Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([O:23]CC)=[O:22])=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>O1CCOCC1.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([OH:23])=[O:22])=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(NC(=O)OCc3ccccc3)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc2[nH]c(C(=O)O)cc2c1)OCc1ccccc1

Procedure:
Ethyl 5-Benzyloxycarbonylaminoindole-2-carboxylate, (PREPARATION 56, 0.76 g) is dissolved in 1,4-dioxane (5.6 ml) and water (0.56 ml). Crushed potassium hydroxide (0.23 g) is added and the reaction is heated to 50° for 5 hr. The reaction is neutralized by adding 4.05 ml of 1N aqueous hydrochloric acid. The reaction is extracted with THF/chloroform (10/90, 3×), saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title acid, NMR (300 MHz, d4-CD3OD) 7.64, 7.34-7.15, 6.98 and 5.09δ.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].Cl.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:29]3[CH2:30][CH2:31][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH3:19])[CH2:27][CH2:28]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc2cccc(OCC3CO3)c2o1
Reactant: Cc1ccccc1N1CCNCC1
Agent: Cl
Product: Cc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(N)=O)oc23)CC1

Procedure:
The procedures of Example 10 were repeated except that 1.2 g (0.005 mole) of 2-carbamoyl-7-(2,3-epoxypropoxy)benzofuran and 1.2 g (0.0055 mole) of 1-(2-methylphenyl)piperazine hydrochloride were employed. The obtained concentrated residue was crystallized from ethyl acetate and petroleum ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1.[H-].[Na+].[CH3:26]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1
Reactant: CI
Reactant: CN1C(=O)COc2ccc(C(=O)Cc3ccc(Br)cc3Cl)cc21
Agent: [H-]
Agent: [Na+]
Product: CC(C(=O)c1ccc2c(c1)N(C)C(=O)CO2)c1ccc(Br)cc1Cl

Procedure:
In analogy to Example 1, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-acetyl]-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with sodium hydride and methyl iodide to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=406.1 [M−H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([Li])CCC.CI>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:21])[C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]CCCC
Reactant: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(C(C)C(=O)O)ccc1OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Specifically, a solution of 2-(4-benzyloxy-3-methoxyphenyl) acetic acid 15.0 g, 55.1 mmoles) in dry THF (350 mL) was cooled to -78° C. under argon and treated dropwise with n-butyllithium (42 mL, 2.6M in hexanes). The yellow suspension was then allowed to warm to -10° C. and stirred for 60 minutes. A solution of methyl iodide (3.9 mL, 62.6 mmoles) in THF (15 mL total solution) was then added dropwise via syringe over 30 min resulting in a now homogeneous and clear solution. After 2 hours the THF was rotary evaporated and the residue was dissolved in ethyl acetate (500 mL), extracted with 10% phosphoric acid (3×100 mL), extracted with brine (1×100 mL) and dried over magnesium sulfate. Rotary evaporation afforded a yellow oil which solidified on standing. The solid was triturated with n-pentane and filtered to give 2-(4-benzyloxy-3-methoxyphenyl)propionic acid (14.0 g, 89%) as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[O:12][C:11](=[O:16])[CH2:10]1.[NH3:19].CO>>[C:11]([CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:18])([F:17])[F:1])[CH2:14][C:13]([OH:12])=[O:15])(=[O:16])[NH2:19]
Reactant: N
Reactant: O=C1CC(c2ccccc2C(F)(F)F)CC(=O)O1
Solvent: CO
Product: NC(=O)CC(CC(=O)O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Saturated ammonia/methanol (10 mL) was added to 4-(2-trifluoromethylphenyl)dihydropyrane-2,6-dione (636 mg), and the mixture was stirred at room temperature for 15 hours. Concentration under reduced pressure gave a crude product (716 mg) which was used for the next reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:20])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.Br[CH2:24]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[CH:17]=[C:16]4[O:19][CH2:24][O:20][C:15]4=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCBr
Reactant: N#Cc1cnc2cc(O)c(O)cc2c1Nc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnc2cc3c(cc2c1Nc1cccc(Br)c1)OCO3
Temperature: 111 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A mixture of 2.17 g (6.09 mmole) of 4-[(3-bromophenyl)amino]-6,7-dihydroxy-3-quinolinecarbonitrile, 0.59ml (1.18 g; 9.14 mmole) of bromochloromethane and 2.98 g (9.14 mmole) of cesium carbonate in 20 ml of N, N-dimethylformamide was heated and stirred for 2 hours in an oil bath at 111° C. The reaction was poured into 75 ml of water and extracted with four 50 ml portions of methylene chloride. The combined methylene chloride extracts were washed with several portions of water. This solution was taken to an oil in vacuo and this was dissolved in ethyl acetate. This solution was washed repeatedly with water, then with brine. The solution was dried over anhydrous magnesium sulfate, and taken to a solid in vacuo to give 0.95 g of 8-[(3-bromophenyl)amino]-[1,3]-dioxolo[4,5-g]quinoline-7-carbonitrile, m.p. 201-205° C.: mass spectrum (electrospray, m/e): M+H 368.1, 370.1.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:6]1([CH2:22][CH2:23][CH3:24])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[C:17][Si](C)(C)C)[CH:14]=2)[S:9][CH2:8][CH2:7]1)[CH2:4][CH3:5]>O.C(O)C>[CH2:22]([C:6]1([CH2:3][CH2:4][CH3:5])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[CH:17])[CH:14]=2)[S:9][CH2:8][CH2:7]1)[CH2:23][CH3:24]
Reactant: CCCC1(CCC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#Cc1ccc2c(c1)C(CCC)(CCC)CCS2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.82 g (32.4 mmol) of potassium hydroxide in 1.8 mL of water and 10.0 mL of ethanol was added to 1.22 g (3.70 mol) of (4,4-dipropylthiochroman-6-yl)(trimethylsilyl)acetylene (Compound 30) and the resulting mixture stirred at room temperature for 5 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aq H2SO4 and the product was extracted with 2×50 mL of ether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:5]=[C:4]([C:17]([OH:19])=[O:18])[C:3]=1[Cl:20].[F:21][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[NH2:1][C:2]1[C:7]([F:21])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:5]=[C:4]([C:17]([OH:19])=[O:18])[C:3]=1[Cl:20]
Reactant: F[B-](F)(F)F
Reactant: Nc1cc(Oc2ccc(Cl)c(Cl)c2)nc(C(=O)O)c1Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Nc1c(F)c(Oc2ccc(Cl)c(Cl)c2)nc(C(=O)O)c1Cl

Procedure:
4-Amino-3-chloro-6-(3,4-dichlorophenoxy)pyridine-2-carboxylic acid was fluorinated with [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate)] (F-TEDA) in refluxing acetonitrile; mp 156-160° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[N:5]2[CH:4]=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O>[CH3:21][N:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[N:6]2[C:2](=[O:1])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][N:5]2[C:10]1=[O:11]
Reactant: CCOC(=O)c1cn2c(=O)[nH]c3ccccc3n2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn2c(=O)n(C)c3ccccc3n2c1=O
Reaction time: 20 h

Procedure:
5.22 g 5,6-dihydro-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester, made as in Example 1, 2.76 g K2CO3 and 50 mM CH3I are dissolved in 100 ml dimethylformamide and stirred for 20 hours. The crystalline 5,6-dihydro-6-methyl-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester is isolated after filtration and recrystallized from dimethylformamide/ethanol. The yield is 4.7 g as white needles with a melting point of 243°-244° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:43]1([O:52]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO>CN(C)C=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([NH:43][OH:52])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(1-pyrrolidinylcarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 13) (288 mg, 0.79 mmol) and N,N-diisopropylethylamine (138 μl, 0.79 mmol) in N,N-dimethylformamide (6 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (452 mg, 1.19 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Further N,N-diisopropylethylamine (552 μl, 3.16 mmol) was then added, followed by the hydroxylamine hydrochloride (165 mg, 2.38 mmol) and the mixture stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue wasa partitioned between ethyl acetate and pH 7 aqueous buffer. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2) to afford the title compound as a foam (126 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][C:12]=1[CH3:13])(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+].C(OCC)(=O)C>CN(C=O)C>[N:20]([CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][C:12]=1[CH3:13])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1sc(-c2ccccc2)nc1CCOS(C)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccccc2)nc1CCN=[N+]=[N-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
To a brown solution of 2-(5-methyl-2-phenylthiazol-4-yl)ethyl methanesulfonate (200 mg, 673 μmol; prepared according to WO 2001/021602) in DMF (2.5 mL) was added sodium azide (52.5 mg, 807 μmol) at RT. The mixture was heated to 60° C. and stirred for 3 h and was then allowed to slowly cool down to RT. The reaction mixture was poured into ethyl acetate (50 mL) and the organic phase was washed with water (3×25 mL) and brine (1×25 mL). The aqueous layers were back-extracted with ethyl acetate (1×50 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 174 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as colorless oil (107 mg, 438 μmol, 65.1%).
Reaction SMILES: [OH-].[K+].[N:3]#[C:4][NH2:5].[F:6][C:7]([F:28])([F:27])[C:8]1[CH:26]=[CH:25][C:11]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.Cl>O.CC(C)=O>[C:4]([NH:5][C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:11]2[CH:25]=[CH:26][C:8]([C:7]([F:28])([F:6])[F:27])=[CH:9][CH:10]=2)=[CH:24][CH:23]=1)[CH3:22])#[N:3]
Reactant: N#CN
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)NC#N
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
10.4 g (0.1575 mole) of 85% potassium hydroxide are dissolved in 75 ml of water. 3.5 g (0.0825 mole) of cyanamide are added at 20° C. and the clear, colourless solution is cooled to 10° C. Then a solution of 25.8 g (0.075 mole) of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride in 15 ml of acetone is added dropwise such that the temperature does not exceed 15° C. After the reaction mixture has been stirred for 45 minutes at this temperature, 9 g (0,09 mole) of 37% aqueous hydrochloric acid are added dropwise at 5° C. The product precipitates as an oil which crystallises on standing over 30 minutes. The colourless crystals are isolated by filtration, washed with water, dried over phosphorous pentoxide, affording 24.9 g (95.0% of theory) of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid N-cyanamide with a melting point of 125°-127° C.
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:23]=[C:22]([N+]([O-])=O)[CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>CC(C)=O>[Cl:12][C:13]1[CH:23]=[C:22]([S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(C)(C)S
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(SC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
2-Methyl-2-propanethiol (7.47 g) was added to a suspension of potassium carbonate (9.52 g) in acetone. Ethyl 2-chloro-4-nitrobenzoate (10 g) was added and the mixture was stirred at room temperature overnight. Further 2-methyl-2-propanethiol (1.0 g) was added and the mixture was stirred and heated to 30° C. for 1 hour. Further 2-methyl-2-propanethiol (1.0 g) was added and the mixture was stirred and heated at reflux for 0.5 hours. Potassium carbonate (9.52 g) and 2-methyl-2-propanethiol was added and the mixture was stirred and heated at reflux overnight. Water was added and it was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give ethyl 2-chloro-4-(1,1-dimethylethylsulphenyl)benzoate (12.1 g) as a red oil NMR (CDCl3) 1.3 (s,9H) 1.35(t,3H) 4.3(q,2H) 7.1-7.7 (m,3H).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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.[CH2:21]1[O:23][C@H:22]1[CH2:24][OH:25].C(N(CC)CC)C>C(Cl)Cl>[C:2]1([C:1]([O:25][CH2:24][C@H:22]2[O:23][CH2:21]2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1CO1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(C(OC[C@@H]2CO2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 2 h
Yield: 130.9 %

Procedure:
A solution of trityl chloride (48.25 g, 173 mmol) in anhydrous CH2Cl2 (150 mL) was added to a stirred solution of (S)-(−)-glycidol (12.21 g, 164 mmol) and triethylamine (34.5 mL, 247 mmol) in anhydrous CH2Cl2 (250 mL) at −20° C. under a N2 atmosphere. After 2 h, CH2Cl2 was removed under vacuum. The mixture was taken up in EtOAc (500 mL) before it was washed with H2O (2×200 mL). The organic layer was dried, filtered and concentrated to give the crude title compound (67.9 g) contaminated with trityl alcohol, which can be removed by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=O)[CH3:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:18])[NH2:17].C(O)(=O)C>C(O)C>[CH3:15][N:16]([CH3:18])[N:17]=[C:12]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1)[CH3:13]
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: CN(C)N
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NN(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of 1-[1-(4-chlorophenyl)cyclobutyl]ethanone (40 g), N,N-dimethylhydrazine (50 ml), glacial acetic acid (2 ml) and ethanol (35 ml) was heated under reflux for 78 hours. Removal of the solvent gave a residue which was distilled (104°-106°/0.1 mm Hg) to give 1- [1-(4-chlorophenyl)cyclobutyl]ethanone N,N-dimethylhydrazone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[C:9]1([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][C:18]3[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccc(-c2ccccc2)nc1
Reactant: OB(O)c1ccncc1
Product: c1ccc(-c2ccc(Cc3ccncc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 61a (355 mg, 1.43 mmol) and 4-pyridineboronic acid (264 mg, 2.15 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (2:1) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Beige solid. Yield: 140 mg, 40%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.77 (s, 2H), 6.88-6.93 (m, 2H), 7.15-7.21 (m, 1H), 7.21-7.31 (m, 3H), 7.45 (dd, J=8.2, 0.9 Hz, 1H), 7.72-7.78 (m, 2H), 8.28-8.33 (m, 2H), 8.33-8.37 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=38.0, 120.3, 124.0, 126.7, 128.7, 128.9, 132.7, 137.1, 138.9, 148.7, 149.9, 150.0, 156.0; (ESI): m/z=246.85 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]4[CH2:25][CH2:26][N:27](C(OCC)=O)[CH2:28][C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CC(O)C>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:13]4[CH2:25][CH2:26][NH:27][CH2:28][C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)N1CCc2c(c3cc(OCc4ccccc4)ccc3n2Cc2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1ccc(COc2ccc3c(c2)c2c(n3Cc3ccccc3)CCNC2)cc1
Yield: 91.9 %

Procedure:
A mixture of intermediate (2) (0.067 mol) and KOH (0.67 mol) in 2-propanol (250 ml) was stirred and refluxed for 5 hours. The solvent was evaporated. Water (300 ml) was added and the organic solvent was removed azeotropically. The precipitate was filtered off and dissolved in CH2Cl2 (300 ml). The organic solution was dried, filtered and the solvent was evaporated. The residue was washed in CH3CN (50 ml), filtered off and dried, yielding 22.7 g (92%) of 2,3,4,5-tetrahydro-8-(phenyl-methoxy)-5-(phenylmethyl)-1H-pyrido[4,3-b]indole (intermediate 3).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[CH2:11]([CH2:13][NH2:14])[OH:12]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH:14][CH2:13][CH2:11][OH:12]
Reactant: Fc1cccc(F)c1CBr
Reactant: NCCO
Solvent: CCO
Product: OCCNCc1c(F)cccc1F
Temperature: 75 °C
Yield: 97.5 %

Procedure:
A mixture of 2,6-difluorobenzyl bromide (3.7 g, 17.8 mmol) and ethanolamine (6.46 mL, 107 mmol) in ethanol (18 mL) was heated at 75° C. for 16 h. The reaction mixture was concentrated and the resulting residue was diluted with dichloromethane (50 mL). The organic layer was partitioned with water (75 mL) and the aqueous layer extracted with dichloromethane (50 mL). Combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound as a yellow solid (3.25 g). (m/z): [M+H]+ calcd for C9H11F2NO, 188.08. found, 188.1. 1H NMR (d6-DMSO, 300 MHz) δ (ppm): 7.37-7.34 (m, 1H), 7.10-7.05 (m, 2H), 4.47 (t, J=5.4 Hz, 1H), 3.75 (s, 2H), 3.42 (q, J=5.5 Hz, 2H), 2.25 (t, J=5.7 Hz, 2H), 1.82 (br s, 1H).
Reaction SMILES: C([CH:18]1[CH:21]([NH:22][C@H:23]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[C:24]([NH:26][N:27]2[CH2:31][CH2:30][C@H:29]([N:32]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:28]2)=[O:25])[CH2:20][N:19]1[CH3:52])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>N1CCCCC1.CN(C=O)C>[CH3:52][N:19]1[CH2:20][CH:21]([NH:22][C@H:23]([CH2:44][C:45]2[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=2)[C:24]([NH:26][N:27]2[CH2:31][CH2:30][C@H:29]([N:32]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:28]2)=[O:25])[CH2:18]1
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC2CN(C)C2C(=O)OCC2c3ccccc3-c3ccccc32)C1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC2CN(C)C2)C1
Reaction time: 0.5 h
Yield: 10.3 %

Procedure:
(2R)-2-{Fmoc[1-(methyl)azetidine-3-yl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step D (71.1 mg, 1 mmol) was dissolved in 50% of piperidine-DMF (2 mL). After being stirred 30 min., the reaction mixture was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (52 mg, 73.5%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8](=O)[C:7]=2[CH:14]=1)[CH3:2].[NH2:15]C(N)=O.O>CN(C)C=O>[CH2:1]([C:3]1[CH:14]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:11][C:10](=[O:12])[NH:15][C:8]2=[O:9])[CH3:2]
Reactant: NC(N)=O
Reactant: CCc1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc2[nH]c(=O)[nH]c(=O)c2c1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A mixture of 6-ethyl-2H-3,1-benzoxazine-2,4(1H)-dione (19.55 g) and urea (6.18 g) in dry N,N-dimethylformamide (98 ml) was heated under reflux for 3 hours and 40 minutes. After the reaction mixture was cooled to ambient temperature, to the mixture was added water with stirring to give crystals, which were separated by filtration, washed with water and dried under reduced pressure to give crystalline 6-ethyl-1H,3H-quinazoline-2,4-dione (11.74 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:29])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH2:24][C:25](O)=[O:26])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:28]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:29])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH2:24][C:25]([N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)=[O:26])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:28]=1
Reactant: C1COCCN1
Reactant: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2,6-dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinolin-6-yl acetic acid (prepared using Methods C and A) (1.0 g, 2.3 mmol) in DMF (7 mL) was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (0.82 g, 2.6 mmol) and morpholine (0.24 mL, 2.8 mmol), and the mixture stirred 18 h at room temperature. Ice water was added, the precipitate collected, washed with water and dried to give the title compound, 0.97 g, 84%, mp >300° C.; MS (ES) 500, 502 (MH+).