Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[C:15]([Br:18])[C:16]=1[NH2:17].O>N1C=CC=CC=1>[Br:10][C:11]1[CH:12]=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[C:15]([Br:18])[C:16]=1[NH:17][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1c(Br)cc(-c2ccccc2)cc1Br
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1c(Br)cc(-c2ccccc2)cc1Br)c1ccccc1
Reaction time: 16 h

Procedure:
Benzoyl chloride (4.0 mL, 0.035 mol) was added to a solution of 3,5-dibromobiphenyl-4-amine (10.5 g, 0.032 mol) in pyridine (75 mL). This was stirred for 16 h before being poured into water. The crude solid was filtered, washed with water and chromatographed (silica gel). The column was eluted first with hexanes and dichloromethane (1:1) then dichloromethane to afford the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6](=[O:17])[C:7]([N+:14]([O-:16])=[O:15])=[C:8]1[NH:13][CH2:12][CH2:11][CH2:10][S:9]1.[H-].[Na+].[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([N:13]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[C:7]([N+:14]([O-:16])=[O:15])[C:6](=[O:17])[CH2:5][O:4][C:3]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=1[Cl:1])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: O=C(COc1ccc(Cl)cc1Cl)C(=C1NCCCS1)[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: CC(=O)N1CCCSC1=C(C(=O)COc1ccc(Cl)cc1Cl)[N+](=O)[O-]

Procedure:
5 was prepared as a yellow solid, melting point: 120°-120.5° (with decomposition) by the treatment of 5C with sodium hydride and acetyl chloride, by the general procedure described in Example 1.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[N:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][N:15]1[CH2:16][CH2:17][N:12]([C:18]2[N:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:13][CH2:14]1
Reactant: ClCc1nc2cccnc2s1
Reactant: N#Cc1cccnc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccnc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 2-(1-piperazinyl)nicotinonitrile (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.75 (m, 4H) 3.68 (m, 4H) 4.07 (s, 2H) 6.94 (m, 1H) 7.56 (m, 1H) 8.08 (dd, J=7.80, 2.03 Hz, 1H) 8.33 (dd, J=8.31, 1.53 Hz, 1H) 8.42 (dd, J=4.75, 1.70 Hz, 1H) 8.60 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 337 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[N:14][C:15]([O:19][CH3:20])=[C:16]([CH3:18])[CH:17]=1)(=[O:10])=[O:9].Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[CH3:20][O:19][C:15]1[N:14]=[CH:13][C:12]([N:11]2[C:22](=[O:24])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:9])=[O:10])=[CH:17][C:16]=1[CH3:18]
Reactant: COc1ncc(NS(=O)(=O)c2ccccc2N)cc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COc1ncc(N2C(=O)Nc3ccccc3S2(=O)=O)cc1C
Yield: 385.5 %

Procedure:
The title compound was prepared from 2-amino-N-(6-methoxy-5-methylpyridin-3-yl)benzenesulfonamide (2.60 g) and triphosgene (815 mg, 2.75 mmol) in anhydrous 1,4-dioxane (160 mL) using the methods of (IntA1) step 3. Concentration in vacuo after completion of the reaction yielded the title compound (3.38 g, 10.6 mmol, approximately 80% purity by LCMS) which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]([OH:29])=O)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]([Cl:33])=[O:29])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)COc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetic acid (150 mg, 0.39 mmol) in dichloromethane (3 mL) is added oxalyl chloride (490 mg, 3.9 mmol) and 1 drop of N,N-dimethylformamide. The mixture is stirred at room temperature for 5 h, concentrated in vacuo, and residual solvents removed by co-evaporation three times with chloroform to yield [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetyl chloride as a yellow solid. To a solution of [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetyl chloride (50 mg, 0.12 mmol) in dichloromethane at room temperature is added 1-methyl-piperazine (62 mg, 62 mmol) and the mixture stirred for 2.5 h. The mixture is partitioned between dichloromethane and water, the organic portion dried (sodium sulfate), filtered, and concentrated in vacuo. The crude residue is chromatographed on SiO2 (89% dichloromethane 10% methanol 1% concentrated ammonium hydroxide) to yield the title compound, 28 mg (48%), as a light brown solid.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:22]1([CH2:34][C:35]([NH2:37])=[O:36])[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1>>[C:22]1([C:34]2[C:35](=[O:36])[NH:37][C:3](=[O:21])[C:4]=2[C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1c[nH]c2cc(-c3cccnc3)ccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(-c3cccnc3)ccc12

Procedure:
Beginning with (6-(pyridin-3-yl)indol-3-yl)oxoacetic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:28][C:29]2[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=2)[C:9]2[C:10]([C:25]([OH:27])=O)=[N:11][N:12]([C:15]3[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([C:15]4[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=4)[C:13]=3[CH3:14])[C:25](=[O:27])[N:28]2[C:29]2[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=2)=[CH:6][CH:7]=1
Reactant: COc1ncc(-n2nc(C(=O)O)c(C(Nc3cc(C)c(=O)n(C)c3)c3ccc(Cl)cc3)c2C)c(OC)n1
Solvent: CO
Solvent: ClCCl
Product: COc1ncc(-n2nc3c(c2C)C(c2ccc(Cl)cc2)N(c2cc(C)c(=O)n(C)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-methyl-1H-pyrazole-3-carboxylic acid (Step 56.2). tR: 4.10 min (HPLC 1); tR: 0.94 min (LC-MS 2); ESI-MS: 507 [M+H]+ (LC-MS 2); Rf=0.44 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-1.95 (m, 6H) 3.35 (s, 3H) 3.92 (s, 3H) 3.96 (s, 3H) 6.21 (s, 1H) 7.26-7.33 (m, 2H) 7.35-7.44 (m, 3H) 7.75 (d, J=2.7 Hz, 1H) 8.53 (d, J=0.8 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:7]([O:9]C)=[O:8].Cl>CO>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CON=C(C(=O)OC)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
A 2 N aqueous solution of sodium hydroxide (11 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(4-hydroxyphenyl)acetate (syn isomer) (2.1 g.) in methanol (30 ml.) and the mixture was stirred for 18 hours at ambient temperature. The reaction mixture was adjusted to pH 7 with 10% hydrochloric acid and methanol was removed. To the residue was added water and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, subjected to salting-out and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ethyl acetate was distilled off to give crystals of 2-methoxyimino-2-(4-hydroxyphenyl)acetic acid (syn isomer) (1.5 g.).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>O>[CH2:10]([NH:14][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1)[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Solvent: O
Product: CC(C)Cn1cnc2c(NCc3ccccc3)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
When the TLC indicated the disappearance of 4-chloro-1-isobutyl-1H-imidazo(4,5-c)quinoline, the reaction mixture was cooled to room temperature resulting in a solid mass. 60 mL of water was added and the reaction mixture was stirred for 30 min. The solids were then separated by filtration and the solids were washed with 20 mL of water. The solids were then dried in an oven at 85° C. resulting in 11.3 grams (90% yield) of 4-(N-benzylamino)-1-isobutyl-1H-imidazo(4,5-c)quinoline.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)C.Cl[CH:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][CH2:20][C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]1=2>O1CCCC1>[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:17]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClC1c2ccccc2CCc2ccccc21
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1c2ccccc2CCc2ccccc21

Procedure:
A mixture of 11.4 g of magnesium shavings, 151.5 g of diethyl malonate and 300 ml of dry ethanol is warmed to 60° under argon over a period of 30 minutes. After the vigorous reaction has faded, the mixture is heated to boiling under reflux for an additional 1 hour and then concentrated in vacuo. The residue is treated twice with 300 ml of dry benzene each time and in each case evaporated well. The residue obtained is dissolved under argon in 350 ml of dry tetrahydrofuran. Thereto there is added dropwise at room temperature over a period of 20 minutes a solution of 195.5 g of 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene in 500 ml of dry tetrahydrofuran. The mixture is heated to boiling under reflux overnight while stirring and then evaporated in vacuo. The residue obtained is partitioned between 2.0 l of toluene and 500 ml of ice-water. The organic phase is washed successively twice with 500 ml of 1N hydrochloric acid each time, twice with 500 ml of water each time, twice with 250 ml of saturated sodium bicarbonate solution each time and several times with water, dried over magnesium sulfate and evaporated in vacuo. Diethyl 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-malonate is obtained as an orange oil.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[CH3:9][O:10][C:11](=[O:23])[CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2.BrCCBr>C1COCC1>[CH3:9][O:10][C:11]([C:12]1([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[CH2:3][CH2:2]1)=[O:23]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccc2ncccc2c1
Agent: [Li+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc3ncccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
A solution of LDA (1.8 M solution in toluene, 14.8 ml, 26.6 mmol) was added dropwise to a solution of quinolin-6-yl-acetic acid methyl ester (2.14 g, 10.64 mmol) in dry THF (40 mL) under a nitrogen atmosphere at −78° C. After 30 min, 1,2-dibromoethane (2.40 g, 12.76 mmol) was added dropwise over 3 min. The resulting mixture was stirred for 1 h at room temperature, then quenched with satd aq. NH4Cl. The mixture was extracted with DCM, washed with brine, dried over Na2SO4, and stripped of solvent. The residue was purified by flash chromatography in silica gel eluting with a EtOAC/hexane gradient to afford 463 mg (20%) of the title compound as yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.91 (dd, 1H), 8.12 (d, 1H), 8.07 (d, 1H), 7.77-7.74 (m, 2H), 7.40 (dd, 1H), 3.65 (s, 3H), 1.73-1.71 (m, 2H), 1.33-1.30 (m, 2H). LCMS (method A): [MH]+=228, tR=4.37 min.
Reaction SMILES: [CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C1C[O:36]CC1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@@:4]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])([CH2:1][CH2:2][CH2:3][OH:36])[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: C=CC[C@]1(c2ccccc2F)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)O1
Reactant: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCCO)(c2ccccc2F)OC1=O
Reaction time: 2 h
Yield: 17 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (80 mg, 0.18 mmol) in THF (10 mL) was added BH3 THF (1.5 mL, 1 mol/L) at 0° C. under nitrogen. The formed mixture was stirred for 2 h. The reaction was quenched by water. Then aq NaOH (0.3 mL, 3 mol/L) solution and H2O2 (3 mL) was added to the above mixture. The resulting mixture was stirred for 1.5 h. The mixture was extracted with EtOAc, and the combined organic phase was concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (15 mg, 17%). LC-MS Method 2 tR=1.48, min, m/z=452.2; 1H NMR (CD3OD) 1.22-1.34 (m, 2H), 1.53 (d, 3H), 1.62-1.73 (m, 1H), 1.98-2.33 (m, 4H), 2.61 (d, 1H), 3.13 (m, 1H), 3.51 (m, 2H), 5.61 (m, 1H), 7.01-7.19 (m, 5H), 7.23 (m, 1H), 7.31-7.43 (m, 4H), 7.53 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[N:17]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[N:18]=[CH:19][N:20]=4)[S:13][C:10]=3[C:11]=2[N:12]=1.[CH3:29][N:30](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:29]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[N:17]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[N:18]=[CH:19][N:20]=4)[S:13][C:10]=3[C:11]=2[N:12]=1)#[N:30]
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 200 °C
Yield: 60 %

Procedure:
To solution containing 3-(2-chloro-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)-2-(2,4-difluorophenyl)-2H-1,2,4-triazole (0.030 g, 0.072 mmol), zinc cyanide (16.9 mg, 0.144 mmol), and tetrakis(triphenylphosphine)palladium(0) (4.16 mg, 0.00360 mmol) in N,N-dimethylformamide (1.00 mL, 12.9 mmol) was evacuated then back-filled with nitrogen. The reaction mixture was heated in microwave to 200° C. for 10 min. The reaction mixture was quenched with sat.NH4Cl then extracted EtOAc (3×). The crude product was purified by column chromatography (EtOAc/Hex) (eluted 50% EtOAc) to give 366 (60% yield). MS: (ESI+)=408.0
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH2:12][OH:13])=[N:9][N:8]=1>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH:12]=[O:13])=[N:9][N:8]=1
Reactant: OCc1nnc(-c2ccccn2)s1
Solvent: CCOC(C)=O
Product: O=Cc1nnc(-c2ccccn2)s1
Temperature: 85 °C
Yield: 73 %

Procedure:
The compound prepared in Example 148 (0.18 g) and IBX (o-iodoxybenzoic acid; 0.40 g) were stirred in ethyl acetate (8 mL) and heated at 85° C. for 14 hours. The reaction was cooled, filtered and washed with ethyl acetate. The solution was washed twice with sodium hydrogen carbonate aqueous solution and then brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound (0.13 g) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9]([C:12](=O)[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[NH2:26][N:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>CO>[F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9](/[C:12](=[N:26]/[N:27]3[CH2:31][C:30](=[O:32])[NH:29][C:28]3=[O:33])/[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: NN1CC(=O)NC1=O
Reactant: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Solvent: CO
Product: C/C(=N\N1CC(=O)NC1=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Yield: 23.7 %

Procedure:
A solution of 1-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (20 mg, 0.059 mmol) and 1-aminoimidazolidine-2,4-dione (13.6 mg, 0.12 mmol) was stirred in MeOH at room temperature over a weekend. Light yellow solid was filtered to give the title compound (6 mg, 0.014 mmol). The filtrate was purified on HPLC (acidic with 0.05% TFA) to give the title compound as TFA salt (8 mg, 0.0145 mmol). The combined yield was 48%. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.46 (s, 1H), 9.02 (d, 1H), 8.55 (d, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.18 (d, 1H), 8.0 (s, 1H), 7.98 (s, 1H), 7.65 (d, 1H), 4.54 (s, 2H), 2.24 (s, 3H). LCMS (method B): [MH]+=437.1, tR=2.06 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:33])[C:30]=1[O:31][CH3:32])[C:25](O)=[O:26]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:28]=[C:29]([CH3:33])[C:30]([O:31][CH3:32])=[C:22]([CH3:21])[CH:23]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: COc1c(C)cc(C(=O)O)cc1C
Agent: Cl
Product: COc1c(C)cc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1C

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 3,5-dimethyl-4-methoxybenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:13].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=[CH:6][C:5]=2[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(=O)c2cccc(C)c2o1
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)c2c([N+](=O)[O-])ccc(C)c2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 g (11.48 mmol) of 2,8-dimethyl-4H-chromen-4-one are dissolved in 15 ml of concentrated sulfuric acid and, at 0° C., 0.7 g (11.48 mmol) of fuming nitric acid is added, during which the temperature should not exceed 5° C. The mixture is then stirred at room temperature for 1 h. The reaction mixture is poured into ice-water, whereupon a colorless solid precipitates. This is filtered off and washed several times with water and ice-cold methanol. 2.3 g (90.8% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:28])[C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([O:24][CH2:25][C:26]#[CH:27])[CH:16]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Sn](Cl)Cl.N>C(OCC)(=O)C.CO>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH:10]2[CH2:11][CH2:12][CH:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH2:8][CH2:9]2)=[O:28])=[CH:16][C:17]=1[O:24][CH2:25][C:26]#[CH:27]
Reactant: C#CCOc1cc(C(=O)NC2CCC(N3CCOCC3)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: C#CCOc1cc(C(=O)NC2CCC(N3CCOCC3)CC2)ccc1N
Temperature: 50 °C
Reaction time: 16 h

Procedure:
38.7 g (0.1 mol) N-(4-morpholin-4-yl-cyclohexyl)-4-nitro-3-prop-2-ynyloxy-benzamide are dissolved in 400 ml of ethyl acetate and 25 ml of methanol. To this solution are added 75 g tin (II)chloride.3H2O. The mixture is stirred for 16 h at 50° C. Then it is cooled to ambient temperature and 80 ml of conc. aqueous ammonia are added.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].[NH2:15]C(N)=O>>[Cl:14][C:12]1[CH:13]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:8])[NH:15][C:1](=[O:2])[CH2:4]2
Reactant: O=C(O)Cc1cc(Cl)ccc1C(=O)O
Reactant: NC(N)=O
Product: O=C1Cc2cc(Cl)ccc2C(=O)N1
Reaction time: 0.25 h
Yield: 34 %

Procedure:
An amount of 2-(carboxymethyl)-4-chlorobenzoic acid (8.4 g, 39.14 mmol) and 2.82 g (47 mmol) of urea is vigorously stirred at 160° C. Solids were melted, boiled and hardened after 15 min. Continue to heat and blow nitrogen through to remove water generated from reaction until total dryness. After cooling, the solid is ground to fine powder. After successively washing with saturated NaHCO3 solution, water, methanol, ether and hexane, the powder is dried in oven (60° C.) overnight to give 2.6 g (34.0% yield) of light yellow solid: MS (ESI) m/z 194.0 (M−H)−1 Analysis for C9H6ClNO2, Calcd: C, 55.26; H, 3.09; N, 7.16. Found: C, 54.86; H, 2.96; N, 7.12
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1CCNCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CS(=O)(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 199 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(piperidin-4-yl)thiophene-2-carboxamide (0.2 g, 0.46 mmol) and methanesulfonyl chloride (79.0 mg, 0.69 mmol). The title compound was obtained as a solid (40 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.73 (1H, m), 8.48 (1H, s), 3.80 (1H, m), 3.77 (2H, m), 2.84 (3H, s), 2.81 (2H, m), 1.89 (2H, m), 1.56 (2H, m). MS m/z: 509.25, 511.28 [M+H]+.