Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][C:13](=[O:17])[N:14]([CH3:16])[CH3:15])[CH2:9][C@H:8]1[CH:18]=[C:19]([CH3:46])[C:20](=O)[CH2:21][C@H:22]1[N:25]([C:26](=O)[C:27]([O:29]CC=C)=O)[C:24](=[O:34])[C@@H:23]1[C@H:35]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH3:36])=[O:6])[CH:2]=[CH2:3].P([O:54][CH2:55][CH3:56])(OCC)OCC.[C:57]1(C)C=CC=CC=1>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][C:13](=[O:17])[N:14]([CH3:15])[CH3:16])[CH2:9][C@H:8]1[CH:18]=[C:19]([C:20]1[CH2:21][C@H:22]2[N:25]([C:24](=[O:34])[C@@H:23]2[C@H:35]([O:37][Si:38]([C:41]([CH3:43])([CH3:42])[CH3:44])([CH3:40])[CH3:39])[CH3:36])[C:26]=1[C:27]([O:54][CH2:55][CH:56]=[CH2:57])=[O:29])[CH3:46])=[O:6])[CH:2]=[CH2:3]
Reactant: CCOP(OCC)OCC
Reactant: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)C(C)=C[C@@H]1C[C@@H](OC(=O)N(C)C)CN1C(=O)OCC=C
Reactant: Cc1ccccc1
Product: C=CCOC(=O)C1=C(C(C)=C[C@@H]2C[C@@H](OC(=O)N(C)C)CN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Temperature: 90 °C

Procedure:
To a solution of allyl 2-[(3S,4R)-4-[4-{(2S,4R)-1-allyloxycarbonyl-4-(dimethylcarbamoyloxy)pyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]glyoxylate (0.44 g) in toluene (15 ml) was added triethyl phosphite (0.61 ml) and the resulting mixture was heated to 90° C. for 15 hours under nitrogen atmosphere. After evaporation of the solvent in vacuo, to the residue were added xylene (20 ml) and hydroquinone (20 mg) and the resulting mixture was heated to reflux for 10 hours under nitrogen atmosphere. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (50 ml) eluting with a mixture of n-hexane and ethyl acetate (8:2-1:1 V/V) to give allyl (5R,6S)-3-[2-{(2S,4R)-1-allyloxycarbonyl-4-(dimethylcarbamoyloxy)pyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]- 7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.26 g).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][C:13]=1[F:21].N>>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:14][C:13]=1[F:21]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Agent: N
Product: Fc1cc(-c2nc(-c3cccnc3)no2)ccc1Cl

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 4-chloro-3-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.64 (ddd, J=7.9, 5.0, 1.0 Hz, 1H), 7.78 (dd, J=8.3, 7.5 Hz, 1H), 8.07 (ddd, J=8.3, 2.0, 0.8 Hz, 1H), 8.12 (dd, J=9.5, 2.0 Hz, 1H), 8.55 (dt, J=7.9, 2.0 Hz, 1H), 8.74 (dd, J=5.0, 1.8 Hz, 1H), 9.28-9.30 (m, 1H) ppm; MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[CH2:12]([C:16]1([N:23]([CH3:25])[CH3:24])[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)[CH2:13][CH2:14][CH3:15].F[C:27]([F:33])(F)S(O)(=O)=O.[OH-].[Na+]>ClCCl>[CH2:12]([C:16]1([N:23]([CH3:25])[CH3:24])[CH2:21][CH2:20][C:19]([C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH3:11])=[CH:3][C:27]([F:33])=[CH:10][CH:9]=3)([C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH3:11])=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:18][CH2:17]1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCCCC1(N(C)C)CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccc(F)cc3c2C)(c2[nH]c3ccc(F)cc3c2C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-fluoro-3-methyl indole (596 mg, 4 mmol) together with 4-butyl-4-(dimethylamino)-cyclohexanone (788 mg, 4 mmol, synthesis cf. WO2008009415, ketone unit Ket-4) was dissolved in dichloromethane (30 ml) and mixed with trifluoromethane sulphonic acid (400 μl, 4.6 mmol). The batch was stirred for 24 h at RT. For work up the reaction mixture was mixed with 2N NaOH (30 ml) and stirred for 20 min at RT. After separation of the organic phase the aqueous phase was extracted with dichloromethane (3×15 ml). The combined organic extracts were dried over Na2SO4 and then concentrated to low volume. The raw product obtained (1.4 g) was purified by column chromatography [silica gel 60 (50 g); ethyl acetate (500 ml)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1F.[OH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([OH:20])[CH2:22]1
Reactant: OC1CCCNC1
Reactant: CC1Cc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1Cc2c(N3CCCC(O)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 38.3 %

Procedure:
8,9-Difluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (5 g) and a solution of 7.5 g of 3-hydroxypiperidine in 50 ml of hexamethylphosphoric triamide were reacted with heating at 120° to 130° C. for 7 hours with stirring. After completion of reaction, hexamethylphosphoric triamide and unreacted 3-hydroxypiperidine were distilled off under reduced pressure. Recrystallization of the residue from dimethylformamide gave 2.5 g of 8-fluoro-9-(3-hydroxy-1-piperidyl)-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid. m.p. 251°-253° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C@H:27]([NH:29][CH2:30][C:31]([F:34])([CH3:33])[CH3:32])[CH3:28])=[CH:18]1.C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[C@@H:8]1[C:18]2[NH:17][C:25]3[C:20]([C:19]=2[CH2:26][C@@H:27]([CH3:28])[N:29]1[CH2:30][C:31]([F:34])([CH3:33])[CH3:32])=[CH:21][CH:22]=[CH:23][CH:24]=3
Reactant: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Reactant: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(C)F
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(C)F)c(F)c1
Temperature: 80 °C
Yield: 68 %

Procedure:
(E)-Methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (6.58 g, 29.09 mmol) was added to a suspension of (R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (6.02 g. 24.24 mmol) in toluene (51.1 ml) and acetic acid (2.78 ml, 48.48 mmol). The reaction was heated to 80° C. for 5 hours. The reaction mixture was purified by ion exchange chromatography, using an SCX-2 column. The desired product was eluted from the column using 7M NH3/methanol and pure fractions were evaporated to dryness to afford a brown solid. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford the title product (7.52 g, 68.0%) as a yellow solid. 1H NMR (400 MHz, DMSO, 100° C.) δ 1.10 (3H, d), 1.12-1.31 (6H, m), 2.28-2.72 (2H, n), 2.84-3.09 (2H, m), 3.52-3.69 (1H, m), 3.76 (3H, s), 5.30 (1H, s), 6.64 (1H, d), 6.9-7.11 (2H, m), 7.21 (1H, d), 7.32 (2H, d), 7.42 (1H, d), 7.58 (1H, d), 10.14 (1H, s). m/z: ES+ [M+H]+ 457
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4](C)[C:5]([C:7]1[N:8]=[C:9]([CH3:19])[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:6].C(N(CC)CC)C.Cl[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1>C1COCC1>[O:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([CH3:19])[S:10][C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[O:6]
Reactant: Cc1nc(C(=O)N(C)CCN)c(-c2ccc(F)cc2)s1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(C(=O)NCCNc2nc3ccccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (2-amino-ethyl)-methyl-amide, D5 (120 mg, 0.41 mmol) in THF (7 ml) was treated with triethylamine (0.057 ml) and 2-chlorobenzoxazole (0.047 ml, 0.41 mmol). The reaction mixture was stirred at room temperature, under argon for 16 h then the volatiles removed in vacuo. The residue was chromatographed (silica gel, 25% ethyl acetate-pentane) to afford the title compound as a white solid (97 mg, 58%).
Reaction SMILES: [ClH:1].O.C([O:7][C:8]([C@H:10]1[CH2:13][C@@H:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=4)[O:24][N:23]=3)=[CH:18][CH:17]=2)[CH2:11]1)=[O:9])(C)(C)C.C(OCC)C>O1CCOCC1>[ClH:1].[CH2:33]([C:30]1[CH:29]=[CH:28][C:27]([C:25]2[O:24][N:23]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C@@H:12]4[CH2:13][C@H:10]([C:8]([OH:9])=[O:7])[CH2:11]4)=[CH:17][CH:18]=3)[N:26]=2)=[CH:32][CH:31]=1)[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CN[C@H]4C[C@@H](C(=O)OC(C)(C)C)C4)cc3)no2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CN[C@H]4C[C@@H](C(=O)O)C4)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl (4.0 M in dioxane, 21.6 mL) and water (3.6 mL) was added to a solution of 3-{4-[5(4-isobutyl-phenyl)-[1,2,4]oxadiazole-3-yl]-benzylamino}-cis-cyclobutanecarboxylic acid tert-butyl ester (4.0 g, 8.67 mmol) in dioxane (20.0 mL) and stirred at room temperature for 1 hour. Diethyl ether (50.0 mL) was added to the reaction mixture and the resulting slurry was stirred for 2 hours and filtered to yield the title compound (2.8 g, 79% yield) as a solid.
Reaction SMILES: Cl[C:2]1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[C:27]1([CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:49](O)=[O:50])=[C:46](C)[N:47]=3)[C:39]2=[O:52])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1.[NH2:53][CH2:54][C:55]1[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=1>>[C:27]1([CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[SH:44]([CH3:2])[C:45]([C:49]([NH:53][CH2:54][C:55]4[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=4)=[O:50])=[CH:46][N:47]=3)[C:39]2=[O:52])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3nccc4ccccc34)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Product: C[SH]1C(C(=O)NCc2cccnc2)=CN=C1N1CCN(Cc2nccc3ccccc23)C1=O
Yield: 43 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(isoquinolin-1-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)-pyridine, the title compound was obtained as a colorless solid in 43% yield: mp 151-153° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.53 (d, J=3.0 Hz, 1H), 8.45 (d, J=6.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 7.86 (d, J=6.0 Hz, 1H), 7.74-7.63 (m, 4H), 7.31-7.28 (m, 1H), 6.06 (br s, 1H), 5.12 (s, 2H), 4.59 (d, J=6.0 Hz, 1H), 2H), 4.08 (t, J=6.0 Hz, 2H), 3.61 (t, J=6.0 Hz, 2H), 2.61 (s, 3H); MS (ES+) m/z 459.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([NH:37][C:38]([C:40]2[CH:44]=[CH:43][S:42][CH:41]=2)=[O:39])[CH:31]=[CH:30]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(Cl)Cl.O>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][CH2:13][NH:12][C:7]1[C:8]2[C:3](=[C:2]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[CH:33]=[C:32]([NH:37][C:38]([C:40]3[CH:44]=[CH:43][S:42][CH:41]=3)=[O:39])[CH:31]=[CH:30]4)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: CN(C)CCCNc1nccc2c(Br)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CN(C)CCCNc1nccc2c(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)cccc12
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a microwave vial containing 5-bromo-N-(3(dimethylamino)propyl) isoquinolin-1-amine (Step 5, 0.055 g, 0.2 mmol) in 1,4-Dioxane (2 mL), was added N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (0.100 g, 0.3 mmol), Fibrecat catalyst (0.005 g, 5% by wt.), along with 2 M Potassium Carbonate (0.5 mL, 1 mmol). The reaction mixture was placed into CEM Microwave for 10 minutes at 80° C., while supplying 60 Watts of energy via power-max. The mixture was diluted with DCM and H2O, and extracted with DCM (3×10 mL). Then dried organics (over sodium sulfate), was filtered, and concentrated in-vacuo. The crude was purified on reverse-phase HPLC. This gave an off-white amorphous solid after drying, which was titled product (0.023 g, 0.08 mmol). MS (ESI pos. ion) m/z: 481 (M+H). Calc'd Exact Mass for C29H28N4OS: 480
Reaction SMILES: OC1C2C=CC=CC=2S(=O)(=O)N(C)C=1C(NC1C=CC=CN=1)=O.[Na].[S:25]1([C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:29](=[O:30])[NH:28]1)(=[O:27])=[O:26].Cl[CH2:38][C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40]>CN(C)C=O>[O:30]=[C:29]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=2[S:25](=[O:26])(=[O:27])[N:28]1[CH2:38][C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40]
Reactant: CC(C)OC(=O)CCl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CN1C(=O)c2ccccc2S1(=O)=O

Procedure:
A process for manufacturing 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, of formula I, ##STR6## which comprises the following reaction sequence: reacting saccharin sodium with isopropyl chloroacetate in dimethylformamide to obtain isopropyl 3-oxo-1,2-benzoisothiazoline-2-acetate 1,1-dioxide, of formula II ##STR7## reacting the isopropyl 3-oxo-1,2-benzoisothiazoline-2-acetate 1,1-dioxide of formula II with sodium isopropylate in isopropanol at a temperature between 60° C. and the boiling point of the solvent, for a time between 15 minutes and 3 hours, to produce an intermediate of formula III ##STR8## methylating the intermediate of formula III in an aqueous-alcoholic basic medium with dimethyl sulfate to produce an intermediate compound of formula IV ##STR9## condensing the intermediate compound of formula IV with 2-aminopyridine in xylene to obtain a final product of formula I.
Reaction SMILES: O.[S-2:2].[Na+].[Na+].Cl[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1.CC(C)=O.Cl>O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([SH:2])=[CH:7][C:8]=1[C:15]([F:18])([F:17])[F:16])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(S)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
A stirred solution of sodium sulfide monohydrate 65.4 g. (0.276 moles) in 1 liter of water is treated with 50 g. (0.222 moles) of 4-chloro-2-trifluoromethylnitrobenzene in 500 ml. of acetone over 11/2 hour. The reaction mixture is stirred for 141/2 hours and the resultant solution treated with 25 ml. of concentrated hydrochloric acid. An oil separates from the reaction mixture which is dissolved in 200 ml. of ether, washed with water and extracted with 2.5 N sodium hydroxide solution. The aqueous solution is washed with ether and acidified with 25 ml. of hydrochloric acid. The resulting oil is extracted with ether and the ether solution washed with water affording 47 g. of 4-nitro-3-trifluoromethylbenzenethiol which is used in the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:39])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]3[O:33][CH2:32]3)[CH:24]=2)[CH:20]=1)=[O:13]>>[CH3:39][N:8]([CH3:7])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]([OH:33])[CH2:32][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:24]=2)[CH:20]=1)=[O:13]
Reactant: C1COCCN1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC2CO2)c1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(O)CN2CCOCC2)c1
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 29, morpholine was reacted with N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-(2,3-epoxypropoxy)-benzamide to give the title compound in 64% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 2.44 (m, 4H), 2.94 (s, 6H), 3.15 (m, 1H), 3.55 (t, 4H), 3.96 (m, 2H), 4.06 (m, 1H), 4.89 (m, 1H), 6.9 (m, 1H), 7.14 (m, 1H), 7.21 (m, 3H), 7.32 (t, 1H), 7.42 (t, 1H), 7.56 (m, 3H), 7.79 (d, 1H), 9.88 (br s, 1H), 10.08 (br s, 1H); Mass Spectrum: M+H+ 533.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14]Cl)[CH:8]=1)[C:4]([OH:6])=[O:5].[C:16]([S-:21])(=[S:20])[O:17][CH2:18][CH3:19].[K]>O>[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][S:21][C:16]([O:17][CH2:18][CH3:19])=[S:20])[CH:8]=1)[C:4]([OH:6])=[O:5]
Reactant: NC(C(=O)O)c1ccc(O)c(CCl)c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K]
Solvent: O
Product: CCOC(=S)SCc1cc(C(N)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To a solution of (-)-α-amino-3-(chloromethyl)-4-hydroxybenzeneacetic acid hydrochloride (1 g, 0.004 mole) in 20 ml of water is added carbonodithioic acid, O-ethyl ester, potassium salt (1.26 g, 0.08 mole). Within a few minutes a precipitate begins to form. The mixture is stirred at room temperature for 3 hours. The solid precipitate is filtered, washed with water and dried to give 58.3% of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](Cl)=[O:29])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[OH:12][C:3]1[C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[CH:26]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(Cl)c1cccc(-c2ccncc2)c1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2cccc(-c3ccncc3)c2)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-4-yl)benzoic acid (1.5 g, 7.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum giving 1.5 g of crude 3-(pyridin-4-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (950 g, 5.8 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) was added crude 3-(pyridin-4-yl)benzoyl chloride (1.5 g, 7 mmol) portion wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 2-hydroxy-3-(3-(pyridin-4-yl)benzamido)benzoate as a yellow solid (1.8 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][S:6][C:7]1[S:11][C:10]([NH2:12])=[N:9][CH:8]=1)[CH3:2].[C:14](C1NC=CN=1)(C1NC=CN=1)=[O:15].[CH:26]1([NH:32][C@H:33]2[CH2:38][CH2:37][C@H:36]([CH2:39][O:40][CH3:41])[CH2:35][CH2:34]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C1C=CN=CC=1.ClCCl.O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:14]([N:32]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C@H:33]2[CH2:38][CH2:37][C@H:36]([CH2:39][O:40][CH3:41])[CH2:35][CH2:34]2)=[O:15])=[N:9][CH:8]=1)[CH3:2]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COC[C@H]1CC[C@H](NC2CCCCC2)CC1
Reactant: CCOC(=O)CSc1cnc(N)s1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](COC)CC2)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester, carbonyl diimidazole (0.34 g) and 4-dimethylaminopyridine (12 mg) in dichloromethane (10 mL) and tetrahydrofuran (10 mL) was stirred at room temperature for 5 h. Cyclohexyl-(trans-4-methoxymethyl-cyclohexyl)-amine was added and the reaction stirred overnight at room temperature. Purification by flash chromatography gave {2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](O)=[N:6][CH:7]=1.P(Br)(Br)[Br:11]>>[Br:11][C:5]1[C:4]([F:9])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: Oc1ncc(Br)cc1F
Reactant: BrP(Br)Br
Product: Fc1cc(Br)cnc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
97.6 g (508.0 mmol) of 5-bromo-3-fluoro-2-hydroxypyridine are stirred at 150° C. for 6 hours in 500 ml of phosphorus tribromide. The mixture is subsequently poured into ice water, stirred for 2 hours and extracted three times with dichloromethane, and the organic phase is washed with sodium hydrogencarbonate solution until neutral, dried over sodium sulfate and evaporated to dryness. Chromatographic purification (silica gel/dichloromethane) gives 76.53 g of 2,5-dibromo-3-fluoropyridine. ##STR22##
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[Br:15][C:16]1[CH:17]=[C:18]2[CH2:27][CH2:26][N:25]3[C:19]2=[C:20]([CH:32]=1)[CH:21]=[N:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=13.C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl>[Br:15][C:16]1[CH:17]=[C:18]2[CH:27]=[CH:26][N:25]3[C:19]2=[C:20]([CH:32]=1)[CH:21]=[N:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=13
Reactant: Brc1cc2c3c(c1)CCN3c1ccccc1N=C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Brc1cc2c3c(ccn3-c3ccccc3N=C2)c1

Procedure:
A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 22 g) in toluene (200 ml) was added dropwise to a refluxing solution of 4-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (10 g) in toluene (750 ml) under nitrogen. The mixture was refluxed for 1 hour, cooled, stirred with triethylamine (3 g) for 10 minutes, and fed to a flash chromatography column (slurry packed with silica, 300 g in dichloromethane). The column was eluted with dichloromethane (4 liter); 1% methanol/dichloromethane (2 liter); 1% methanol/0.5% ammonium hydroxide/dichloromethane (2 liter), until the desired product was separated from the remaining quinone. The crude product (10 g) was purified carefully on a second flash chromatography column (silica gel, 180 g; eluted with 20:80% hexane/dichloromethane, 6 liter). The desired product was isolated as a solid (5.4 g). Recrystallization from ethanol (70 ml) gave crystals which turned to powder after vacuum drying at 110° C. The yield was 3.2 g, m.p. 122°-123° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][S:12][C:5]=2[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>>[ClH:13].[Cl:13][C:14]1[CH:19]=[C:18]([O:9][CH:7]2[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]3[S:12][CH:11]=[CH:10][C:6]2=3)[CH:17]=[CH:16][C:15]=1[C:21]([F:22])([F:23])[F:24]
Reactant: Fc1ccc(C(F)(F)F)c(Cl)c1
Reactant: CN1CCc2sccc2C(O)C1
Product: CN1CCc2sccc2C(Oc2ccc(C(F)(F)F)c(Cl)c2)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 28) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-chloro-4-fluorobenzotrifluoride instead of 1,3-difluorobenzene to give the objective compound.