2C[C@H]3OB([C@H](CC4CCC4)NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@@H](N)CCc4ccccc4)O[C@@]3(C)[C@H]1C2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC1CCC1)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reaction time: 8 h
Yield: 53 %

Procedure:
Into a 20 mL scintillation vial was added (2S)-2-amino-N-[(1S)-1-benzyl-2-({(1R)-2-cyclobutyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}amino)-2-oxoethyl]-4-phenylbutanamide.HCl (52.0 mg, 0.0836 mmol), acetonitrile (5.20 mL, 0.0996 mol), acetic anhydride (8.68 μL, 0.092 mmol), N,N-diisopropylethylamine (36.4 μL, 0.209 mmol) and N,N-dimethylaminopyridine (0.0005 g, 0.004 mmol). The mixture was stirred overnight and the precipitate was filtered and washed with Et2O to give 0.028 g (53% yield) of product as a white solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([O:20][Si](C)(C)C)([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.B>C1COCC1>[NH2:19][CH2:18][C:16]1([OH:20])[CH2:17][N:14]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15]1
Reactant: C[Si](C)(C)OC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: NCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-benzhydryl-3-(trimethylsilyloxy)azetidine-3-carbonitrile (example 33, step b) (3.5 g) in THF (50 mL) was treated with borane methylsulfide complex (2M in THF, 20.8 mL) and the resultant mixture heated at 70° C. for 1 hour under nitrogen. The mixture was cooled to room temperature and quenched carefully with methanol (50 mL) followed by treatment with ethylenediamine (2.81 mL). This mixture was stirred at 20° C. for 1 hour and then at 55° C. for 1 hour. The mixture was cooled to room temperature and treated with tetrabutylammonium fluoride (1M in THF, 15.6 mL), then stirred at room temperature for 40 minutes. Solvents were evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 6 to 7% methanol in dichloromethane with 1% triethylamine. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.95 g.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:29]=[O:30].C(=O)([O-])[O-].[K+].[K+].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C)C=O.C(OCC)(=O)C.O>[N:37]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:15]=2[O:16][CH3:17])[C:12]([C:18](=[O:28])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=2)=[N:11][CH:10]=[C:9]3[CH:29]=[O:30])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCBr)c(OC)cc23)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCN4CCCC4)c(OC)cc23)c1
Temperature: 85 °C
Yield: 104.8 %

Procedure:
To a stirred solution 6-(3-bromo-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde (62 g, 0.13 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (181 mg, 1.30 mmol) and pyrrolidine (0.032 mL, 0.66 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to afford product 6-(3-pyrrolidin-1-yl-propoxy)-7-methoxy-1-(3-ethoxy-benzoyl)-isoquinoline-4-carbaldehyde as a colorless oil (63 mg, 99% yield).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[N:15](C(OC(C)(C)C)=O)[N:14]=[C:13]([CH2:23][CH2:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=2)[CH:12]=1.N1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([CH2:24][CH2:23][C:13]2[CH:12]=[C:11]([NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH:15][N:14]=2)[CH:26]=[C:27]([O:33][CH3:34])[CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: COc1cc(CCc2cc(NC(=O)c3ccccc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
Benzoyl chloride (56 μl, 0.47 mmol, 1.1 eq) was added dropwise to a mixture of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (150 mg, 0.43 mmol, 1 eq) and pyridine (104 μl, 1.29 mmol, 3 eq) in DCM (1.5 ml) at ambient temperature. After stirring at ambient temperature for 2 h, a solution of TFA (321 μl, 4.32 mmol, 10 eq) in DCM (2.7 ml) was added dropwise and stirring was continued for a further 1 h. The reaction mixture was concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a 33-53% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless foamy solid (100 mg, 66% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([O:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:22]=2)[NH:19][C:18]([C:30]2[S:31][CH:32]([CH2:35][C:36](O)=[O:37])[CH2:33][N:34]=2)=[CH:17]3)=[CH:9][CH:8]=1.O.O[N:41]1[C:45]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.CN>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([O:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:22]=2)[NH:19][C:18]([C:30]2[S:31][CH:32]([CH2:35][C:36]([NH:41][CH3:45])=[O:37])[CH2:33][N:34]=2)=[CH:17]3)=[CH:9][CH:8]=1
Reactant: COCCOCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COCCOC)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of {2-[5-({6-[(2-methoxyethoxy)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (157 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (67 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (83 mg), methylamine hydrochloride (30 mg), and triethylamine (0.060 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (84 mg, yield 52%) as a yellow oil.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=O)[S:8][CH:9]=1.[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N+]=[N-].[Cl-].[NH4+]>CO>[Cl:4][C:5]1[C:6]2[NH:12][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:10][C:7]=2[S:8][CH:9]=1
Reactant: O=Cc1cc(Cl)cs1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cc2scc(Cl)c2[nH]1
Temperature: -25 °C

Procedure:
Methanolic sodium methoxide solution (28%) (5 ml, 25.9 mmol) was diluted with MeOH (5 ml) and was cooled to −25° C. under nitrogen. A solution of 4-chloro-2-thiophenecarboxaldehyde (J Heterocyclic Chem, 1976, 13, 393; 1.1 g, 7.5 mmol) and methyl azidoacetate (3.0 g, 26.1 mmol) in MeOH (20 ml) was added dropwise, maintaining the temperature at −25° C. On completion of addition the solution was allowed to warm to 5° C. over a period of approximately 16 hours. The solution was added to saturated aqueous ammonium chloride (250 ml) and the mixture was extracted using DCM. The combined organic layers were concentrated at 0° C. The residue was taken up in xylene (30 ml) and this solution was added dropwise to xylene (120 ml) under reflux. The solution was heated under reflux for 30 minutes before being cooled and concentrated. The title compound was purified by a mixture of crystallisation (EtOAc/isohexane) and chromatography on a Bond Elut column eluting with a graduated solvent of 5–50% EtOAc in isohexane (640 mg, 40%). NMR (CDCl3) 9.1 (1H, br), 7.1 (2H, s), 3.9 (3H, s); m/z 214.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[F:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: O=C(Cl)c1ccccc1F
Product: O=C(NC1CCCc2c1[nH]c1ccc(Cl)cc21)c1ccccc1F

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 2-fluorobenzoyl chloride in a similar manner as described in Example 14 to give a white solid (63% yield). 1H-NMR (CDCl3): δ 8.93 (s, 1H), 8.14 (m, 1H), 7.49 (m, 1H), 7.45 (m, 1H), 7.28 (m, 1H), 7.22 (d, 1H), 7.10 (m, 3H), 5.35 (m, 1H), 2.72 (m, 2H), 2.31 (m, 1H), 1.98 (m, 3H); MS m/z 343 (M+1).