Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.O[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([S:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:30]=1.O>O1CCOCC1>[Br:20][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([S:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CSc1nccc(O)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CSc1nccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 52.5 g (0.20 mol) of triphenylphosphine are initially charged in 600 ml of dioxane, and 35.6 g (0.20 mol) of N-bromosuccinimide are added a little at a time, with cooling. The mixture is stirred at RT for 30 min. 8.6 g (0.04 mol) of ethyl [(4-hydroxy-2-pyrimidinyl)thio]acetate are then added and the mixture is heated at reflux for 45 min. A total of 2 l of water are added to the mixture, which is then extracted 3× with in each case 300 ml of methyl tert-butyl ketone. The organic phase is washed 2× with water and 1× with concentrated NaCl solution, dried over magnesium sulphate and concentrated. The residue is stirred in 60 ml of methyl tert-butyl ketone and filtered off. The mother liquor is concentrated and the residue is purified by silica gel chromatography (dichloromethane).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23]
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Reactant: OB(O)c1cc2ccccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cc4ccccc4o3)sc2n1
Temperature: 100 °C
Yield: 10 %

Procedure:
To solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (100 mg, 0.232 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added 1-benzofuran-2-ylboronic acid (56.3 mg, 0.347 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol) and potassium carbonate (112 mg, 0.811 mmol) and the reaction mixture heated at 100° C. using a microwave reactor for 30 min. The mixture was then filtered through celite, washing with DCM (20 mL×2) and the filtrate dried (phase separation cartridge) and concentrated. The residue was then purified by MDAP (acidic conditions), followed by MDAP (basic conditions) to afford the title compound (10.89 mg). LCMS (A) m/z: 469 [M+1]+, Rt 1.42 min (acidic).
Reaction SMILES: [OH:1][CH:2]1[N:6]([C:7]2[N:8]=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[C:5](=[O:15])[C:4]2[S:16][CH2:17][CH2:18][S:19][C:3]1=2.[H-].[Na+].Cl[C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24].C(O)C>O1CCCC1>[CH3:14][O:13][C:10]1[N:9]=[N:8][C:7]([N:6]2[CH:2]([O:1][C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[O:24])[C:3]3[S:19][CH2:18][CH2:17][S:16][C:4]=3[C:5]2=[O:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(N2C(=O)C3=C(SCCS3)C2O)nn1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(N2C(=O)C3=C(SCCS3)C2OC(=O)N2CCN(C)CC2)nn1
Temperature: 5 °C
Reaction time: 4 h
Yield: 60.7 %

Procedure:
A solution of 5-hydroxy-6-(6-methoxypyridazin-3-yl)-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (8.9 g.) in anhydrous tetrahydrofuran (90 cc.) is treated for 30 minutes at about 15°-20°C, with sodium hydride (0.87 g.), and a solution of 1-chlorocarbonyl-4-methylpiperazine (19.5 g.) in anhydrous tetrahydrofuran (120 cc.) is then added, at 5°C. The reaction mixture is stirred for 4 hours at 5°C. After evaporating the solvent under reduced pressure (20 mm.Hg), the residue is taken up in an ice-cold normal aqueous solution of methanesulphonic acid (150 cc.). The acid solution obtained is rapidly washed twice with diethyl ether (total 100 cc.) and then rendered alkaline by adding 10N sodium hydroxide solution (25 cc.). The oil which separates out is extracted three times with methylene chloride (total 300 cc.). The combined organic extracts are washed twice with distilled water (total 100 cc.), dried over anhydrous magnesium sulphate and evaporated. The crystals obtained (8.7 g.; m.p. 196°-198°C.) are dissolved in boiling ethanol (300 cc.). After filtering the boiling solution and then cooling it for three hours at 2°C, the crystals which have appeared are filtered off, washed three times with ice-cold ethanol (total 45 cc.) and dried under reduced pressure (20mm.Hg). 6-(6-Methoxypyridazin-3-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (7.7 g.), melting at 200°C, is thus obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[O:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:37]=[N+:38]=[N-:39])(C)C>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:39][N:38]=[N:37][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH3:32]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (0.7 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heated under reflux for 4 days. The reaction mixture was concentrated to dryness and to the residue were added methanol (20 ml) and 1N-HCl (10 ml). The mixture was stirred at room temperature for 30 minutes and adjusted to pH 3 to 4 with 1N NaOH. After removal of the solvent, the residue was partitioned between chloroform and water. The organic layer was washed with water and dried, and the solvent was evaporated to dryness to give a syrup. The syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (0.35 g, 45%), m.p. 158°-159° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[C:9]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)=[N:10][OH:11].[H-].[Na+].I[CH:25]([CH3:27])[CH3:26].O>CN(C)C=O>[CH:25]([O:11][N:10]=[C:9]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[C:8]1[CH:17]=[CH:18][CH:19]=[C:6]([O:5][CH2:4][CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[CH:7]=1)([CH3:27])[CH3:26]
Reactant: CC(C)(C)CCOc1cccc(C(=NO)n2cncn2)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)ON=C(c1cccc(OCCC(C)(C)C)c1)n1cncn1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 75.7 %

Procedure:
To a solution of 1.6 g (5.6 mmol) of 1-[3-(3,3-dimethylbutoxy)benzohydroximoyl]-1H-1,2,4-triazole dissolved in 100 ml of N,N-dimethylformamide was added 0.16 g (6.7 mmol) of sodium hydride. The mixture was stirred for 20 minutes at 80° C. And then allowed to sit and cool naturally to about 50° C. To the mixture was added 1.1 g (6.5 mmol) of 2-iodopropane and stirred for 1 hour at about 50° C. The reaction mixture was allowed to sit and cool naturally to room temperature. The cooled mixture was poured into water and extracted with ethyl acetate. After being washed with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent in the organic layer was removed under reduced pressure. The residue was purified by column chromatography, thus obtaining 1.4 g (yield: 87%) of the desired product having a refractive index of [nD20 ] 1.5289 at 20° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:12]=1.C1COCC1.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C1(C)C=CC=CC=1>[CH:14]([O:13][C:11]1[CH:12]=[C:7]([B:26]([OH:27])[OH:25])[CH:8]=[N:9][CH:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)Oc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)Oc1cncc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred, −78° C. solution of 2.5 M n-butyllithium (44.0 mL, 110 mmol) in toluene (120 mL) was slowly added a solution of 3-bromo-5-isopropoxypyridine (21.6 g, 100 mmol) in toluene (40 mL) while maintaining the temperature below −50° C. After the addition was complete, the reaction was stirred at −78° C. for 30 min. Distilled THF (40 mL) was added, and the reaction stirred for 15 min at −78° C., followed by the addition of triisopropylborate (27.7 mL, 120 mmol) in one portion. After warming to −15° C., the reaction was quenched with 1M HCl (260 mL), and stirred for one hour. The mixture was then neutralized (to pH 7) with 5 M NaOH and extracted with THF (4×100 mL). The combined extracts were dried (Na2SO4), filtered and concentrated. The residue was dissolved in 1:1 THF/MeOH, filtered, concentrated, and dissolved in warm acetonitrile. Upon cooling, the acetonitrile solution deposited a light brown powder, which was collected by filtration and vacuum dried (8.94 g, 49%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:20][C:21]([CH3:29])=[CH:22][C:23]=1[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=O>>[CH3:29][C:21]1[NH:20][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:23]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:22]=1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1cc(CCC(=O)O)c(C=O)[nH]1
Product: Cc1cc(CCC(=O)O)c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 3-(2-formyl-5-methyl-1H-pyrrol-3-yl)-propionic acid (42 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][C:45]([N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][C:45]([N:47]4[CH2:48][CH2:49][CH2:50][CH2:51]4)=[O:46])[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H50N5O3Cl2 [(M+H)+] 718.3285, observed 718.3286.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:9][C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][N:4]=1)(=[O:21])=[O:20]
Reactant: OCc1ncc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ncc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
Intermediate 9 (3,5-difluoro-2-pyridinyl)methanol (114 mg, 0.786 mmol) was dissolved in DCM (anh) (6 mL) at 0° C. N,N-diethylethanamine (ALDRICH, 0.131 mL, 0.943 mmol) and methanesulfonyl chloride (ALDRICH, 0.067 mL, 0.864 mmol) were added. Reaction mixture was stirred at 0° C. for 1 h 30 min. Crude of reaction was partitioned between water and DCM, aqueous layer was extracted with DCM (2×10 mL). Organic layers were dried over MgSO4 (anh) and filtered. Solvent was eliminated to yield title compound (3,5-difluoro-2-pyridinyl)methyl methanesulfonate (137 mg, 0.614 mmol, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.58 (d, 1H), 8.06-8.11 (m, 1H), 5.36 (d, 2H), 3.27 (s, 3H). [ES+MS] m/z 224 (MH+).
Reaction SMILES: C([NH:8][C:9]1[C:14]2=[N:15][O:16][N:17]=[C:13]2[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([C:21]([O:23]CC)=O)=[O:20])(C(OCC)=O)=O>Cl>[OH:20][C:19]1[C:21]([OH:23])=[N:8][C:9]2[C:14]3=[N:15][O:16][N:17]=[C:13]3[CH:12]=[CH:11][C:10]=2[N:18]=1
Reactant: CCOC(=O)C(=O)Nc1ccc2nonc2c1NC(=O)C(=O)OCC
Agent: Cl
Product: Oc1nc2ccc3nonc3c2nc1O
Temperature: 0 °C
Yield: 96.6 %

Procedure:
A mixture of 2,5 g (7,1 mmol) 4,5-diethoxalylaminobenzofurazan and 20 ml 1N hydrochloric acid was refluxed for 3 h. After cooling to 0° C., the precipitate was filtered off and washed with water to give 1,4 g (97%) 7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline, m.p. >300° C. NMR (DMSO-d6): 12,8 (1H, broad s), 12.3 (1H, broad s), 7.70 (1H,d), 7.37 (1H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[C:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:25]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[C:15]3[CH2:16][CH2:17][N:18]([C:31](=[O:32])[CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH2:19][CH2:20]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: O=C(O)Cc1cccnc1
Reactant: Clc1ccc2c(c1)OCc1cccnc1C2=C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3OCc3cccnc32)CC1

Procedure:
The title compound was prepared according to the method of Example 4 from 4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-piperidine, 3-pyridine-acetic acid hydrochloride, HOBT, EDCl and NMM in DMF. 4-(8-Chloro-5,11-dihydro[1]benz-oxepino[4,3-b]pyridin-11-ylidene)-1-(3-pyridine-acetyl)piperidine was obtained as a white foam; MS (CI, M+H)=432; anal.: found: C, 68.85; H, 5.53; N, 9.49; C25H22ClN3O2 requires: C, 69.52; H,5.13; N,9.73.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2.[CH2:15](I)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2)[CH:16]=[CH2:15]
Reactant: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C)c2[nH]c(=O)c(C)cc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
5-Hydroxy-3,8-dimethylcarbostyril (4 g, 21.16 mmol) and allyl iodide (3.73 g, 22.2 mmol) were dissolved in dimethylformamide (44 ml), to which potassium carbonate (6.1 g, 44.2 mmol) was added, and stirred for 2 hours in a bath at 70° C. The solvent was distilled off, and the residue was dissolved in chloroform, and washed with water. After drying and condensing, the resultant residue was purified by silica gel chromatography (chloroform), and was subjected to recrystallization (chloroform-n-hexane) to obtain 4.32 g of the title compound as pale yellow prisms (89.2%).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-:13].[Na+]>CC(C)=O>[I:13][CH2:2][C@@H:3]([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: OC(CCl)COc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O[C@H](CI)COc1ccccc1

Procedure:
A mixture of 55 g (0.29 mol) of 1-chloro-2-hydroxy-3-phenoxypropane, 170 g (1.1 mol) sodium iodide in 1.0 of acetone is refluxed in the dark under a nitrogen atmosphere for 3 days. The acetone is removed in vacuo, the residue slurried in chloroform, filtered and the filtrate stripped to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl.[CH3:33][N:34]([CH3:41])[CH2:35]/[CH:36]=[CH:37]/[C:38](O)=[O:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]3[S:25][C:26]4[CH2:27][N:28]([C:38](=[O:39])/[CH:37]=[CH:36]/[CH2:35][N:34]([CH3:41])[CH3:33])[CH2:29][CH2:30][C:31]=4[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: N#Cc1cnc2sc3c(c2c1Nc1ccc(OCc2ccccn2)c(Cl)c1)CCNC3
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from 4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c′]dipyridine-3-carbonitrile from Example 57A (100 mg, 0.22 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (52 mg, 0.31 mmol) to yield 71 mg (53%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[C:13]12[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:18]C(=O)[O:16][C:14]2=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:5][O:4][N:3]([CH3:2])[C:14](=[O:16])[C:13]1[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:18]
Reactant: CNOC
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (51.2 g, 0.53 mmol) in 90-95% aqueous ethanol (200 ml) is added triethylamine (53 g, 0.53 mmol) and, after 10 minutes stirring at 25° C., isatoic anhydride (37.0 g, 0.35 mmol) in portions. The reaction is then heated at reflux for 1.5 hrs and poured onto an equal volume of ice and saturated sodium bicarbonate. The ethanol is then removed by rotary evaporation, the resulting aqueous mixture extracted with ethyl acetate (3×150 ml), the combined extracts washed with water, brine, dried over magnesium sulfate and activated charcoal, and concentrated to an orange oil. The oil is chromatographed on silica gel (1:1 diethyl ether:hexanes, then acetone) and distilled to give N-methoxy-N-methyl anthranilic acid amide as a pale yellow oil; yield 47.4 g (75%); b.p. 148°-151° C./0.35 mm.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH2:6][CH2:7][CH3:8])[CH2:4][SH:5].CO[C:13](OC)(OC)[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]23[S:5][CH2:4][C:3]([CH2:6][CH2:7][CH3:8])([CH2:9][O:10]2)[CH2:2][O:1]3)=[CH:15][CH:16]=1
Reactant: CCCC(CO)(CO)CS
Reactant: COC(OC)(OC)c1ccc(Br)cc1
Product: CCCC12COC(c3ccc(Br)cc3)(OC1)SC2

Procedure:
Using a method analogous to that described in stage iv of Example 5 2,2-di-hydroxymethyl-pentan-1-thiol and trimethyl 4-bromo-orthobenzoate were reacted together to give 1-(4-bromophenyl)-4-n-propyl-2,6-dioxa-7-thiabicyclo[2,2,2]octane (colourless solid).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:14][C:15]([CH:17]([CH2:27][CH2:28][CH3:29])[CH2:18][C:19]1([C:24](O)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[Cl:4][C:24]([C:19]1([CH2:18][CH:17]([CH2:27][CH2:28][CH3:29])[C:15]([O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:25]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCC(CC1(C(=O)O)CCCC1)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCCC(CC1(C(=O)Cl)CCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.15 ml, 13.2 mmol) was added to an ice-cooled solution of 1-{2-[(benzyloxy)carbonyl]pentyl}cyclopentanecarboxylic acid (EP 274234) (2.0 g, 6.3 mmol) in dry dichloromethane (20 ml), and the solution stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue azetroed with dichloromethane (3×), to give the title compound as a golden oil, 2.1 g; 1H NMR (CDCl3, 300 MHz) δ: 0.88 (t, 3H), 1.28 (m, 2H), 1.43 (m, 2H), 1.63 (m, 6H), 2.00 (m, 1H), 2.08-2.35 (m, 3H), 2.44 (m, 1H), 5.15 (s, 2H), 7.28 (m, 5H).
Reaction SMILES: C1C2C(CO[C:16]([N:18](C)[C:19]([CH3:71])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:33]([O:65][CH3:66])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:63][CH3:64])[C@@H:43]([CH3:62])[C:44]([NH:46][C@@H:47]([CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>ClCCl>[CH3:16][NH:18][C:19]([CH3:20])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:33]([O:65][CH3:66])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:63][CH3:64])[C@@H:43]([CH3:62])[C:44]([NH:46][C@@H:47]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:48]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:49])=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])[CH3:71]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC)C(C)C
Temperature: 25 °C
Yield: 81 %

Procedure:
To a stirring solution of #129 (823 mg, 0.826 mmol, 1.00 eq.) in 15 mL of dichloromethane, diethylamine (4 mL, 40 mmol, 50 eq.) was added. The reaction was allowed to stir at room temperature for ˜14½ hours. The reaction was concentrated in vacuo and azeotroped once with heptanes. Residue with diluted with dichloromethane and a small amount of methanol before being reduced down onto silica. Residue was purified by Silica Chromatography (Gradient: 0%-20% methanol in ethyl acetate) producing #130 (518 mg, 81%) as a white solid. LC-MS (Protocol Q): m/z 774.3 [M+H+] retention time=1.48 minutes. HPLC (Protocol A at 25° C.): m/z 774.5 [M+H+], retention time=7.733 minutes (purity >98%). 1H NMR (400 MHz, DMSO-d6), δ 8.36 (d). 8.14 (d), 7.81 (t), 7.14-7.25 (m), 7.01-7.07 (m), 4.87-4.94 (m), 4.78-4.85 (m), 4.67-4.76 (m), 4.46-4.65 (m), 4.29-4.40 (m), 3.93-4.03 (m), 3.70-3.81 (m), 3.49-3.60 (m), 3.38-3.47 (m), 3.29-3.36 (m), 3.15-3.28 (m), 2.98-3.13 (m), 2.94 (br s), 2.74-2.89 (m), 2.64-2.69 (m), 2.18-2.45 (m), 2.02-2.14 (m), 1.90-2.01 (m), 1.62-1.87 (m), 1.40-1.55 (m), 1.37 (d), 1.20-1.33 (m), 1.16 (d), 1.01-1.10 (m), 0.90-0.98 (m), 0.82-0.89 (m), 0.69-0.79 (m).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(OCC)(=O)C>CCCCCCC>[CH:1](=[N:9][C:10]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: O=Cc1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)c(N=Cc2ccccc2)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
Benzaldehyde(8.9 g, 84 mmol) is added to a suspension of 2-amino-4-methylbenzonitrile (10.0 g, 76 mmol) in heptane (250 mL), and the mixture refluxed under nitrogen overnight. The hot solution is decanted into a pre-warmed flask to leave the insoluble brown oil material behind, and the solution cooled to room temperature after adding ethyl acetate (2 mL). The resulting solid is filtered off and washed with heptane:ethyl acetate=100:1 (2×25 mL), and dried under high vacuum to give a beige powder (12.54 g, 57 mmol).