Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Cl.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:20]1[NH:19][CH:23]=[CH:22][N:21]=1
Reactant: c1c[nH]cn1
Reactant: COC(=O)C(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)C(c1ccccc1)(c1ccccc1)c1ncc[nH]1

Procedure:
13 g (0.05 mole) diphenyl-chloroacetic acid methyl ester (b.p. 140°C/0.1 mm Hg, prepared from diphenyl-chloroacetic acid chloride and methanol according to Ber. 22, 1537) are heated with 10 g imidazole in 100 ml acetonitrile at boiling temperature for 18 hours. After distilling off the solvent in a vacuum, 50 ml of water are added and the mixture is extracted with methylene chloride. After drying over sodium sulphate, the solvent is distilled off in a vacuum and the residue recrystallized from a little ethyl acetate. The diphenyl-imidazolyl-acetic acid methyl ester is thus obtained in the form of colourless crystals of m.p. 155°C (with decomposition).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[CH3:13][O:14][NH2:15]>C(O)C.ClCCl>[CH3:13][O:14][N:15]=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(CC(C)=O)=NOC
Yield: 143.3 %

Procedure:
A mixture of ethyl 2,4-dioxopentanoate (10.9 g, 68.7 mmol) and N-methoxyamine hydrochloride (4.01 g, 48.1 mmol) in ethanol (40 ml) was left to stand over molecular sieves 3A (25 g) for 18 h and diluted with dichloromethane (25 ml) The sieves was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with 5% ethyl acetate/n-hexane to give the title compound (12.9 g, 34%).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[O:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[OH-].[Na+].Cl>CO.O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:23])=[O:2])=[C:7]([O:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH:8]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)cc1OC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(C=CC(=O)O)c(OC2CCOCC2)c1
Reaction time: 12 h
Yield: 99.9 %

Procedure:
3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)phenyl]acrylic acid methyl ester (31.5 mg, 0.099 mmol, 1 eq) and sodium hydroxide (19.8 mg, 0.4955 mmole) were added in methanol and H2O. The reaction mixture was stirred for 12 hrs. The reaction mixture was acidified with 5% HCl. The mixture was concentrated in vacuo to yield 3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)-phenyl]acrylic acid (30.1 mg, 100%).
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:4].[CH3:21]I>CN(C=O)C>[C:3]([N:10]([CH3:21])[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:4]
Reactant: CCOC(=O)C(=O)Nc1c(C)cccc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)N(C)c1c(C)cccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
NaH (1 g, 22 mmol) was added in portions to a stirred solution of N-ethoxalyl-2-nitro-6-methylaniline (5 g, 20 mmol) in DMF (50 ml). Methyl iodide (2 ml, 22 mmol) was thereafter added. The mixture was left overnight at room temperature, whereafter the solvent was removed by evaporation in vacuo. The residue was partitioned between ether and water. The organic phase was washed with water, dried over Na2SO4 and evaporated to give the title compound as an oil.
Reaction SMILES: ClC1C(Cl)=C(C=CC=1)N(Cl)Cl.Cl[C:13]1[C:18]([NH2:19])=[C:17](Cl)[C:16]([Cl:21])=[C:15](Cl)[C:14]=1[Cl:23].C1(O)C=CC=CC=1.[I-].[Na+].[H][H]>O>[Cl:21][C:16]1[CH:17]=[C:18]([CH:13]=[C:14]([Cl:23])[CH:15]=1)[NH2:19]
Reactant: [H][H]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Clc1cccc(N(Cl)Cl)c1Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(Cl)c1
Yield: 98 %

Procedure:
131 parts of a mixture of tetrachloroaniline and pentachloroaniline, corresponding to the composition given in Example 3, 200 parts of phenol and 9 parts of sodium iodide are reacted in the presence of 22 parts of a ruthenium-on-charcoal catalyst (5% strength) which is moist with water and has already been used for 6 similar reaction cycles, corresponding to 15 parts of dry catalyst, with hydrogen at 165° C. under a pressure of 40 to a maximum of 50 bars, during the course of 8 hours. After the usual working up, 91.5 parts of 3,5-dichloroaniline are obtained, with complete conversion of the starting material. Yield: 98% of theory.
Reaction SMILES: [I-:1].[CH2:2]([N+:4]1[C:8]2[CH:9]=[C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:18])[CH3:3].[C:19]1([N:25](C2C=CC=CC=2)[CH:26]=N)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>CC(C)=O>[I-:1].[NH:25]([CH:26]=[CH:18][C:5]1[O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][C:8]=2[N+:4]=1[CH2:2][CH3:3])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N=CN(c1ccccc1)c1ccccc1
Reactant: CC[n+]1c(C)oc2ccc(NS(C)(=O)=O)cc21
Agent: [I-]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC[n+]1c(C=CNc2ccccc2)oc2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Yield: 94.5 %

Procedure:
Intermediate E (1.0 g) and diphenylformamidine (2.2 g) were combined in a flask and heated over a hot air gun with manual stirring until a yellow-orange color formed. The reaction was then heated for 1 minute at full heat until it became totally liquid. On cooling to room temperature, the reaction mixture solidified. This solid was dissolved in 20 ml hot acetone, poured into 100 ml diethyl ether with stirring, and stirred for 1 hour. The solid was then filtered out and washed with diethyl ether to give 1.2 g of 2-(2-anilinovinyl)-3-ethyl-5-methylsulfonamidobenzoxazolium iodide (Intermediate F).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:3]=1.BrC1C=C2C(C)=NN(COCC[Si](C)(C)C)C2=NC=1.[C:39]1([C:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=N)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:39]1([C:45]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[N:11][C:8]2[CH:9]=[C:10]3[C:2]([CH3:1])=[N:3][N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])[C:5]3=[N:6][CH:7]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1nn(COCC[Si](C)(C)C)c2ncc(N)cc12
Agent: CC(C)(C)[O-]
Agent: Cc1nn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1nn(COCC[Si](C)(C)C)c2ncc(N=C(c3ccccc3)c3ccccc3)cc12
Temperature: 115 °C

Procedure:
3-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-amine. A degassed mixture of 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (1.7 g, 5 mmol), diphenylmethanimine (1.36 g, 7.5 mmol), tris(dibenzylideneacetone)palladium (0) (920 mg, 1 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.55 g, 2.5 mmol), and sodium tert-butoxide (720 mg, 7.5 mmol) in toluene (30 mL) was heated at 115° C. under nitrogen overnight. The reaction mixture was concentrated, and purified by column chromatography on silica gel (eluting with 5-20% ethyl acetate in petroleum ether) to give N-(diphenylmethylene)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (2.5 g, crude), which was dissolved in tetrahydrofuran (10 mL), and hydrochloric acid (2 N, 10 mL) was added. The mixture was stirred at room temperature for 2 h. The mixture was adjusted to pH=8 with saturated sodium carbonate solution, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography on silica gel (eluting with 10-25% ethyl acetate in petroleum ether) to give 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (1.1 g, 79.1% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 8.10 (s, 1H), 7.18 (s, 1H), 5.7 (s, 1H), 3.58 (d, J=11.2 Hz, 2H), 3.34 (s, 2H), 2.47 (s, 3H), 0.90 (t, J=11.2 Hz, 2H), −0.09 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=2)[CH:3]=1.[CH2:20]([O:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][NH2:28]>CCOC(C)=O>[NH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][NH:28][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=2)[CH:3]=1
Reactant: NCCCOCCCCOCCCN
Reactant: CSc1nc(Cl)cc(Nc2ccc(C(=O)O)cn2)n1
Solvent: CCOC(C)=O
Product: CSc1nc(NCCCOCCCCOCCCN)cc(Nc2ccc(C(=O)O)cn2)n1
Temperature: 100 °C
Yield: 9.1 %

Procedure:
A mixture of 6-(6-chloro-2-(methylthio)pyrimidin-4-ylamino)nicotinic acid (280 mg) and 3,3′-(butane-1,4-diylbis(oxy))dipropan-1-amine (1928 mg) was heated at 100° C. for 16 hours. After cooling to room etmperature, the mixture was diluted with EtOAc (200 mL), washed with H2O (100 mL), brine (100 mL), and dried over MgSO4 and concentrated. The residue was purified by preparative HPLC to give 6-(6-(3-(4-(3-aminopropoxy)butoxy)propylamino)-2-(methylthio)pyrimidin-4-ylamino)nicotinic acid (40 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[F:17][C:18]([F:37])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:30][CH:31]=[C:32]([CH2:34]Cl)[N:33]=2)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[F:37][C:18]([F:17])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:30][CH:31]=[C:32]([CH2:34][N:3]3[C:4]4[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=4)[CH:10]=[C:2]3[CH3:1])[N:33]=2)[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)co2)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1coc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 2-[3,5-bis(trifluoromethyl)phenyl]-4-(chloromethyl)-1,3-oxazole: MS (ES) m/z 518 (M+1).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])#[N:2]>C(O)(C)C.N.[Co]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: N#CCCCCCCCC(=O)O
Agent: [Co]
Agent: N
Solvent: CC(C)O
Product: NCCCCCCCCC(=O)O
Reaction time: 3 h
Yield: 92.5 %

Procedure:
84.5 g of 8-cyanooctanoic acid dissolved in 500 ml of isopropyl alcohol saturated with NH3 are hydrogenated at 50° C. and 80 bar for 3 hours, using 20 g of cobalt-Raney as catalyst. The catalyst is filtered out and the solution is concentrated. Cooling and purification produce 9-aminononanoic acid (80 g) in the form of a crystalline solid product with a m.p. of 190-192° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH2:14])=[O:13])[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19]2>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:14][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19]3)=[O:13])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(N)=O)oc1C(C)C
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(NC(=O)c3cc(C(C)C)c(C(C)C)o3)ccc2[nH]1
Yield: 32.3 %

Procedure:
In the same manner as that of Example 32, 4,5-diisopropylfuran-2-carboxamide (71 mg, 0.364 mmol) and ethyl 5-bromoindole-2-carboxylate (195 mg, 0.728 mmol) were coupled. The reaction mixture was treated in a conventional manner, and the resultant was purified by silica gel chromatography [hexane-ethyl acetate (4:1), and 1% methanol-chloroform] and then recrystallized to obtain ethyl 5-[(4,5-diisopropylfuran-2-carbonyl)amino]-2-indolecarboxylate (45 mg, 32%) as colorless prisms, together with the collected starting material (39 mg, 55%).
Reaction SMILES: [CH2:1]([C:4]([C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)([CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[C:12]([CH3:27])[CH:11]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].Cl.[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42][NH2:43].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42][NH:43][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([C:4]([CH2:1][CH:2]=[CH2:3])([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=3)=[C:12]([CH3:27])[CH:11]=2)[CH2:5][CH:6]=[CH2:7])=[CH:36][CH:35]=1
Reactant: COC(=O)CCN
Reactant: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Yield: 72.4 %

Procedure:
To a mixture of 4-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-benzoic acid (0.349 g, 0.705 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.112 g, 0.804 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.121 g, 0.898 mmol) in DMF (7.0 mL) is added N,N-diisopropylethylamine (0.38 mL, 2.2 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.180 g, 0.938 mmol) and stirred overnight. The reaction mixture is poured into water (25 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts are washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 75% to provide 0.296 g (72%) of the title compound as a white foam. MS (ES): 580.4 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1([C:20]([CH3:24])([CH3:23])[CH2:21]O)[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12]1.C(N(CC)CC)C.[H-].[Na+].C(OP([CH2:42][C:43]([O:45][CH3:46])=[O:44])(OCC)=O)C>ClCCl.C1COCC1.O>[CH3:46][O:45][C:43](=[O:44])[CH:42]=[CH:21][C:20]([N:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12]1)([CH3:24])[CH3:23]
Reactant: CC(C)(CO)n1cnc2ncccc21
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)C=CC(C)(C)n1cnc2ncccc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
To a −78° C. cooled stirred solution of oxalyl chloride (1 eq) in dichloromethane was added dimethyl sulfoxide (2 eq). After an additional 5 minutes, 2-imidazo[4,5-b]pyridin-1-yl-2-methyl-propan-1-ol (1 eq) dissolved in dichloromethane was added to the cooled solution via cannula. The resulting heterogeneous mixture was stirred at −78° C. for 30 minutes, and triethylamine (5 eq) was added to produce a thick white slurry. After stirring at −78° C. for 15 minutes, the mixture was allowed to warm slowly to 0° C., diluted with dichloromethane, washed with NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. Following this, to a solution of sodium hydride (1 eq) in THF was added methyl diethylphosphonoacetate (1 eq) at 0° C. The mixture was stirred at room temperature for 30 minutes and a solution of the latter concentrated residue dissolved in THF was added dropwise to the mixture. The solution was stirred for 1 hour at the same temperature and then poured into H2O, followed by an extraction with ethyl acetate. The organic layer was washed with NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using a solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA to yield 4-imidazo[4,5-b]pyridin-1-yl-4-methyl-pent-2-enoic acid methyl ester (93%). MH+(246)
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:40]([O-])=O)=[C:15]([NH:17][C:18]3[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[C:20]([O:27][C@@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH3:29])[CH:19]=3)[CH:16]=2)[CH2:6][CH2:5]1.[CH3:43]OC(OC)OC.C([O-])=O.[NH4+]>CO.[Pd]>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[N:40]=[CH:43][N:17]([C:18]4[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[C:20]([O:27][C@@H:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:36]([F:39])([F:38])[F:37])[CH3:29])[CH:19]=4)[C:15]=3[CH:16]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1C(F)(F)F
Reactant: COC(OC)OC
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: COC(=O)c1sc(-n2cnc3ccc(CN4CCN(C)CC4)cc32)cc1O[C@H](C)c1ccccc1C(F)(F)F
Temperature: 35 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
Methyl 5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate dihydrochloride (50.0 g, 76.8 mmol) was suspended in MeOH (100 mL) and trimethylorthoformate (200 mL) and stirred for half an hour. Ammonium formate (30.0 g) and 10% Pd/C (25 g, 15.4 mol %) were added and the mixture was heated to 35° C. The temperature was increased to 60° C. over 6 hours and then held at 60° C. overnight before filtering through fibreglass paper, washing with EtOAc (300 mL). The filtrate was washed with aqueous sodium hydroxide (2 M, 250 mL) and then brine (2×150 mL). A solution of HCl (4 M) was prepared by dropwise addition of acetyl chloride (16.4 mL) to MeOH (41.3 mL), cooled with an ice-bath. This solution was warmed to room temperature and then added dropwise over half an hour to the reaction mixture at 45° C. The mixture was stirred for a further half an hour at 45° C., cooled to room temperature over 1 hour and then cooled in an ice-bath for a further hour, filtered, washing with EtOAc (150 mL) and then dried under reduced pressure to give the title compound (42.7 g, 83% th) as off-white crystalline solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.C(N(C(C)C)C(C)C)C>CS(C)=O.O>[Cl:13][C:14]1[N:15]=[N:16][C:17]([N:1]2[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CN(c2ccc(Cl)nn2)C1
Temperature: 25 °C

Procedure:
tert-Butyl azetidin-3-ylcarbamate (500 mg, 2.90 mmol) and 3,6-dichloropyridazine (454 mg, 3.05 mmol) were combined in DMSO (5 mL) and N-ethyl-N-isopropylpropan-2-amine (563 mg, 4.35 mmol), and the mixture was heated overnight at 100° C. The mixture was cooled to room temperature and diluted with water. Filtration provided the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60]O>C(Cl)Cl>[CH3:34][O:33][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH3:54])[N:21]=[CH:20][N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[C:18]2=[O:32]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: COCCOCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOCCOc1cc2ncn(COC(=O)C(C)(C)C)c(=O)c2cc1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 106.7 %

Procedure:
Diethyl azodicarboxylate (864 μl, 5.5 mmol) was added dropwise to a mixture of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one 1.2 g, 3.9 mmol) (prepared as described for the starting material in Example 7), triphenylphosphine (1.44 g, 5.5 mmol) and 2-(2-methoxyethoxy)ethanol (653 μl, 5.5 mmol) in methylene chloride (70 ml) cooled at 0° C. The mixture was stirred for 1.5 hours at ambient temperature and the solvent was removed by evaporation. The residue was purified by column chromatography eluting with a mixture of ethyl acetate/methylene chloride (50/50 followed by 80/20). The purified solid was suspended in ether, collected by filtration and dried under vacuum to give 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.70 g, 100%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C(COC)OC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:22]([O:21][C:20](=[O:26])[NH:19][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[CH:14][CH:13]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(-c2ccncc2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
To a suspension of tert-butyl {(1S)-1-benzyl-2-[(4-bromophenyl)amino]-2-oxoethyl}carbamate (1.0 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (587 mg) and potassium phosphate (1.52 g) in dimethoxyethane (30 mL) was added 1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride (58 mg) and the mixture was stirred at 120° C. for 4 hours. Water was added and the mixture was extracted with chloroform. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to afford tert-butyl[(1S)-1-benzyl-2-oxo-2-{[4-(4-pyridinyl)phenyl]amino}ethyl]carbamate (830 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:6]=[CH:7][C:8]=2[OH:12])[CH2:3]1.C(N(CC)CC)C.[CH2:27]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)[CH2:28][CH2:29][CH3:30]>CN(C)C=O>[OH:12][C:8]1[CH:7]=[CH:6][C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[C:4]2[C:9]=1[CH2:10][CH2:11][C@@H:2]([NH:1][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:40][CH:39]=1)[CH2:3]2
Reactant: CN1CCN(c2ccc(O)c3c2C[C@H](N)CC3)CC1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)N[C@@H]2CCc3c(O)ccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.38 mmol) and triethylamine (79 μL, 0.57 mmol) in N,N-dimethylformamide (30 mL) was 4-butoxybenzoyl chloride in N,N-dimethylformamide (5 mL) added dropwise. After the addition the reaction was stirred at ambient temperature for 15 min. The solvent was evaporated in vacuo and the residue was purified on a silica gel column using chloroformlmethanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent. Yield: 73 mg (44%) as an amorphous solid: mp 125° C. (decomp.); [α]21D−20° (c=0.25, chloroform); EIMS (70 eV) m/z (relative intensity) 437 (16, M+).