Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([S:13]([NH2:16])(=[O:15])=[O:14])[S:10][N:9]=1.S(Cl)(Cl)=O.[CH:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=O>>[N:23]1([CH:21]=[N:16][S:13]([C:11]2[S:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[N:12]=2)(=[O:15])=[O:14])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Cc1ccccc1-c1nsc(S(N)(=O)=O)n1
Reactant: O=CN1CCOCC1
Solvent: O=S(Cl)Cl
Product: Cc1ccccc1-c1nsc(S(=O)(=O)N=CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.5 g of 3-(2-methylphenyl)-1,2,4-thiadiazole-5-sulfonamide in 18 ml of N-formylmorpholine at -5° C. was added 5 ml of thionyl chloride. The resulting mixture was stirred for 3 hours at room temperature, then poured into ice water and stirred for 30 minutes. The solid was collected, washed with water and sucked dry. The solid was then triturated with ether, ether/hexane (1:1) and hexane successively. The product was dried (P2O5) to give 4.52 g of solid, m.p. 151°-153° C.
Reaction SMILES: [OH-:1].[K+].[OH:3][CH:4]([CH2:29][OH:30])[CH2:5][NH:6][C:7](=[O:28])[C:8]1[C:21]([I:22])=[C:20]([NH:23][CH:24]=[O:25])[C:19]([I:26])=[C:10]([C:11]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[O:12])[C:9]=1[I:27].B(O)(O)O.[CH2:35]1[O:37][CH:36]1[CH:38]1[O:40][CH2:39]1.Cl>CO.O>[OH:40][CH:38]([CH:36]([OH:37])[CH2:35][N:23]([C:20]1[C:21]([I:22])=[C:8]([C:7]([NH:6][CH2:5][CH:4]([OH:3])[CH2:29][OH:30])=[O:28])[C:9]([I:27])=[C:10]([C:19]=1[I:26])[C:11]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[O:12])[CH:24]=[O:1])[CH2:39][N:23]([C:20]1[C:19]([I:26])=[C:10]([C:11]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[O:12])[C:9]([I:27])=[C:8]([C:21]=1[I:22])[C:7]([NH:6][CH2:5][CH:4]([OH:3])[CH2:29][OH:30])=[O:28])[CH:24]=[O:25]
Reactant: C1OC1C1CO1
Reactant: [OH-]
Reactant: O=CNc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: Cl
Agent: OB(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=CN(CC(O)C(O)CN(C=O)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a stirred solution of water (10 ml), methanol (5 ml) and potassium hydroxide (1.0 g, 16.4 mmol) was added N1,N3-bis(2,3-dihydroxypropyl)-5-formylamino-2,4,6-triiodoisophthalamide (Example 1a) (10.0 g, 13.6 mmol). To the clear solution was then added boric acid (0.59 g, 9.5 mmol). The pH was continuously maintained at pH 12.6 by addition of potassium hydroxide (10 M) and 1,3-butadiene diepoxide (0.40 g, 4.7 mmol) was added. The pH of the solution was continuously maintained within the interval from 12.6 to 13 by addition of solid boric acid for 5 hours and then left over the weekend. The solution was neutralized by addition of hydrochloric acid (18% w) and then treated with ion exchangers (AMB200C, 20 ml) and (IRA67, 20 ml). The resins were removed by filtration and rinsed with water and the combined aqueous volume was reduced in vacuo. The crude product was purified by preparative HPLC (column Phenomenex Luna C18 10 μm 250×50.0 mm, solvents: A=water and B=acetonitrile; gradient 0-10% B over 60 min; flow 50.0 ml/ min, UV detection at 214 nm and 254 nm). After freeze drying 3.1 g 5.5′-(2,3-dihydroxybutane-1,4-diyl)bis(formylazanediyl)bis(N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide) (43% yield) was obtained.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)[C:7]([Cl:19])=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C@@H:36]([NH2:38])[CH3:37])=[N:34][CH:35]=1>CCCCO.O>[Cl:19][C:7]1[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[N:9][C:2]([NH:38][C@H:36]([C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][N:34]=2)[CH3:37])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: N#Cc1cc(Cl)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(Cl)cc1C#N)c1ccc(F)cn1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A solution of 2,5-dichloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)nicotinonitrile (Method 43, 0.60 g, 2.04 mmol), DIEA (0.34 g, 2.65 mmol), and (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 33; 0.90 g, 6.12 mmol) in n-BuOH was heated to 120° C. for 9 hours. The reaction was then cooled to room temperature, diluted with water (20 ml), and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.42 g, 52%). 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J=2.7 Hz, 1H), 7.61 (s, 1H), 7.51-7.49 (m, 1H), 7.38-7.32 (m, 1H), 6.06 (br s, 1H), 5.28-5.22 (m, 1H), 1.94-1.88 (m, 1H), 1.58 (d, J=6.9 Hz, 3H), 1.01 (br s, 2H), 0.76-0.75 (m, 2H). MS: Calcd.: 397. Found: [M+H]+ 398.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25]Br>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Fc1cc(F)cc(CBr)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)cc(F)c2)c1
Yield: 45 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (180 mg, yield: 45.0%).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C:5]([SH:8])([CH3:7])[CH3:6].[C:12]([O:16][C:17](=[O:20])[CH2:18]Br)([CH3:15])([CH3:14])[CH3:13].Cl>C(O)C>[C:12]([O:16][C:17]([CH2:18][S:8][C:5]([CH3:7])([CH3:6])[C@H:4]([NH:3][C:17]([O:16][CH2:12][CH3:13])=[O:20])[C:9]([OH:11])=[O:10])=[O:20])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N[C@H](C(=O)O)C(C)(C)SCC(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 15 %

Procedure:
NaH (0.81 g; 35.2 mmol) was added in portions to 40 ml, ethanol while cooling. Subsequently D-penicillamine (2.50 g) was added. The mixture kept stirring for 5 minutes at 5° C., after which bromoacetic acid tert.-butyl ester (2.55 mL) was added. The mixture was allowed to stir 16 h at ambient temperature and subsequently hydrolyzed with 2 N HCl. The solvents were distilled off, N the residue was redissolved in 50 mL of water and 50 mL of dioxane and pH 9.5 was adjusted by adding aqueous NaOH. Ethyl chloroformate (2.1 mL) was slowly added at 5° C. while maintaining pH 9.5 by addition of the appropriate amount of aqueous NaOH. Stirring was continued for 6 h at room temperature. Aqueous NaOH was added (pH 10) and the dioxane removed in vacuo followed by extraction of the remaining aqueous solution with ethyl acetate. KHSO4 was added and the acidified aqueous solution extracted with ethyl acetate several times. Evaporation of the solvent in vacuo gave a colorless oil, which was purified by HPLC (RP-18; pH 2.3; H2OCH3OH 3/7) to give 0.86 g (15%) of the title compound as a colorless oil. (+)-APCI-MS: 358 (MNa+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1[C:42](O)=[O:43]>>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:42]([C:34]1[NH:33][C:41]2[C:36]([CH:35]=1)=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:43])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cc2ccccc2[nH]1
Yield: 42.1 %

Procedure:
In a manner analogous to that described in Example 27, from 27 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester and 11.3 mg of 2-indolecarboxylic acid there were obtained 15 mg of N-[3(S)-[[N-(2-indolylcarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester; MS: m/e 592 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:26][CH3:27])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:9][C:8](=[O:18])[N:7]([CH2:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[C:6]=2[CH:25]=1.Cl[C:29]1[N:34]=[C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[S:42]([N:45]([CH3:47])[CH3:46])(=[O:44])=[O:43])[C:32]([Cl:48])=[CH:31][N:30]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:48][C:32]1[C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[S:42](=[O:44])(=[O:43])[N:45]([CH3:46])[CH3:47])=[N:34][C:29]([NH:1][C:2]2[C:3]([O:26][CH3:27])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:9][C:8](=[O:18])[N:7]([CH2:19][C:20](=[O:24])[N:21]([CH3:22])[CH3:23])[C:6]=3[CH:25]=2)=[N:30][CH:31]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)N(CC(=O)N(C)C)C(=O)CN(CC(=O)N(C)C)C2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)N(CC(=O)N(C)C)C(=O)CN(CC(=O)N(C)C)C2
Temperature: 90 °C
Yield: 29.1 %

Procedure:
To a mixture of 2-(8-amino-1-dimethylcarbamoylmethyl-7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-N,N-dimethyl-acetamide (80 mg, 0.21 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (69 mg, 0.20 mmol) in isopropanol (5 mL) was added 10-camphorsulfonic acid (123 mg, 0.53 mmol). The mixture was heated to 90° C. for 20 minutes under microwave irradiation, cooled to room temperature, and concentrated on a rotary evaporator. The residue was dissolved in dichloromethane and stirred with saturated aqueous sodium bicarbonate to neutral pH. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography over silica gel (MeOH/DCM) to give 40 mg (29%) of 2-{8-[5-chloro-4-(2-dimethylsulfamoyl-phenylamino)-pyrimidin-2-ylamino]-1-dimethylcarbamoylmethyl-7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl}-N,N-dimethyl-acetamide as a pale yellow solid; NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.51 (d, J=8 Hz, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.61 (s, 1H), 7.56 (m, 1H), 7.28 (m, 1H), 6.94 (s, 1H), 4.45 (br s, 2H), 4.08 (s, 2H), 3.93 (s, 3H), 3.54 (s, 2H), 3.35 (s, 2H), 3.10 (s, 3H), 3.00 (s, 3H), 2.96 (s, 2H), 2.91 (s, 3H), 2.79 (s, 6H); MS (m/e) 689 (M+1); mp 154° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[S:9].[Br:10][CH:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>CC(C)=O>[BrH:10].[C:20]1([CH:11]2[S:9][C:2]3=[N:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:1]3[C:12]2([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:13])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Reactant: S=C1NCCCCCN1
Solvent: CC(C)=O
Product: Br
Product: OC1(c2ccccc2)C(c2ccccc2)SC2=NCCCCCN21

Procedure:
A 2.16 g. portion of hexahydro-1,3-diazocine-2(1H)-thione is dissolved in 800 ml. of hot acetone. The solution is clarified and then stirred as 4.2 g. of 2-bromo-2-phenylacetophenone in 50 ml. of acetone is added. The solution is stirred at room temperature for 7 hours, then the solid is collected, washed with 200 ml. of acetone and dried in vacuo at 60° C., giving 5.1 g. of the desired product, m.p. 211°-213° C. (dec.).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][CH:11]=1)[CH3:4].O>CCOCC>[Br:1][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:3][CH3:4])=[CH:7][C:8]=1[C:12]([F:13])([F:14])[F:15]
Reactant: CCOc1cccc(C(F)(F)F)c1
Reactant: BrBr
Solvent: O
Solvent: CCOCC
Product: CCOc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Bromine (18.2 g) was slowly added dropwise to Compound (b) (19.3 g) at room temperature, and then the mixture was stirred at room temperature for 1 hour. Water and ether were added for liquid separation, and the aqueous layer was extracted three times with ether. The organic layers were combined, washed with saturated aqueous sodium bicarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 21.0 g of Compound (c).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([C:10]([NH:12][C:13]2[CH:25]=[CH:24][C:16]3S[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:15]=3[CH:14]=2)=[O:11])[CH3:9])=[CH:3][CH:2]=1.[S:26](=[O:30])(=O)(O)[OH:27].OO.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[O:27]=[S:26]1(=[O:30])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:18][C:19]=2[C:15]2[CH:14]=[C:13]([NH:12][C:10]([CH:8]([CH3:9])[CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:11])[CH:25]=[CH:24][C:16]1=2
Reactant: O=S(=O)(O)O
Reactant: CC(Cc1ccncc1)C(=O)Nc1ccc2sc3ccccc3c2c1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(Cc1ccncc1)C(=O)Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-[(2-Pyrid-4-yl-1-methylethyl)carbonylamino]dibenzothiophene (Example 11; 0.39 g, 1.13 mmol) was dissolved in glacial acetic acid (10 ml) and concentrated sulphuric acid (0.5 ml) at 60° C. 30% aqueous hydrogen peroxide (1.3 ml) was added in one portion and the solution was stirred at 60° C. for two hours. The mixture was allowed to cool and then poured into water (50 ml). The mixture was made basic by the addition of solid NaHCO3 and extracted with DCM (2×50 ml). The combined organic layers were washed with brine (50 ml), dried and evaporated in vacuo to leave a pale yellow solid. NMR: 8.45 (d, 2H), 8.3 (d, 1H), 8.0 (d, 1H), 7.95 (d, 1H), 7.9 (d, 1H), 7.8 (t, 1H), 7.7 (dd, 1H), 7.65 (t, 1H), 7.25 (d, 2H), 3.0 (m, 2H), 2.7 (m, 1H), 1.15 (d, 3H); m/z 379.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]([N:39]6[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]6)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(-c3ccc4c(n3)-c3sc(-c5ncnn5-c5ccc(F)cc5F)cc3CCO4)cn2)CC1
Temperature: 150 °C
Yield: 56.5 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (470 mg, 1.0 mmol), 1-Methyl-piperazine (120 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 249 (315 mg, yield: 57%). 1HNMR (DMSO-d6, 400 MHz): δ8.71 (s, 1H), 8.27 (s, 1H), 8.04 (d, J=3.2 Hz, 1H), 7.42 (t, J=2 Hz, 1H), 7.90-7.88 (m, 1H), 7.76-7.78 (m, 2H), 7.46-7.40 (m, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.14 (m, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.26 (s, 2H), 3.50 (s, 3H), 3.10 (s, 2H), 2.38 (s, 4H), 2.18 (s, 3H). ESI-MS: m/z=558 [M+H+]
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[C:11](Br)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:1]1([C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:8][C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cc(Br)cc(C=C(c2ccccc2)c2ccccc2)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cc(C=C(c2ccccc2)c2ccccc2)cc(-c2ccccc2)c1
Yield: 55.8 %

Procedure:
Under an atmosphere of argon, 1-(2,2-diphenylvinyl)-3,5-dibromo-benzene (7.0 g, 17 mmole), phenylboronic acid (2.1 g, 17 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.35 mmole, 2% Pd) were dissolved into toluene (40 ml). To the obtained solution, a 2 M aqueous solution of sodium carbonate (25 ml, 51 mmole, 3 eq) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (30 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+10% dichloromethane, successively) and white needle crystals (3.9 g, 56%) were obtained.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[NH2:22][C:23]1[CH:48]=[CH:47][C:26]([CH2:27][N:28]2[C:33](=[O:34])[C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:30]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[N:29]2)=[CH:25][CH:24]=1>O1CCCC1>[CH3:38][O:37][C:35]([C:32]1[C:33](=[O:34])[N:28]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:9])=[CH:48][CH:47]=2)[N:29]=[C:30]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[CH:31]=1)=[O:36]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2ccc(N)cc2)c1=O
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2ccc(NC(=O)c3cccnc3)cc2)c1=O
Reaction time: 0.08 h
Yield: 78.9 %

Procedure:
To a suspension of nicotinic acid (38 mg, 0.31 mmol) in tetrahydrofuran (2 ml), N-[3-(dimethylamino)-propyl]-N′-ethylcarbodiimide.hydrochloride (WSC.HCl) (60 mg,0.31 mmol) was added at room temperature, followed by stirring for 5 minutes. A solution of 2-(4-aminobenzyl)-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one (76 mg, 0.21 mmol) in tetrahydrofuran (2 ml) was then added, followed by stirring at the same temperature for 13 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform (30 ml). The solution was washed successively with water (30 ml) and a saturated aqueous solution of sodium chloride (brine) (30 ml), and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel preparative chromatography [developer: chloroform/methanol (10/1)], followed by crystallization from chloroform-hexane. The title compound (78 mg, 79.7%) was obtained as yellow prisms.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([O:50][Si](C(C)C)(C(C)C)C(C)C)[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1>>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([OH:50])[CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)[Si](Oc1cc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)ccc1Cl)(C(C)C)C(C)C
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(Cl)c(O)c4)c4ccccc43)cn12
Yield: 76 %

Procedure:
The title compound (193 mg, 76%) was prepared starting from Intermediate E (155 mg, 0.427 mmol) and [5-tert-butyl-2-(4-chloro-3-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporated herein by reference, 260 mg, 0.436 mmol), using analogous procedures to those described in Example 50. LCMS (Method 5): Rt 3.54 min, m/z 655.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.82-2.26 (11H, m), 2.31-2.39 (1H, m), 3.10-3.17 (1H, m), 3.99 (1H, d, J=8.1 Hz), 4.78-4.86 (1H, m), 5.37-5.42 (1H, m), 6.33 (1H, s), 6.89-6.95 (1H, br d), 7.07-7.12 (2H, m), 7.24-7.38 (5H, m), 7.42 (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=9.8 Hz), 8.12 (1H, s), 8.25 (1H, br d), 10.64 (1H, v br).
Reaction SMILES: [Na].C[O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[C:9]=2[S:8][C:7]=1[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1S(C)(=O)=O)=[O:5].[OH2:35]>>[O:35]=[C:23]1[N:22]([CH2:21][C:7]2[S:8][C:9]3[N:10]([CH:18]([CH3:20])[CH3:19])[C:11](=[O:17])[N:12]([CH3:16])[C:13](=[O:15])[C:14]=3[C:6]=2[C:4]([OH:3])=[O:5])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24]1
Reactant: COC(=O)c1c(Cn2c(S(C)(=O)=O)nc3ccccc32)sc2c1c(=O)n(C)c(=O)n2C(C)C
Reactant: O
Agent: [Na]
Product: CC(C)n1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cn3c(=O)[nH]c4ccccc43)sc21

Procedure:
Sodium hydrogenocarbonate (0.55 g) was added to a suspension of the product from example 32 part b) (0.54 g) in water. The reaction mixture was heated at reflux for 17 h. The reaction mixture was washed with ethyl acetate and the aqueous layer was freezed dried to give the sub-title compound (0.7 g). MS(ES)(M++H) 415
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH:22]=O.Cl.Cl.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CN=1.[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51]>CO>[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51].[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1/[CH:1]=[CH:22]/[C:18]1[NH:17][CH:21]=[CH:20][N:19]=1
Reactant: Cc1nc2ccccc2n1-c1ccccn1
Reactant: O=Cc1ncc[nH]1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccn1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ncc[nH]1

Procedure:
Free base of the titled compound was prepared from 2-methyl-1-(2-pyridyl)-1H-benzimidazole and 2-imidazolcarboxaldehyde according to the preparation of (E)-1-(2-pyridyl)-2-[2-(2-pyridyl)ethenyl]-1H-benzimidazole dihydrochloride (Example 44). The free base and oxalic acid were dissolved into MeOH. Concentration and recrystallization from ethyl EtOH/n-hexane yielded the titled compound.