Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]([O-:9])(=[O:8])[C:3]([C:5]([O-:7])=[O:6])=O.[Na+].[Na+].Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21].C(OCC)(=O)C>Cl.O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][N:21]=[C:3]([C:5]([OH:7])=[O:6])[C:2]([OH:9])=[O:8]
Reactant: O=C([O-])C(=O)C(=O)[O-]
Reactant: NNc1ccccc1F
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C(=NNc1ccccc1F)C(=O)O
Reaction time: 8 h

Procedure:
Sodium mesoxalate monohydrate (2.21 g, 12.3 mmol) was dissolved in 1 M hydrochloric acid (50 ml) to give a colourless cloudy solution. 2-Fluorophenylhydrazine hydrochloride (2.00 g, 12.3 mmol) was added portionwise at room temperature to the stirred mixture. A yellow precipitate formed, the mixture was diluted with water (50 ml) and stirring continued overnight. Ethyl acetate (150 ml) was added, the phases were mixed vigorously until the solids had dissolved. The phases were separated and the aqueous phase was washed with ethyl acetate (50 ml). The combined organic phases were dried over magnesium sulfate, filtered and the solvent removed under vacuum. The title compound was isolated as a yellow powder (2.55 g, 11.7 mmol, 92%). LCMS: m/z 227 [M−H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1.Cl[CH2:29][C:30]([NH2:32])=[O:31].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:24][CH2:25]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1
Reactant: NC(=O)CCl
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CN1CCC(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-piperidin-4-ylmethyl-piperazin-2-one (20 mg, 0.047 mmol) in N-methylpyrrolidinone (0.5 mL) is added 2-chloroacetamide (9 mg, 0.094 mmole) and diisopropylethylamine (0.016 mL, 0.094 mmole) and heated at 120° C. for 16 h. The reaction is concentrated and purified by column chromatography (silica, 5% methanol/dichloromethane) to provide 2-{4-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-piperidin-1-yl}-acetamide. 1H NMR (300 MHz, CDCl3) d 7.88-7.83 (m, 3H), 7.47 (dd, 1H), 6.98 (bs, 1H), 5.30 (bs, 1H), 3.86 (s, 2H), 3.46 (s, 4H), 3.28 (d, 2H), 2.95 (s, 2H), 2.82 (d, 2H), 2.06 (t, 2H), 1.69-1.50 (m, 3H), 1.33-1.25 (m, 2H); MS (Ion spray) 485 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7](=O)[NH:8][SH:9](=[O:16])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.O.P(Cl)(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[Cl:23][C:7]1[NH:8][SH:9](=[O:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]2[CH:3]=[C:2]([Cl:1])[CH:19]=[CH:18][C:5]=2[N:6]=1
Reactant: O=C1Nc2ccc(Cl)cc2[SH](=O)(c2ccccc2)N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[SH]1(c2ccccc2)NC(Cl)=Nc2ccc(Cl)cc21

Procedure:
A suspension of 2.92 g (0.01 mole) of 7-chloro-1-phenyl-1,2,4-benzothiadiazin-3(4H)-one-1-oxide in 25 ml of phosphorus oxychloride is treated with 0.5 ml of water and the mixture is heated under reflux for 45 minutes. The solution is then cooled and poured into 100 ml of a mixture of ice and water. The soluble oily material is taken up in chloroform, the chloroform solution dried, filtered, concentrated, and the residual material recrystallized from acetonitrile to give 0.85 g of colorless product, melting point 162°-164°C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)[CH3:2].Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH:5]1[CH2:4][N:3]([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]2[CH:24]=[CH:25][C:26](=[O:30])[O:27][C:28]=2[CH:29]=1
Reactant: CCNCC1COc2ccccc2O1
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCOc1ccc2ccc(=O)oc2c1)CC1COc2ccccc2O1
Temperature: 76 °C
Yield: 51.6 %

Procedure:
N-Ethyl-2,3-dihydro-1,4-benzodioxin-2-methanamine (4.67 g, 24.2 mmole), 7-(3-bromopropoxy)coumarin (6.92 g, 24.4 mmole), and diisopropylethylamine (6.70 ml, 38.5 mmole) were combined in 300 ml of DMF and heated at 76° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue (10 g) was column chromatographed on 225 g of silica gel using 40% ethyl acetate/dichloromethane as eluant. The product-containing fractions were concentrated in vacuum and the residue crystallized from isopropanol with the addition of 30 ml of 4N isopropanolic HCl to give 4.94 g of the title compound as a white solid, monohydrochloride, m.p. 147°-152° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][C:5]([NH:21][CH2:22][C:23]([O:25]C)=[O:24])=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12](OC)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.[CH3:28][O-:29].[Na+].C[OH:32]>Cl>[Cl:1][C:2]1[C:3]([O:29][CH3:28])=[N:4][C:5]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:32])=[C:11]([CH:17]([CH3:18])[CH3:19])[CH:10]=1
Reactant: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Reactant: C[O-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: COc1nc(NCC(=O)O)c(Cl)c(Oc2ccc(O)c(C(C)C)c2)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,5-dichloro-2-fluoro-4-(3-isopropyl-4-methoxyphenoxy)-6-methoxycarbonylmethylamino-pyridine (161 mg) in methanol (3.0 mL) was added a solution of sodium methoxide in methanol (0.5 M, 1.0 mL). The resulting mixture was stirred at ambient temperature for 18 hours, followed by stirring at 80° C. for 5 hours. Cooled reaction mixture was then diluted with 1 N HCl (50 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were dried (Na2SO4) and concentrated. The dried crude product was dissolved in CH2Cl2 (3.0 mL) and treated with a solution of BBr3 in CH2Cl2 (1 mL, 1.0 M) at ambient temperature. The resulting mixture was stirred for 1 hour, poured to stirring water (50 mL), extracted with CH2C2 (20 mL×3) from water, dried (Na2SO4) and concentrated to dryness under reduced pressure. The residue was dissolved in THF:MeOH:H2)=3:1:1 (3 mL), treated with LiOH in one portion (50 mg) and stirred at ambient temperature for 1 hour. The reaction mixture was diluted with a 1.0 M solution of HCl (50 mL), extracted with ethyl acetate (50 mL×3), dried (Na2SO4) and concentrated under reduced pressure. Purification by HPLC afforded the title compound as a white solid (30 mg).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[C:22]1([C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:16]1([C:3]2[C:2]([C:31]3[CH:32]=[CH:33][C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:29][CH:30]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc(-c4ccccc4)cc3)nc2c1
Yield: 51.4 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-phenyl-phenylboronic acid (100 mg, 0.51 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (15:1)) yielded 60 mg (51%) of 2-phenyl-3-(4-phenyl-phenyl)quinoxaline-6-carboxylic acid as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[Se:4][C:3]=1[C:11]([NH2:13])=[O:12].S(=O)(=O)(O)O.N.[CH:20](O)=O>>[C:7]([C:5]1[Se:4][C:3]2[C:11](=[O:12])[NH:13][CH:20]=[N:1][C:2]=2[CH:6]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=CO
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: N
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc2nc[nH]c(=O)c2[se]1
Yield: 80 %

Procedure:
To a solution of 3-amino-5-(tert-butyl)selenophene-2-carboxamide (1 g) in formic acid (10 mL) was added concentrated sulfuric acid (5 mL) slowly for 10 min at rt. The mixture was refluxed for 1.5 h and allowed to rt. The mixture was poured into ice cold water and basified with ammonia solution. The solution was extracted with chloroform (3×200 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as a yellow color solid (900 mg, 80%), mp 240-242° C. 1H NMR (400 MHz, CDCl3): δ 12.61 (1H, br s), 8.16 (1H, s), 7.34 (1H, s), 1.46 (9H, s); LC-MS (negative ion mode): m/z 253, 255 (M−H)−.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12])(=O)C.[OH-].[Na+].Cl>CO.O>[OH:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12]
Reactant: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)NCC1(CC(=O)O)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1(CNC(=O)O[C@@H]2CCC[C@H]2O)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a stirred solution of compound (48) (2.0 g, 5.9 mmol) in methanol (25 mL) was added a solution of NaOH (0.8 g, 20 mmol) in 20 mL of water. The reaction mixture was stirred at room temperature for 2 h (monitored by TLC). The reaction mixture was acidified to about pH 5.0 using 0.1 N HCl and then extracted using ethyl acetate (2×50 mL). The combined extracts were washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified using flash chromatography on silica gel using hexane/ethyl acetate (1:1) as eluant to provide 1.3 g (75%) of compound (49) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ1.36–1.78 (14H, m); 1.99–2.12 (2H, m); 2.34 (2H, s); 3.23 (2H, d, J=6.4 Hz); 4.09 (1H, m); 5.26 (1H, t, J=6.4 Hz); 5.89 (1H, m). MS (ESI): m/z=298.23 (M−H−).
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C1(P(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=C(C3C4C(=CC=CC=4)C=CC=3)C3C(C=2)=CC=CC=3)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[F:12][C:11]1[C:2]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([CH3:13])[CH:5]=[CH:4]2
Reactant: Cc1ccc2c(Br)c(F)ccc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2cc3ccccc3c(-c3cccc4ccccc34)c2P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)ccc2n1
Temperature: 120 °C
Reaction time: 20 h
Yield: 65.8 %

Procedure:
A mixture of 5-bromo6-fluoro-2-methylquinoline (Chem. Pharm. Bull:, 1989, 37(8), 2103-8, 0.285 g), 1,1-dimethylethyl 1-piperazinecarboxylate (0.265 g, 1.2 equiv.), Pd(OA)2 (15 mol %, 0.04 g), bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 30 mol %, 0.221 g), cesium carbonate (1.5 equiv. 0.580 g) and toluene (3.5 mL) were stirred at 120° C. for 20 h in a sealed tube. The mixture was cooled to room temperature and partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. This crude product was purified by flash chromatography [SiO2; DCM-MeOH (99:1)→(90:10)] to afford the title compound as colourless solid (0.270 g, 65% yield).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:28]4[C:24](=[N:25][NH:26][N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[N:52]=[C:51]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:50]=1.[H-].[Na+].C(=O)=O>ClC1C=CC=CC=1.CN(C)C=O>[C:8]1([N:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:28]4[C:24](=[N:25][N:26]([C:49]5[C:58]6[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=6)[N:52]=[C:51]([C:59]6[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=6)[CH:50]=5)[N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4n[nH]nc34)cc2)cc1
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: c1ccc(-c2cc(-n3nc4c(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)ccc(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)c4n3)c3ccccc3n2)cc1
Temperature: 50 °C

Procedure:
A mixture of Intermediate D (605 mg, 1.0 mmol), 4-chloro-2-phenylquinoline (481 mg, 2.0 mmol), 60% NaH (80 mg, 2.0 mmol), and dimethylformamide (15 mL) was stirred under argon and heated at 50° C. for 3 hours. After cooling, the mixture was diluted with chlorobenzene (50 mL) and treated with a piece of dry ice to reduce the pH. The volatiles were removed under reduced pressure, and the residue was chromatographed using silica gel and hexane/dichloromethane (2:1) as an eluent to give 4,7-bis(4-(N,N-diphenylamino)phenyl)-2-(2-phenylquinolin-4-yl)-2H-benzo[d][1,2,3]triazole (Example 17) as orange-pink crystals, 640 mg (79%). 1H NMR (400 MHz, CDCl3): δ 8.70 (m, 3H, 2-phenylquinazolin-4-yl), 8.22 (d, J=8.4 Hz, 1H, 2-phenylquinazolin-4-yl), 8.12 (d, J=8.8 Hz, 4H, p-phenylene), 7.97 (ddd, J=8.4, 6.9 and 1.4 Hz, 1H, 2-phenylquinazolin-4-yl), 7.76 (s, 2H, benzotriazole), 7.68 (ddd, J=8.5, 7.0 and 1.1 Hz, 1H, 2-phenylquinazolin-4-yl), 7.53 (m, 3H, 2-phenylquinazolin-4-yl), 7.25-7.30 (m, 8H, Ph), 7.21 (d, J=8.4 Hz, 4H, p-phenylene), 7.16-7.19 (m, 8H, Ph), 7.05 (tt, J=7.3 and 1.1 Hz, 4H, Ph), 2.86 (s, 3H, quinaldine). UV-vis spectrum (dichloromethane): λmax=452 nm. Fluorimetry (dichloromethane): λmax=654 nm.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[C:13]2[CH:14]=[CH:15][C:16]([N:18]3[CH2:22][CH2:21][NH:20][C:19]3=[O:23])=[CH:17][C:12]=2[CH2:11][CH2:10][O:9]1)(=O)=O.[C:24]([C:26]1[CH:41]=[CH:40][C:29]2[C:30]([N:33]3[CH2:38][CH2:37][NH:36][C@H:35]([CH3:39])[CH2:34]3)=[CH:31][S:32][C:28]=2[CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:41]=[CH:40][C:29]2[C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH2:6][CH2:7][C@H:8]4[C:13]5[CH:14]=[CH:15][C:16]([N:18]6[CH2:22][CH2:21][NH:20][C:19]6=[O:23])=[CH:17][C:12]=5[CH2:11][CH2:10][O:9]4)[C@H:35]([CH3:39])[CH2:34]3)=[CH:31][S:32][C:28]=2[CH:27]=1)#[N:25]
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(N3CCNC3=O)ccc21
Reactant: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1
Product: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1CC[C@@H]1OCCc2cc(N3CCNC3=O)ccc21

Procedure:
The title compound was prepared by condensation of 2-((1S)-6-(2-oxo-imidazolidin-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl)ethyl methanesulfonate and (3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine, as described for Example 1b). M+H=502.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.BrC1C=C([CH2:46][S:47](CC2C=CC=C(Br)C=2)(=[O:49])=[O:48])C=CC=1.C[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]>C1(C)C=CC=CC=1>[CH3:46][S:47]([C:64]1[CH:63]=[C:62]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[N:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=4)[N:12]=3)[CH:10]=2)[CH:61]=[CH:60][CH:59]=1)(=[O:49])=[O:48]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: O=S(=O)(Cc1cccc(Br)c1)Cc1cccc(Br)c1
Reactant: CCCCCCC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1
Reaction time: 1 h
Yield: 64 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example G.1) (0.155 g, 0.24 mmol), commercially available 3-bromo-phenylmethyl sulfone (0.062 g, 0.26 mmol), tetrakis(triphenyl-phosphine)palladium (0.017 g, 0.015 mmol) in toluene (5 mL) was heated under reflux conditions for 15 h. Heptane (5 mL) was added at room temperature and the mixture was stirred for 1 h. The precipitate was collected by filtration, washed with heptane and dried. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) yielded the title compound (0.078 g, 64%) as a white solid. MS (ISP) 512.9 [(M+H)+]; mp 231° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].O>C1COCC1>[C:13]([Si:17]([CH3:19])([CH3:18])[N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
To a solution of 5-fluoro-1H-indole (30.0 g, 0.222 mol) in anhydrous THF (250 mL) was added sodium hydride (60% suspension in mineral oil, 10.22 g, 0.255 mol) portionwise and maintaining the solution at 0° C. The reaction mixture was stirred at 0° C. for 20 min, then a solution of tert-butyl-chloro-dimethyl-silane (40.15 g, 0.266 mol) in anhydrous THF (20 mL) was added and the solution stirred at RT for 25 h. The reaction mixture was poured into H2O and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4), then concentrated in vacuo. The resultant residue was purified by column chromatography (silica gel, cyclohexane:DCM 100% to 50:50) to provide the title compound as a colourless oil (41.2 g, 74%).
Reaction SMILES: [C:1](=[O:3])=[O:2].[OH2:4].Cl.[C:6]1(C)[C:7]([CH3:12])=[CH:8][CH:9]=[CH:10][CH:11]=1>C1COCC1>[CH2:12]([O:4][C:6]1[C:7]([CH3:12])=[C:8]([CH:9]=[CH:10][CH:11]=1)[C:1]([OH:3])=[O:2])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:6]=1
Reactant: Cc1ccccc1C
Reactant: O=C=O
Reactant: O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(OCc2ccccc2)cccc1C(=O)O
Temperature: 0 °C

Procedure:
232.7 g of 2-benzyloxy-6-chlorotoluene (232.7 g, 1.0 mol) are subjected to a Grignard reaction with 26.7 g (1.1 mol) of magnesium turnings in 550 ml of THF. The brown-black solution of (3-benzyloxy-2-methylphenyl)magnesium chloride in THF formed therefrom is stirred until cold by means of an ice bath at 0° C. CO2 gas is passed into the stirred reaction mixture slowly such that the temperature does not exceed 10° C. The solid suspension in THF formed therefrom is hydrolyzed with cooling by slow addition of 50 ml of water and 445 g (1.2 mol) of hydrochloric acid (10% strength). The hydrolyzed reaction mixture is diluted with 430 g of xylene. The phases are separated and the organic phase is washed with 100 g of water. The product-containing organic phase separated off is distilled until the bottom is free of THF. The bottom is then stirred at 0° C. until cold. The crystallized product is filtered off and washed with 50 ml of xylene. After drying in vacuo, 152.3 g of 3-benzyloxy-2-methylbenzoic acid are obtained. This corresponds to a yield of 62.9% of theory.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(N(CC)CC)C>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:20][NH:21][C:22]([NH2:24])=[O:23])=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: NNC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)NNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
To a solution of Cbz-Pro (1.25 g), semicarbazide hydrochloride (5.5 g), and HOBt (6.75 g) in DMF (100 mL) is added triethylamine (7.5 mL) and DCC (10.5 g) at 0° C. with stirring. The reaction is stirred at 0° C. for 24 hours. The precipitate is filtered and the filtrate is concentrated in vacuo. The residue is triturated with saturated NaHCO3 solution, filtered, washed with water and dried to give Cbz-Pro-azaGlyNH2. Cbz-Pro-azaGlyNH2 (10 g) is catalytically hydrogenated in (1:1) methanol/DMF at pH 4.5 in the presence of Pd catalyst. At the end of the hydrogenation the catalyst is filtered and the filtrate is concentrated in vacuo to give H-Pro-azaGlyNH2.HCl. To a solution of H-Pro-azaGlyNH2.HCl (2.08 g), HOBt (1.63 g), and Boc-Lys(N,N-epsilon-isopropyl,Cbz)-OH (1.26 g) in DMF (40 mL), DCC (2.1 g) is added with stirring at 0° C. for 2 hours and then at 4° C. for 24 hours. After workup and trituration with ether Boc-Lys(N,N-epsilon-isopropyl,Cbz)-Pro-azaGlyNH2 is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[N:12][C:11]=1[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:16][C:14]1[N:13]=[N:12][C:11]([CH3:17])=[C:10]([O:8][C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=1
Reactant: Cc1nnc(Cl)cc1Cl
Reactant: Nc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nnc(Cl)cc1Oc1cccnc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
2-Aminopyridin-3-ol (5.0 g, 45.4 mmol) and 4,6-dichloro-3-methylpyridazine (7.4 g, 45.4 mmol, prepared according to WO 2003/041712) were dissolved in DMSO (100 mL). Cs2CO3 (16.3 g, 49.9 mmol) was added and the reaction stirred at ambient temperature for one hour. The reaction was diluted with water and the material was extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated. Flash chromatography followed by trituration of the concentrated solid with EtOH gave 3-(6-chloro-3-methylpyridazin-4-yloxy)pyridin-2-amine (5.98 g, 25.3 mmol, 55%) as a solid.