Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[CH2:11][CH2:10][CH2:9]1.[S:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1.C([O-])([O-])=O.[Na+].[Na+]>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>[S:17]1[CH:21]=[CH:20][C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:18]1
Reactant: Brc1ccccc1C1CCCc2cncn21
Reactant: OB(O)c1ccsc1
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: c1ccc(C2CCCc3cncn32)c(-c2ccsc2)c1

Procedure:
To a solution of 5-(2-bromophenyl)-5,6,7,8,-tetrahydroimidazo[1,5-a]pyridine (95 mg, 0.343 mmol) in DME (2 mL) is added thiophene-3-boronic acid (53 mg, 0.414 mmol), aqueous Na2CO3 (2M, 0.5 mL, 1.0 mmol), and Pd(PPh3)4 (20 mg). The reaction mixture is run under microwave irradiation at 120° C. for 20 min. The mixture is partitioned between EtOAc and brine. The organic layer is washed by brine, dried over Na2SO4 and concentrated to give an oil. The crude reaction mixture is subjected to flash chromatography eluting with acetone:hexane to yield the desired compound. MS (ESI) m/z 280 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CCOCC1)C3
Temperature: 25 °C

Procedure:
A mixture of 7.85 g (0.03 m) of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano [3,4-c]pyridin-5-one, 6.15 g (0.033 m) of N-(2-chloroethyl) morpholine HCl and 7.08 g (0.07 m) of triethylamine in 250 cc of ethanol was refluxed for 6 hr. and filtered hot. Treatment of the hot reaction solution with excess HCl 6 hr. and cooling to room temperature afforded crude product. Crystallization from 75% EtOH afforded analytical material mp. 238°-40°C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]4[N:38]([CH3:39])[N:37]=[C:36]([NH2:40])[CH:35]=4)[CH2:26][CH2:25]3)=[CH:21][CH:22]=[CH:23][C:16]1=2.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]4[N:38]([CH3:39])[N:37]=[C:36]([NH:40][C:1](=[O:3])[CH3:2])[CH:35]=4)[CH2:28][CH2:29]3)=[CH:21][CH:22]=[CH:23][C:16]1=2
Reactant: Cn1nc(N)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(OCCCN2CCN(c3cccc4sccc34)CC2)n(C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Acetic anhydride (1 ml) and triethylamine (0.09 ml, 0.65 mmol) were added to a dichloromethane solution (4 ml) of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl-amine (0.20 g, 0.54 mmol) and the mixture was stirred at room temperature for 6 hours. An aqueous potassium carbonate solution was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain N-{5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl}acetamide (0.19 g, 89% yield) as white powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][CH:16]([NH2:18])[CH3:17].CCN(C(C)C)C(C)C>C(O)C>[CH:16]([NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)([CH3:17])[CH3:15]
Reactant: CC(C)N
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 60 °C
Yield: 91.9 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10 g, 43.0 mmol), propan-2-amine (4.21 mL, 49.4 mmol) and DIEA (9.76 mL, 55.9 mmol) in ethanol (140 mL) was heated at 60° C. overnight. After cooling to room temperature, the solvent was concentrated under reduced pressure and water was added. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to give ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (10.10 g, 39.5 mmol, 92% yield) as a colorless oil. MS (ESI) m/z 256.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:12]([C:19](OCC)=[O:20])#[C:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[O:20]=[C:19]1[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]2[C:2]([CH2:3][O:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=32)=[N:1]1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: NC1=Nc2ccccc2OC1
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2n1-c1ccccc1OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
A solution of the compound of formula II, 3-amino-2H-1,4-benzoxazine(1.75 g, 11.08 mmol, described in Example 3) and diethyl acetylenedicarboxylate (2.2g, 12.9 mmol) dissolved in ethanol (30 ml) was stirred at room temperature for 21/2 hours. The precipitate was collected to give 1.30 g of the title compound as colourless crystals; mp 174°-175° C. (after recrystallization from ethyl acetate-hexane); IR(CHCl3) 1738, 1650 cm-1 ; NMR(CDCl3)δ1.2 (t, J=7Hz, 3H), 4.3(q,J=7Hz, 2H), 4.92 (s, 3H), 6.68 (s,1H), 7.3 (m,4H); M+ 272; Anal. Calc'd: C, 61.76%; H, 4.44%; N, 10.29%; Found: C, 61.99%; H, 4.35%; N, 10.32%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([SH:8])[CH2:4][CH2:3]1.CN(C)C=O.[H-].[Na+].[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19](F)[CH:18]=1>O>[F:16][C:17]1[CH:18]=[C:19]([S:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: CN1CCC(S)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Sc2cc(F)cc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 10.7 %

Procedure:
Combine 1-methyl-piperidine-4-thiol (1.4 g, 10.67 mmol) and N,N-dimethylformamide (10 mL) and cool to 0° C. Add 95% sodium hydride (0.28 g, 11.20 mmol), warm to ambient temperature and stir. After 40 min., add 1,3-difluoro-5-nitro-benzene (1.21 mL, 10.67 mmol), stir and heat at 65° C. After 3 hr., cool to ambient temperature and add water (50 mL). Extract with ethyl acetate (3×50 mL), wash combined organic layers with water (3×50 mL), aqueous NaCl solution (50 mL), dry organic layer over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride to obtain the title compound (0.31 g, 11%). Mass spectrum (electrospray): m/z=271.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1.[CH3:12][NH:13][CH3:14]>C1COCC1>[CH3:12][N:13]([CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1)[CH3:14]
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: CNC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CN(C)C)cs1
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
N-(4-(Chloromethyl)thiazol-2-yl)acetamide (2.0 g, 10 mmol) in 20 mL THF was added in portions to dimethylamine (4.7 g, 105 mmol). After addition, the mixture was stirred for an additional 30 minutes. The solvent was removed under reduced pressure. 200 mL distilled water was then added to the resulting residue, and the mixture was extracted with EtOAc. The EtOAc solution was washed with brine solution and dried over sodium sulfate. After removing the solvent, an off-white solid was obtained as the crude product (1.3 g, yield=80%). LCMS (API-ES) m/z (%) 200.1 (100%, M++H). 1H NMR (400 MHz, CDCl3) δ ppm 2.24 (s, 3H) 2.26 (s, 6H) 3.43 (s, 2H) 6.73 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30].CC(C[AlH]CC(C)C)C.O>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30]
Reactant: Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1OCCCC(=O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1OCCCCO
Temperature: 0 °C
Yield: 93.9 %

Procedure:
Compound 47 (50 mg, 0.11 mmol) was dissolved in THF (5 mL) and cooled to 0° C. under nitrogen. DIBAL (1.5 M in hexane, 500 ul, 0.33 mmol) was added drop-wise over several minutes. The ice bath was removed and the stirring reaction allowed to warm to ambient temperature. The reaction was then cooled back to 0° C. and water (10 mL) added dropwise over several minutes. The ice bath was then removed and the reaction was stirred until solids began to form. The solids were filtered and the filtrate washed several times with dichloromethane. The filtrate was concentrated in vacuuo to give 42 mg (98%) of compound 48 as a clear oil. 1H NMR (400 MHz, CDCl3): δ 0.93 (s, 6H), 0.95 (s, 6H), 1.29 (s, 2H), 1.75 (s, 2H), 1.90 (s, 2H), 2.08-2.17 (m, 5H), 2.55 (t, J=7.3 Hz, 2H), 3.72 (t, J=6.3 Hz, 2H), 3.97 (t, J=6.1 Hz, 2H), 6.70 (d, J=9.0 Hz, 1H), 6.91-6.99 (m, 2H), 7.10-7.20 (m, 3H), 7.20-7.30 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])#N.C(O)=[O:19]>[Al].[Ni]>[CH:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])=[O:19]
Reactant: N#Cc1cc2c(=O)c3ccccc3ccn2c1
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Product: O=Cc1cc2c(=O)c3ccccc3ccn2c1

Procedure:
2-Cyano-11H-pyrrolo[2,1-b][3]benzazepin-11-one (222 mg.) and 222 mg. nickel-aluminum alloy in 2 ml. 75% formic acid is refluxed for 11/2 hours. The solid is filtered off and washed with ethanol. The filtrate is diluted with 50 ml. water and extracted twice with 50 ml. methylene chloride. The organic layer is washed with water, 5% sodium bicarbonate and with water; it is then dried over magnesium sulfate and evaporated to dryness. Addition of ether induces crystallization and the crystals are filtered and air-dried to yield 2-formyl-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][CH2:21][C:22](O)=[O:23].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(OCC)C>[Cl:20][CH2:21][C:22]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: O=C(O)CCl
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCl

Procedure:
A solution of 1-octadecanol 5 (5 0 g, 180 mmol), chloroacetic acid (17.5 g, 180 mmol) and concentrated sulfuric acid (0.1 mL) in 350 mL of toluene was refluxed overnight in a flask equipped with a Dean-Stark trap. The solution was diluted with 500 mL of diethyl ether and extracted twice with a saturated bicarbonate solution (500 mL). The aqueous phase was subsequently extracted with 400 mL of diethyl ether. The combined organic layers were dried with sodium sulfate and evaporated in vacuo yielding a brown solid, which was used without further purification. 1H-NMR (CDCl3) δ=4.20 (t, 2H), 4.07 (s, 2H), 1.68 (q, 2H), 1.30 (m, 30H), 0.89 (t, 3H) ppm. FT-IR: ν=2919, 2851, 1749 (C═O stretch), 1333, 1208 (C—O stretch), 786 cm−1.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:4](=[O:7])[NH:5][N:6]=1.Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C.C(OCC)(=O)C>[CH3:21][O:20][C:18](=[O:19])[CH2:17][N:5]1[C:4](=[O:7])[N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:2]([Br:1])=[N:6]1
Reactant: O=c1[nH]nc(Br)n1Cc1ccccc1F
Reactant: COC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)Cn1nc(Br)n(Cc2ccccc2F)c1=O

Procedure:
300 mg (1.1 mmol) of the compound from Example 135A are stirred under reflux for 2 hrs together with 150 mg (1.38 mmol) of methyl chloroacetate and 168 mg (1.21 mmol) of potassium carbonate in 10 ml acetonitrile. After cooling, the mixture is diluted with ethyl acetate and treated with 1 N hydrochloric acid. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulphate and freed of the volatile components on the rotary evaporator. The residue is dried under high vacuum. The product thus obtained (360 mg, purity ca. 73% by LC/MS) is used in the next synthetic step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH:5]([CH:10]([OH:12])[CH3:11])[CH2:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[CH3:1][C:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[CH:5]([CH:10]([O:12][C:13](=[O:15])[CH3:14])[CH3:11])[CH2:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1=CCC(C(C)O)C(C)(C)C1
Solvent: O
Product: CC(=O)OC(C)C1CC=C(C)CC1(C)C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A 1 liter flask, provided with a mechanical stirrer, a heater and a reflux condenser fitted with a calcium chloride drying tube, is charged with 190.8 g of 1,5,5-trimethyl-4-(1-hydroxyethyl)-cyclohex-1-ene and 173.8 g of acetic anhydride. The mixture is brought to 100° for 4 hours. After cooling, the mixture is immersed in 250 ml of water and extracted with 3 times 100 ml of benzene. The extract is then washed once with 100 ml of water, twice with 100 ml of a 9% solution of sodium bicarbonate and twice more with 100 ml of water. The solvent is distilled off on a water bath, finally, under a pressure of 30 mm of mercury; the crude ester is distilled in a 500 ml three-necked flask fitted with a 1 meter adiabatic column filled with unoxidisable 4×4 mm particles, under a vacuum of 0.5 mm of mercury. 197 g of 1,5,5-trimethyl-4-(1 -acetoxyethyl)-cyclohex-1-ene (81.3%) are obtained having the following physical properties:
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=2[C:18]2([CH2:23][O:24][CH3:25])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.S(Cl)([Cl:28])=O>C(Cl)Cl>[Cl:28][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=2)=[C:11]([C:18]2([CH2:23][O:24][CH3:25])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: COCC1(c2cc(CO)ccc2-c2cc(OC)ncc2F)CCCC1
Solvent: ClCCl
Product: COCC1(c2cc(CCl)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-(methoxymethyl)cyclopentyl)phenyl)methanol (71.0 mg, 206 μmol) DMF (10 uL), and DCM (4.0 mL) was slowly added thionyl chloride (15.0 μL, 206 μmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed providing the product which was used in the next step. MS ESI (pos.) m/e: 364.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH2:10])=[C:4]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:3]=1.[CH2:17]([N:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[N:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH:10][C:29]([C:27]2[CH:26]=[N:25][N:24]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:28]=2)=[O:30])=[C:4]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:3]=1
Reactant: O=C(O)c1cnn(Cc2ccccc2)c1
Reactant: COC(=O)COc1cc(N)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
Methyl 2-(6-amino-3-(aminomethyl)-2-methylpyridin-4-yloxy)acetate (271 mg, 0.909 mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid (synthesis description below) (184 mg, 0.909 mmol) and DIPEA (0.794 ml, 4.54 mmol) were dissolved in DMF (2 ml), then HATU (518 mg, 1.363 mmol) was added and the reaction mixture was stirred over night at rt. Purification by prep HPLC (Sun-Fire C18, 100×30mm 5 to 100% ACN and 0.1% TFA, flow 40 mml/min.) offered the titled compound after lyophilisation. HPLC (Method C) Rtc=2.789 min, MS (Method D): [M+H]+=410.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[O:33][C:34]([CH:37]=[O:38])=[CH:35][CH:36]=2)=[CH:4][N:3]=1.[BH4-].[Na+]>CN(C)C=O.CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[O:33][C:34]([CH2:37][OH:38])=[CH:35][CH:36]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(-c4ccc(C=O)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(-c2csc3c(-c4ccc(CO)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.3 %

Procedure:
A mixture of N-{4-[4-amino-7-(5-formyl-2-furyl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (0.060 g, 0.12 mmol) and sodium borohydride (0.013 g, 0.344 mmol) in N,N-dimethylformamide (4 mL) and methanol (4 mL) was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (10 mL) and 0.1 N hydrochloric acid (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 25 cm; 40% acetonitrile—0.1M ammonium acetate isocratic for 5 minutes, then 40–100% acetonitrile—0.1M ammonium acetate over 30 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to give the title compound (2.1 mg, 0.004 mmol) as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.Br[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].Cl>O1CCCC1.C(OCC)C>[C:23]([O:22][C:20](=[O:21])[CH2:19][CH2:18][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)C1CCCC1
Reactant: CC(C)(C)OC(=O)CCBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a stirred solution of lithium diisopropylamide (0.43 mole) in dry tetrahydrofuran (300 ml) at -20° C. under nitrogen atmosphere was added cyclopentane carboxylic acid (22.7 g; 0.20 mole). The solution was allowed to warm to room temperature and after 2 hours was cooled to -10° C. and added by cannula to a stirred solution of t-butyl 3-bromopropionate (44.4 g, 0.21 mole) in tetrahydrofuran (100 ml). The resulting solution was allowed to warm to room temperature and kept overnight. Hydrochloric acid (3N, 250 ml) was cautiously added, followed by diethyl ether (500 ml) and the layers allowed to separate. The aqueous layer was washed with diethyl ether (300 ml) and the ether layers were combined, washed with water (300 ml), dried over magnesium sulphate and evaporated to give an oil. The oil was taken up in diethyl ether (300 ml) and washed with saturated sodium hydrogen carbonate solution (3×100 ml) until no further cyclopentane carboxylic acid remained. The diethyl ether solution was then extracted with 10% sodium carbonate solution, (4×150 ml), the aqueous phase separated, acidified with 2N hydrochloric acid, and extracted with diethyl ether (3×200 ml). The diethyl ether layer was separated, washed with water (300 ml), dried over magnesium sulphate and evaporated to give an oil that readily crystallised. Recrystallisation from pentane gave a colourless solid (10.4 g, 21%) m.p. 78°-81° C. (from pentane). Found: C,64.70;; H,9.18. C13H22O4 requires: C,64.44; H,9.15%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]1[O:40][C:39]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[CH:33]=1)([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]1[O:40][C:39]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[CH:33]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1cc3cnccc3o1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)c(-c1cc3cnccc3o1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 79.7 %

Procedure:
In a round-bottom flask equipped with a balloon, a mixture 2-(5-Nitro-1-trityl-1H-indazol-3-yl)-furo[3,2-c]pyridine (210 mg, 0.4 mmol) and 5% Pd on carbon (21 mg) in ethyl acetate and methanol (10 mL, 1:1) was hydrogenated overnight at room temperature to give 157 mg desired product (80% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])CCC.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1>CCCCCC>[OH:24][C:21]1([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN1CCC(O)(c2cnc3ccccc3c2)CC1
Yield: 53.84 %

Procedure:
95.01 g of 3-bromoquinoline were treated with 200 ml of a 2.5M solution of butyllithium in hexane and 51.62 g of 1-methylpiperid-4-one in accordance with the procedure described in Stage A of Example 1, in order to obtain the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:21][C:18]1[CH:17]=[CH:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:20][CH:19]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(/C(C#N)=C/c2ccc(OC(C)=O)cc2)cc1OC
Yield: 95 %

Procedure:
Compound 1 (0.28 g) was acetylated with acetic anhydride and pyridine in accordance with a customary method, to thereby produce the target product (0.30 g, yield: 95%).