Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21]O.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][N:28]1[C:24](=[O:34])[C:25]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:26]2[C:27]1=[O:29]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1ccnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
In the manner given in Example 17, 3.47 g. (20.0 mmol) of 2',5-dichloro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with 3.24 g. (22.0 mmol) of phthalimide and 5.76 g. (22.0 mmol) of triphenylphosphine suspended in 200 ml. of cold (0°-5°) tetrahydrofuran and finally with 3.83 g. (22.0 mmol) of diethyl azodicarboxylate, added slowly over three-fourths hour. After overnight stirring, the resulting solid is filtered and crystallized to afford 2',5-dichloro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: C(OCC1C(N2CCN3C4CCCCC=4C=C3C2=O)=NC=CC=1C1C=C(NC2C=CC(N3CCN(C4COC4)C[C@@H]3CC)=CN=2)C(=O)N(C)C=1)(=O)C.[C:53]([O:56][CH2:57][C:58]1[C:59]([N:73]2[CH2:85][CH2:84][N:76]3[C:77]4[CH2:78][CH2:79][CH2:80][CH2:81][C:82]=4[CH:83]=[C:75]3[C:74]2=[O:86])=[N:60][CH:61]=[CH:62][C:63]=1B1OC(C)(C)C(C)(C)O1)(=[O:55])[CH3:54].Cl[C:88]1[CH:89]=[C:90]([NH:96][C:97]2[CH:105]=[C:100]3[CH2:101][O:102][CH2:103][CH2:104][N:99]3[N:98]=2)[C:91](=[O:95])[N:92]([CH3:94])[N:93]=1>>[C:53]([O:56][CH2:57][C:58]1[C:59]([N:73]2[CH2:85][CH2:84][N:76]3[C:77]4[CH2:78][CH2:79][CH2:80][CH2:81][C:82]=4[CH:83]=[C:75]3[C:74]2=[O:86])=[N:60][CH:61]=[CH:62][C:63]=1[C:88]1[CH:89]=[C:90]([NH:96][C:97]2[CH:105]=[C:100]3[CH2:101][O:102][CH2:103][CH2:104][N:99]3[N:98]=2)[C:91](=[O:95])[N:92]([CH3:94])[N:93]=1)(=[O:55])[CH3:54]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1nc(Cl)cc(Nc2cc3n(n2)CCOC3)c1=O
Agent: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 32.9 %

Procedure:
Following the procedures as described for compound 131a, reaction of 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (200 mg, 0.52 mmol) and 132a (146 mg, 0.52 mmol) afforded 132b as a yellow solid (100 mg, 53%). LCMS: [M+H]+ 585
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH:16]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])([CH3:18])[CH3:17].O>CC(C)=O>[CH3:17][CH:16]([O:19][CH2:20][CH2:21][CH2:22][NH:23][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH3:18]
Reactant: CC(C)OCCCN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)OCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 66.4 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mole) and 3-isopropoxy-1-propylamine (3.51 g, 0.030 mole) was heated at 140° C. for 5 hrs. After standing at ambient temperature for 18 hrs the mixture was dissolved in acetone (20 ml) and the solution poured into water (120 ml). A solid formed rapidly and was collected by filtration and dried at ambient temperature. The solid (2.80 g, 89%) was recrystallized from toluene-isooctone to yield 2.08 g of a fluffy white solid, m.p. 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9]Cl>CN(C)C=O>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: ClCl
Solvent: CN(C)C=O
Product: Oc1ccc(Cl)nc1Cl
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
100 g (0.77 mole) of 2-chloro-3-pyridinol (I) was dissolved in 350 ml of dimethylformamide. 70 ml of chlorine (measured at -80°; 0.93 mole) was introduced in the course of 1.5 hours into the stirred solution at 0°. The reaction mixture was then stirred for 1.5 hours at 20° C. and subsequently concentrated in a rotary evaporator (bath: 50°; 10 torr). 400 ml of water and 100 ml of ether were added to the residue; the two phases were separated and the aqueous phase was extracted 5 times with 100 ml of ether each time. The combined ether phases were washed with water and dried. The solvent was removed in vacuo; the semisolid residue was stirred with 1.6 liters of water, and the resulting suspension was adjusted to pH 3. The suspension was heated to boiling, and after a few minutes the solution was decanted from an oily residue. The solution was purified with active charcoal, and the yellow product obtained on cooling was recrystallised from water; m.p. 136°-138° C.; yield 42 g.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].[CH:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[C:24]1=[O:33])[CH2:30]2.O>O1CCCC1>[OH:33][CH:24]1[CH:23]2[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][C:25]1([CH:6]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)[CH2:26]3)[CH2:30]2
Reactant: N#Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2ncc[nH]2)C23CC4CC(CC(C4)C2O)C3)cc1
Reaction time: 0.5 h

Procedure:
5.0 g of 4-[1-(imidazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour at -60° combined With 4 3 g of 2-adamantanone, further stirred for 1 hour, and heated to 25°. Then water is added, the mixture is extracted three times with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 6.66 g of crude 4-[2-hydroxy-adamant-1-yl-1-(imidazolyl)methyl]benzonitrile.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:13])[CH:11]=[CH2:12].CC(N)(C)CC(C)(C)C.C(O)(=O)C>[Pd]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: [Pd]
Agent: CC(C)(C)CC(C)(C)N
Solvent: CC(=O)O
Product: CCCCC(CC)COC(=O)C=Cc1ccc(OC)cc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of 4.68 g (20 mmol) of p-iodoanisole, 4.05 g (22 mmol) of 2-ethylhexyl acrylate, 2.84 g (22 mmol) of 1,1,3,3-tetramethylbutylamine, 1.32 g (22 mmol) of acetic acid and 32 mg of palladium on charcoal (5%) is stirred at 150° C. for 3 hours. After working up as in Example 1 there is obtained 2-ethylhexyl p-methoxycinnamate in 92% yield.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH2:20][NH2:21])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[NH:21][CH2:20][CH2:19][CH2:18][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[CH:25]=[CH:24][CH:23]=[N:22][C:10]1=2)[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: NCCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.6 g (0.0045 mole) of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine in dry methylene chloride was added 0.53 g (0.0052 mole) of triethylamine. To this solution was added dropwise, while cooling, 0.54 g (0.0050 mole) of ethyl chloroformate. The mixture was stirred at room temperature for 2 hr. The methylene chloride solution of the product (as indicated by chemical ionization mass spec) was washed with dilute sodium hydroxide-sodium chloride saturated aqueous solution and dried and concentrated to dryness. The residue was triturated in isopropyl ether. Yield was 1.5 g of title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][N:16]([C:18]([N:20]2[CH2:25][CH2:24][S:23][CH2:22][CH2:21]2)=[O:19])[CH2:15][CH:14]([C:26](O)=[O:27])[CH2:13]1.O[N:30]=[C:31]([O:33][CH2:34][CH3:35])[NH2:32]>>[CH2:34]([O:33][C:31]1[N:32]=[C:26]([CH:14]2[CH2:13][CH:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[F:1])[CH2:17][N:16]([C:18]([N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[O:19])[CH2:15]2)[O:27][N:30]=1)[CH3:35]
Reactant: CCOC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2F)CN(C(=O)N2CCSCC2)C1
Product: CCOc1noc(C2CC(c3ccc(C(F)(F)F)cc3F)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 4, 254 mg (0.405 mmol) of the compound from Example 90A and 63 mg (0.607 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were reacted. Yield: 70 mg (35% of theory).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:14](COCC[Si](C)(C)C)[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[NH2:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CC1(C)CC=C(c2cc(C(N)=O)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC=C(c2cc(C(N)=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 19 %

Procedure:
The title compound was prepared by the procedure of Example 24, step (b) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-carbamoyl-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step, 100 mg, 0.203 mmol) and tetrabutylammonium fluoride (1.01 mL, 1.01 mmol, 1.0 M in THF). Silica gel chromatography (5% MeOH/DCM) afforded the title compound (14.1 mg, 19%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.42 (d, 1H, J=8.6 Hz), 8.00 (s, 1H), 7.81 (dd, 1H, J=8.6, 2.3 Hz), 7.75 (d, 1H, J=2.3 Hz), 5.81 (m, 1H), 2.28-2.40 (m, 2H), 2.04-2.17 (m, 2H), 1.63 (t, 2H, J=6.3 Hz), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C20H21N5O2, 364.2 (M+H), found 364.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH2:15]Cl.C(N1C2C(=CC=C(C(O)=O)C=2)C=C1)C1C=CC=CC=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][N:8]2[CH2:15][C:14]2[C:13]([Cl:12])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])=[CH:4][CH:3]=1
Reactant: Cc1n[nH]c2cc(Br)ccc12
Reactant: ClCc1c(Cl)cccc1Cl
Agent: O=C(O)c1ccc2ccn(Cc3ccccc3)c2c1
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(Br)ccc12
Yield: 62 %

Procedure:
The titled compound (10.4 g) as a white solid was prepared from the 6-bromo-3-methyl-1H-indazole (9.57 g) obtained with the method described in the document (JP 2009-528363 W) and 2,6-dichlorobenzyl chloride (9.79 g) according to the method of the process (1) of Example 66.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[N:31]1[NH:32][N:33]=[N:34][C:35]=1[C:36]1[CH:37]=[C:38]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[NH2:39].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC(=O)OCC>N1C=CC=CC=1>[N:34]1[NH:33][N:32]=[N:31][C:35]=1[C:36]1[CH:37]=[C:38]([NH:39][C:27](=[O:29])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:6]3[CH:7]=[N:8][C:9]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:21][C:22]=2[F:30])[CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:42]=1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: Nc1cc(-c2nn[nH]n2)cc(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4nn[nH]n4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (100 mg, 0.243 mmol) in pyridine (10 mL) were added 3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)aniline (55.7 mg, 0.243 mmol) and T3P® (EA solvate) (220 mg, 0.346 mmol). The mixture was stirred at 20° C. for 1 h. LCMS showed the reaction was finished. The reaction was quenched with ice-water. The mixture was concentrated to give crude product, which was purified by TLC to give N-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (75 mg, 0.104 mmol, 42.9% yield): 1H NMR (400 MHz, CD3OD-d4) δ 8.62 (d, J=4.4 Hz, 2H), 8.04 (d, J=1.5 Hz, 1H), 7.94 (s, 1H), 7.61 (dd, J=6.1, 7.8 Hz, 2H), 7.38 (d, J=8.6 Hz, 3H), 6.92-6.85 (m, 3H), 5.35 (s, 2H), 4.15 (d, J=6.8 Hz, 2H), 3.77 (s, 2H), 3.38-3.33 (m, 3H), 1.30-1.18 (m, 3H). ES-LCMS m/z 623 (M+H).
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[N:29]=[C:30]([CH3:40])[S:31][C:32]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])=[O:27])[CH2:20]2.Cl[C:42]1[N:47]=[C:46]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:45]=[CH:44][N:43]=1>>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:32]1[S:31][C:30]([CH3:40])=[N:29][C:28]=1[C:26]([N:21]1[CH2:22][CH:23]2[CH:19]([CH2:25][N:24]2[C:42]2[N:47]=[C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:45]=[CH:44][N:43]=2)[CH2:20]1)=[O:27]
Reactant: Clc1nccc(-c2ccccc2)n1
Reactant: Cc1nc(C(=O)N2CC3CNC3C2)c(-c2ccccc2F)s1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: Cc1nc(C(=O)N2CC3CN(c4nccc(-c5ccccc5)n4)C3C2)c(-c2ccccc2F)s1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 21 and 2-chloro-4-phenyl-pyrimidine. MS (ESI) mass calcd. for C26H22FN5OS, 471.56; m/z found, 472.1 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:28][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:28][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([NH:27][C:29](=[O:31])[CH3:30])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
To a solution of 2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydro-benzo[b]thieno[2,3-d]oxepin-8-amine HCl salt (0.2 g, 0.464 mmol) in 10 ml of dried DCM was added TEA (0.32 mL, 2.3 mmol). The mixture was stirred at 0° C. for 20 min and 0.2 ml of acetic anhydride was added. After stirred for 10 min, the solution was quenched with water and evaporated to the crude product, which was purified by preparative TLC to give 115 (80 mg, 39%). 1H NMR (DMSO-d6, 400 MHz): δ 10.02 (s, 1H), 8.81 (s, 1H), 7.79-7.15 (m, 7H), 6.54 (s, 1H), 4.16 (t, J=4.8 Hz, 2H), 2.95 (t, J=4.8 Hz, 2H), 1.99 (s, 3H). MS: (ESI+) 437.1
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][Cl:24]>>[Cl:24][CH2:23][CH2:22][CH2:21][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: COC(=O)Cc1ccccc1Sc1ccc(O)cc1
Product: COC(=O)Cc1ccccc1Sc1ccc(OCCCCl)cc1
Yield: 73.3 %

Procedure:
Using the procedure described in Example 34, methyl 2-(4-hydroxyphenylsulfanyl)phenyl-acetate and 1-bromo-3-chloropropane provided 73.3% yield of the title ester, m.p. 48-51° C. For C18H19ClO3S (350.9) calculated: 61.62% C, 5.46% H, 10.10% Cl, 9.14% S; found: 61.12% C, 5.44% H, 10.15% Cl, 9.13% S. 1H NMR spectrum (CDCl3): CH2(COO) 3.84 s; CH3 3.67 s; CH2(O) 4.09 t, J=6.0 Hz; CH2(Cl) 3.73 t, J=6.0 Hz.
Reaction SMILES: C[C@H](N)C1C=CC=CC=1.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH:19]([C:35]3[C:43]4[C:38](=[CH:39][C:40]([C:44]([OH:46])=[O:45])=[CH:41][CH:42]=4)[N:37]([CH3:47])[CH:36]=3)[C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[O:21])=[CH:18][C:13]=2[O:12][CH2:11]1>O1CCCC1.COCCOC>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C@@H:19]([C:35]3[C:43]4[C:38](=[CH:39][C:40]([C:44]([OH:46])=[O:45])=[CH:41][CH:42]=4)[N:37]([CH3:47])[CH:36]=3)[C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=3[O:33][CH3:34])(=[O:24])=[O:25])=[O:21])=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)O)ccc12
Agent: C[C@H](N)c1ccccc1
Solvent: C1CCOC1
Solvent: COCCOC
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)[C@@H](c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)O)ccc12
Temperature: 55 °C

Procedure:
(S)-(−)-α-Methylbenzylamine (0.53 kg) was added over a period of 15 minutes to a stirred suspension of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid (from step (c), 1.17 kg, 2.18 moles) in tetrahydrofuran (6.5 liters, 5.5 ml/g) and 1,2-dimethoxyethane (6.5 liters, 5.5 ml/g) at 60° C. under a nitrogen atmosphere. The resulting solution was allowed to cool to 55° C., seeded with 13.6 g of the (S)-(−)-α-methylbenzylamine salt of the title compound of Example 1 (prepared by conventional methods) and stirred for 24 h. The resulting suspension was allowed to cool to 45° C. over a period of 48 h and stirred at this temperature for an additional 48 h. The suspension was allowed to cool to room temperature and the precipitated (S)-(−)-α-methylbenzylamine salt (of the title compound) collected by filtration (1.316 kg, 84%, ratio of (S)-(−)-α-methylbenzylamine to (S)-(+)-acid in the salt 1.5:1). The salt was partitioned between ethyl acetate (6.8 liters), tetrahydrofuran (1.4 liters) and 1M hydrochloric acid (6.8 liters) and the organic phase was separated and then washed with 1M hydrochloric acid (3×0.9 liters) and water (2×0.7 liters). The organic phase was dried by azeotropic distillation with ethyl acetate at constant volume, concentrated to a volume of 3.5 liters and then n-hexane (3.5 liters) added. The precipitated product was granulated at 0° C. for 1 h and filtered to give the title compound as a white crystalline solid (0.936 kg, 91.6%). The enantiomeric excess of the compound was found to be >94% using chiral stationary phase HPLC.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][CH:5]=1.[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][CH:15]=1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[F:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Reactant: c1ccc2[nH]cnc2c1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2[nH]cc(CCn3cnc4ccccc43)c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-5-fluoro-1H-indole (7.26 g, 30 mmol), benz-imidazole (3.54 g, 30 mmol) and ethyl-diisopropylamine (5.1 ml, 30 mmol) in abs. chloroform (80 ml) was boiled under reflux for 20 h. The reaction solution was then washed twice with water, dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (50:1).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[F:28][C:29]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:30]=1[CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:29]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:30]=1[CH2:31][N:32]1[CH2:33][CH2:34][N:35]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:36][CH2:37]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Fc1ccc(CN2CCNCC2)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCN2CCN(Cc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title B compound, 4-(2,4-difluorobenzyl)piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=478.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.30 (m, 4H), 2.36 (m, 4H), 2.67 (t, 2H, J=6.8 Hz), 3.47 (s, 2H), 4.22 (t, 2H, J=6.8 Hz), 6.58 (d, 1H, J=3.6 Hz), 6.72 (m, 1H), 7.06 (dt, 1H, J=8.4 Hz and 2.0 Hz), 7.14 (d, 1H, J=3.2 Hz), 7.20 (m, 2H), 7.42 (dd, 1H, J=15.2 Hz and 8.0 Hz), 754 (br s, NH2), 7.93 (s, 1H). Anal. calculated for (C24H24F2N80+0.5 H2O): C, 59.13; H, 5.17; F, 7.79; N, 22.98; O, 4.92. Found C, 58.84; H, 4.97; N, 22.63.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=O)[C:7]2[N:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:4]1)[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([N:3]1[C:8](=[S:29])[C:7]2[N:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccccn2)c2cccnc2c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCn1nc(-c2ccccn2)c2cccnc2c1=S
Temperature: 25 °C

Procedure:
A mixture of 7-ethyl-5-(pyridin-2-yl)pyrido[2,3-d]pyridazin-8(7H)-one RL-8 (90 mg, 0.36 mmol), 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (145 mg, 0.36 mmol), and toluene (8 mL) was heated to 115° C. for 3.5 h. After cooling to ambient temperature, the reaction mixture was diluted with 20 mL of ethyl acetate and washed with a 1:1 solution of saturated brine/1 N NaOH. The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and purified by normal phase flash chromatography eluting with 0-10% methanol in dichloromethane over 22 minutes. Like fractions containing the desired product were pooled, concentrated under reduced pressure, and dried overnight at 60° C. under vacuum to give 7-ethyl-5-(pyridin-2-yl)pyrido[2,3-d]pyridazine-8(7H)-thione RL-9 (52 mg, 0.20 mmol). 1H NMR (400 MHz, DMSO-d6) δ 9.17 (dd, J=4.3, 1.7 Hz, 1H), 8.98 (dd, J=8.3, 1.7 Hz, 1H), 8.77 (ddd, J=4.8, 1.7, 1.0 Hz, 1H), 8.08-7.97 (m, 2H), 7.91 (dd, J=8.3, 4.3 Hz, 1H), 7.59 (ddd, J=7.3, 4.8, 1.5 Hz, 1H), 4.86 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).