Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.OC1C2N=NNC=2C=CC=1.C(N=C=NC(C)C)(C)C.[S:32]([NH2:42])(=[O:41])([C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1)=[O:33]>CN(C=O)C>[S:32]([C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])=[CH:38][CH:39]=1)(=[O:33])(=[O:41])[NH2:42]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(NC(=O)c2n[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
A mixture of indazole-3-carboxylic acid (324 mg, 2 mmol), hydroxybenzotriazole (297 mg, 2.2 mmol) and diisopropylcarbodiimide (344 μl, 2.2 mmol) in DMF (10 ml) is stirred for 30 min at room temperature. Sulphanilamide (380 mg, 2.2 mmol) is added. The reaction mixture is stirred overnight at room temperature and then filtered. The filtrate is evaporated and is then extracted with AcOEt/H2O. The organic phase is dried over MgSO4, filtered and evaporated under vacuum to give a yellow solid (640 mg). This compound is recrystallized successively from AcOEt/CH2Cl2 and AcOEt/MeOH.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=O)=[CH:48][CH:47]=2)=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[NH2:64][CH:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>CC(N(C)C)=O>[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([NH:64][CH:65]4[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]4)=[O:52])=[CH:48][CH:47]=2)=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(C)(C)C(=O)N4C)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of HATU (126 mg, 0.33 mmol) in DMA (5 mL) was added to a mixture of 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]benzoic acid, (Intermediate 129; 123 mg, 0.3 mmol) DIPEA (261 uL, 1.5 mmol) and 4-amino N-methylpiperidine (43 mg, 0.375) in DMA (5 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purified by SCX. The compound was eluted from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave a pale yellow amorphous solid. (100 mg, 66%)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[N:21]([CH2:26][CH:27](OS(C)(=O)=O)[CH3:28])[S:22]([CH3:25])(=[O:24])=[O:23]>CN(C)C=O>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[N:21]([CH2:26][CH:27]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH3:28])[S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cccc(C)c1N(CC(C)OS(C)(=O)=O)S(C)(=O)=O
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1N(CC(C)N1C(=O)c2ccccc2C1=O)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
33.3 g/0.19 moles of potassium phthalimide are added to a solution of 30 g (89 mmoles) of 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-methanesulfonyloxy-propane in 300 ml of dry dimethyl formamide, and the mixture is stirred at 145°-150° C. for one hour. The mixture is cooled, poured onto 800 ml of ice water, and the aqueous mixture is extracted thrice with 200 ml of chloroform, each. The chloroform solution is washed thrice with 50 ml of n sodium hydroxide solution and then thrice with 100 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The oily residue is triturated with 35 ml of isopropanol, the separated crystalline substance is filtered off, washed with ice-cold isopropanol and dried. 22 g (64.1%) of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-phthalimido-propane are obtained as a colourless, crystalline substance; m.p.: 124°-127° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[S:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[CH:9][C:10]=1[C:11]2=O.B.C1COCC1>O1CCCC1>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[S:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[CH:9][C:10]=1[CH2:11]2
Reactant: O=c1c2cc([N+](=O)[O-])ccc2sc2c(Br)cccc12
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)Cc1cccc(Br)c1S2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a cooled (0° C.) suspension of 5-bromo-2-nitro-thioxanthen-9-one (23.03 g, 68.5 mmol) in anhydrous tetrahydrofuran (100 ml) under nitrogen atmosphere, was added drop wise borane-THF complex (151 ml, 1.0M in THF). The mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was cooled (0° C.) and the excess borane was quenched with acetone. The solvent was evaporated in vacuo and the residue was triturated in saturated sodium bicarbonate (100 ml). The solid was filtered, washed with water and dried overnight in a vacuum dissicator to give the title compound (22.07 g, 100%). 1HNMR (300 MHz, CDCl3): δH=4.02 (2H, s), 7.17 (1H, m), 7.27 (1H, m), 7.51 (1H, m), 7.62 (1H, m), 8.09 (1H, m), 8.20 (1H, d).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:21][O:20][C:19]3[CH:22]=[C:23]4[C:27](=[CH:28][C:18]1=3)[CH2:26][C:25]([CH3:30])([CH3:29])[O:24]4)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14]CC)=[O:13].O=C1C2(C3=CC4OCOC=4C=C3OC2)C2C(=CC=CC=2)N1CC(OCC)=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:21][O:20][C:19]3[CH:22]=[C:23]4[C:27](=[CH:28][C:18]1=3)[CH2:26][C:25]([CH3:30])([CH3:29])[O:24]4)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CC(C)(C)O4)c2c(Br)cccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: CC1(C)Cc2cc3c(cc2O1)OCC31C(=O)N(CC(=O)O)c2cccc(Br)c21

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl (4′-bromo-6,6-dimethyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate to replace ethyl (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained. The product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[CH:11](Br)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH:11]([CH3:13])[CH3:12])[CH:7]=1
Reactant: CC(C)Br
Reactant: OCc1ccc(Cl)cc1O
Product: CC(C)Oc1cc(Cl)ccc1CO

Procedure:
The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol (PREPARATION 7) and isopropylbromide according to the procedure for the preparation of Example 111, part A. 1H NMR (400 MHz, CDCl3): δ 1.36 (6H, d, J=6.4 Hz), 2.40 (1H, s), 4.55-4.59 (1H, m), 4.61 (2H, s), 6.86 (1H, d, J=2.0 Hz), 6.89 (1H, dd, J=1.6 Hz, 7.6 Hz), 7.18 (1H, d, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH:28]=[N:27][NH:26][C:25]=3[CH2:24]2)[C:11](=O)[N:10]1[CH3:32].C(N(CC)CC)C.[CH:40]1([S:43](Cl)(=[O:45])=[O:44])[CH2:42][CH2:41]1.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48].C(Cl)Cl>ClCCl>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:43]([CH:40]4[CH2:42][CH2:41]4)(=[O:45])=[O:44])[CH:28]=3)[CH2:24]2)[CH2:11][N:10]1[CH3:32]
Reactant: CN1C(=O)[C@H](N2Cc3cn[nH]c3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN1C[C@H](N2Cc3cn(S(=O)(=O)C4CC4)nc3C2)C[C@H](N)[C@H]1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of tert-butyl [(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-1-methyl-6-oxopiperidin-3-yl]carbamate (70 mg, 0.161 mmol) in dichloromethane (4 mL) at room temperature, triethylamine (0.068 mL, 0.484 mmol) and cyclopropanesulfonyl chloride (0.037 mL, 0.363 mmol) were added. The mixture was stirred for 4 days at room temperature. The residue was purified by preparative TLC on silica gel, eluting with CH2Cl2/MeOH/aqueous NH3 (95/4/1) to give first eluting isomer as isomer A and second eluting isomer as isomer B. Isomer A was treated with TFA/CH2Cl2=1:1 for 1 h to give the title compound. LC-MS: 437.89 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2OC(=O)[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:22]>ClC1C=CC=CC=1Cl>[CH2:26]([O:25][C:23]([C:21]1[S:17][N:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[N:22]=1)=[O:24])[CH3:27]
Reactant: O=c1oc(-c2ccc(OCc3ccccc3)cc2)ns1
Reactant: CCOC(=O)C#N
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nc(-c2ccc(OCc3ccccc3)cc2)ns1
Temperature: 150 °C
Yield: 68 %

Procedure:
To a solution of 5-(4-benzyloxyphenyl)-[1,3,4]oxathiazol-2-one (0.31 g, 1.08 mmol) in 1,2-dichlorobenzene (2 ml) was added ethyl cyanoformate (0.43 ml, 4.35 mmol). The resulting reaction mixture was refluxed overnight at 150° C. After the completion of the reaction (TLC monitoring), added ice-cold water and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum, to get the product (0.250 g, 65%). MS ES+ (341.12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][CH3:22])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reaction time: 5 h
Yield: 89.1 %

Procedure:
In 10 ml of acetone was dissolved 1.5 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 1.5 g of methyl iodide and 1.3 g of potassium carbonate were added to the solution, followed by stirring at 40° to 50° C. for 5 hours. After cooling, the insoluble matter was filtered out, and the filtrate was concentrated under reduced pressure. The residual, oily substance was purified by means of column chromatography with the use of silica gel (developing solvent of acetone-hexane), thereby producing 1.4 g (yield of 90%) of the subject compound in white crystals, m.p. 97°-98° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]([CH2:51][C:52]([O:54]C(C)(C)C)=[O:53])[CH:10]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)[CH2:11][N:12]([CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[CH2:13][CH:14]([CH3:32])[N:15]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:7])(C)(C)C.[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62]>>[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62].[C:6]([CH2:8][N:9]([CH2:51][C:52]([OH:54])=[O:53])[CH:10]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)[CH2:11][N:12]([CH2:33][C:34]([OH:36])=[O:35])[CH2:13][CH:14]([CH3:32])[N:15]([CH2:16][C:17]([OH:19])=[O:18])[CH2:24][C:25]([OH:27])=[O:26])([OH:7])=[O:5]
Reactant: CC(CN(CC(=O)OC(C)(C)C)CC(Cc1ccc([N+](=O)[O-])cc1)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(CN(CC(=O)O)CC(Cc1ccc([N+](=O)[O-])cc1)N(CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.75 %

Procedure:
A solution containing 5.0 g (6.08 mmol) of N,N,N′,N″,N″-pentakis[(tert-butoxycarbonyl)methyl]-2-[(4-nitrophenyl)methyl]-6-methyldiethylenetriamine in 35 ml of trifluoroacetic acid was allowed to stir at room temperature for 48 h. The solvent was removed under reduced pressure and the resultant solid dried under vacuum to produce 4.02 g of product as a pale yellow solid with a yield of 74.75%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:23]3[C:30]4[CH2:31][CH2:32][CH:33]([CH2:35][CH2:36][OH:37])[CH2:34][C:29]=4[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:23]3[C:30]4[CH2:31][CH2:32][CH:33]([CH2:35][CH2:36][O:37][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:34][C:29]=4[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Methanesulfonyl chloride (0.48 mL, 707 mg, 6.17 mmol, 1.2 equiv.) was added to a suspension of 2-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethanol (2.4 g, 5.14 mmol, 1 equiv.) in anhydrous DCM (20 mL) at 0° C. The resulting mixture was stirred overnight during which time it was warmed to ambient temperature. The standard aqueous work-up gave Methanesulfonic acid 2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethyl ester as a slight yellow solid (2.3 g, 79%). 1H-NMR (CD3OD) δ 8.56 (s, 1H), 8.33 (s, 1H), 7.85 (t, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.51 (dd, J=2.5, 9.1 Hz, 1H), 7.34 (m, 1H), 7.20 (d, J=8.8 Hz, 1H), 5.27 (s, 2H), 4.35 (t, 2H), 3.19 (s, 3H), 3.15 (m, 3H), 2.97 (m, 1H), 2.17 (m, 2H), 1.81 (m, 2H), 1.54 (m, 1H).; LCMS RT=3.03 min; [M+H]+=545.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].ClCCl.CO>C1(C)C=CC=CC=1>[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16](=[NH:17])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(I)c1
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: N=C(Nc1ccccc1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 500 mL 3-neck round bottom flask was added aniline (3.13 g, 33.6 mmol) and 150 mL of toluene. The solution was cooled in an ice bath under nitrogen. Next trimethylaluminum solution in toluene was added dropwise via dropping funnel (2.0 M, 23.5 mL, 47.0 mmol) and the reaction mixture was stirred at room temperature for 2 h. Next 3-iodobenzonitrile (10 g, 44 mmol) in 50 mL of toluene was added and the reaction mixture was heated to 70° C. overnight under nitrogen. The reaction mixture was cooled in an ice bath and then poured onto a stirring slurry of silica gel in 2:1 dichloromethane/methanol. The silica gel was filtered off and washed with dichloromethane and methanol. The filtrate was evaporated leaving a solid which was triturated with hexane, filtered, and washed with more hexane and dried (7.84 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:19][NH2:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: NN=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 103.2 %

Procedure:
1.33 g (5 mmol) of 4'-chloro-2-(4-chlorophenyl)acetophenone was dissolved in 25 ml of ethanol, and 1.25 g (25 mmol) of hydrazine monohydrate was added thereto. The mixture was refluxed under heating for 2 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, and water was added to the residue. The mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 1.44 g of [4'-chloro-2-(4-chlorophenyl)acetophenone]hydrazone as a yellow oily substance.
Reaction SMILES: COC(OC(OC)(C)C)(C)C.[Br-].[OH:13][CH2:14][CH2:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:41]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])=O.OS(O)(=O)=O>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:49][O:48][C:46](=[O:47])[CH2:45][CH2:44][CH2:43]/[CH:41]=[CH:16]\[CH2:15][CH2:14][OH:13]
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCC=O
Agent: COC(C)(C)OC(C)(C)OC
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CCC/C=C\CCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a suspension of 14.2 g (30 mmoles) of the 2-methoxy-2-propyl ether of (3-hydroxypropyl)triphenylphosphonium bromide in 150 ml of tetrahydrofuran and 30 ml of hexamethylphosphorictriamide was slowly added 19 ml of n-butyllithium (1.6 M in hexane), at -78° C., under argon. The solution quickly turned yellow in color. Without delay, 2.6 g (20 mmoles) of methyl 4-formylbutyrate in 30 ml of tetrahydrofuran was added, and the resulting mixture was stirred for 30 min. at -78° C., allowed to warm to room temperature, and then stirred for 1 hour at room temperature. To the reaction mixture was added 1 N H2SO4 solution (pH 1 to 2). After stirring for 1 hour at room temperature, the product was extracted with ether. The ether extracts were washed with brine, saturated aqueous NaHCO3, and brine, then dried over MgSO4 and concentrated under reduced pressure. The resultant oily material was chromatographed on silica gel to give 2.00 g (58.3%) of (Z)-8-hydroxy-5-octenoic acid methyl ester.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH2:13])=[N:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21](O)=[O:22])[CH:16]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:21](=[O:22])[C:17]2[CH:16]=[C:15]([Cl:14])[CH:20]=[CH:19][N:18]=2)=[N:2]1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: NCCNc1nsc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCNc1nsc2ccccc12)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
A mixture of N1-(benzo[d]isothiazol-3-yl)ethane-1,2-diamine (100 mg, 0.52 mmol), 4-chloropicolinic acid (90 mg, 0.57 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg, 0.57 mmol) and triethylamine (174 μL, 1.1 mmol) in dichloromethane (5 mL) was allowed to stir at room temperature overnight. The reaction mixture was washed successively with 1N aqueous hydrochloric acid, saturated sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by flash column chromatography, on silica gel, eluting with a mixture of 1% methanol in dichloromethane and selected fractions were combined and concentrated under reduced pressure to give N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-4-chloropicolinamide (50 mg) as a white solid. 1H NMR (300 MHz, CDCl3): 8.66 (broad s, 1H), 8.41 (d, 1H), 8.20 (s, 1H), 7.78 (t, 2H), 7.65-7.38 (m, 3H), 5.95 (broad s, 1H), 3.84 ppm (m, 4H). MW=333 confirmed by LC-MS, tr=12.38 min (Method Y) MH+=334.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=3[CH3:20])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:23][NH2:24].C1C(O)=CC(C(O)=O)=C(O)C=1>O1CCOCC1>[CH3:20][C:14]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([N:10]1[CH2:9][CH2:8][C:5]2[N:6]=[N:7][C:2]([NH:23][NH2:24])=[CH:3][C:4]=2[CH2:11]1)=[O:21]
Reactant: NN
Reactant: Cc1cccc(C(=O)N2CCc3nnc(Cl)cc3C2)c1C
Agent: O=C(O)c1cc(O)ccc1O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(C(=O)N2CCc3nnc(NN)cc3C2)c1C

Procedure:
10.3 g of 3-chloro-6-(2,3-dimethylbenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 50 cc of hydrazine hydrate in 80 cc of dioxane are heated in an oil bath of 80°. After a reaction time of 60 hours, the mixture is concentrated in a vacuum, the oily residue is divided between 250 cc of chloroform and 150 cc of water, and after concentrating the chloroform phase, the resulting oily crude base is reacted with gentisic acid as described in Example 10. The gentisinate of the title compound has a M.P. of 176°-179° (decomp.) after recrystallization from 150 cc of methanol and 100 cc of water.
Reaction SMILES: [CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH:3][CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.CNN.[OH-].[Na+]>C(O)C>[CH2:4]([NH2:5])[CH:3]=[C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:26])[CH3:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCN1C(=O)c2ccccc2C1=O
Agent: CNN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCN
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A solution 2.50 g (7.1 mmol) of Part (1) compound in 15 ml of absolute ethanol at room temperature under argon was treated with 1.9 ml (35.57 mmol, 5.0 eq.) of methyl hydrazine and stirred for 2 hours at room temperature and 4 hours at reflux. After cooling and the addition of 7.1 ml (7.1 mmol, 1.0 eq.) of 1M NaOH, the ethanol was removed under reduced pressure. The residue was extracted with 350 ml of ethyl ether and the ether layer washed with 100 ml of 1M NaOH, 50 ml of H2O and 50 ml of brine, dried (MgSO4) and evaporated to obtain 1.45 g of crude product. Purification by bulb-to-bulb distillation at 120° C./0.005 mm provided 1.405 g (89%) of title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]([Br:14])[CH:7]=1.Cl[CH2:25][C:26]1[CH:30]=[C:29]([CH3:31])[O:28][N:27]=1>>[NH2:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]([Br:14])[C:9]([O:13][CH2:25][C:26]2[CH:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[C:10]([Br:12])[CH:11]=1)[C:3]([OH:2])=[O:23]
Reactant: Cc1cc(CCl)no1
Reactant: COC(=O)C(Cc1cc(Br)c(O)c(Br)c1)NC(=O)OC(C)(C)C
Product: Cc1cc(COc2c(Br)cc(CC(N)C(=O)O)cc2Br)no1
Yield: 22 %

Procedure:
Methyl-2-tert-butoxycarbonylamino-3-(3,5-dibromo-4-hydroxyphenyl)propionate (0.035 mmol) was coupled with 3-chloromethyl-5-methylisoxazole and hydrolyzed using the method described in “General procedure for the preparation of Examples 8-22”. This gave 22% yield of 2-amino-3-[3,5-dibromo-4-(5-methylisoxazol-3-ylmethoxy)phenyl]propionic acid. LC/MS (electrospray): m/z 433 (M−1).
Reaction SMILES: O=[C:2]([CH3:5])[CH:3]=O.[F:6][C:7]1[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=1>O>[F:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][CH:12]=1)[N:13]=[C:2]([CH3:5])[CH:3]=[N:14]2
Reactant: Nc1ccc(F)cc1N
Reactant: CC(=O)C=O
Solvent: O
Product: Cc1cnc2cc(F)ccc2n1
Yield: 79.8 %

Procedure:
A solution of 2-oxo-propionaldehyde (0.19 mL, 1.20 mmol) and 4-fluoro-benzene-1,2-diamine (150 mg, 1.19 mmol) in water (1.3 mL) was placed in a microwave tube and heated for 1 min. at 150 W. Then the reaction mixture was diluted with water and extracted twice with AcOEt. The organic phase was washed with water, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 154 mg (0.95 mmol, 80%) of 6-fluoro-2-methyl-quinoxaline.