Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.CN1CCN(C2C=CC(C(O)=O)=CC=2)CC1.[CH2:34]([O:41][CH2:42][CH2:43][O:44][C:45]1[CH:53]=[C:52]2[C:48]([C:49]([NH2:54])=[N:50][NH:51]2)=[CH:47][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[CH2:34]([O:41][CH2:42][CH2:43][O:44][C:45]1[CH:53]=[C:52]2[C:48]([C:49]([NH:54][C:13](=[O:14])[C:12]3[CH:16]=[CH:17][C:9]([N:6]4[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]4)=[CH:10][CH:11]=3)=[N:50][NH:51]2)=[CH:47][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Nc1n[nH]c2cc(OCCOCc3ccccc3)ccc12
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Agent: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4cc(OCCOCc5ccccc5)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A stirred suspension of 4-(4-methyl-piperazin-1-yl)-benzoyl chloride hydrochloride, prepared from 4.55 g (20.7 mmol) of 4-(4-methyl-piperazin-1-yl)-benzoic acid as described above in preparation 3, in dry pyridine (50 ml) was treated dropwise, at 0° C., under argon atmosphere, with a solution of 6-(2-benzyloxy-ethoxy)-1H-indazol-3-ylamine (5.31 g, 18.8 mmol) in 80 ml of dry pyridine. The reaction mixture was allowed to warm to r.t. under stirring overnight, then concentrated to 30 ml by rotary evaporation, poured into 500 ml of saturated solution of NaHCO3 and extracted with 300+100 ml of DCM. The organic layers were combined, dried over sodium sulfate and evaporated to dryness. The crude residue was treated with 200 ml of EtOAc and stirred at reflux for 2 h. After cooling to r.t. the solid was filtered, washed with EtOAc and dried in oven at 50° C. under high vacuum to afford 5.23 g (yield: 57%) of the title compound as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][O:25][CH3:26])[CH:20]=[CH:19][C:18]=1[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH2:33])[CH2:28]1>ClCCl>[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][O:25][CH3:26])[CH:20]=[CH:19][C:18]=1[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:28]1
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(C2CCCC(N)C2)c(OCOC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(C2CCCC(NS(C)(=O)=O)C2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.014 ml) and methanesulfonyl chloride (8 μl) were added to a solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexylamine (27 mg) in dichloromethane (1 ml), and the mixture was stirred under argon at ambient temperature. After 1 hr, the mixture was partitioned between ethyl acetate (20 ml) and sodium hydrogen carbonate (20 ml of a saturated aqueous solution). The aqueous layer was extracted with ethyl acetate (2×20 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to furnish the title compound as an oil and a mixture of diastereoisomers; m/z (ES+) 374 (M+H)+.
Reaction SMILES: [Na].[C:2]([C:5]1[N:6]2[CH:9]([S:10][CH2:11][C:12]=1[CH2:13][S:14][C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[CH:8]([NH:21][C:22](=[O:30])[CH2:23][C:24]1[S:25][C:26](=[O:29])[S:27][CH:28]=1)[C:7]2=[O:31])([OH:4])=[O:3].[C:32]([O:35][CH2:36]I)(=[O:34])[CH3:33].O>CN(C)C=O>[C:32]([O:35][CH2:36][O:3][C:2]([C:5]1[N:6]2[CH:9]([S:10][CH2:11][C:12]=1[CH2:13][S:14][C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[CH:8]([NH:21][C:22](=[O:30])[CH2:23][C:24]1[S:25][C:26](=[O:29])[S:27][CH:28]=1)[C:7]2=[O:31])=[O:4])(=[O:34])[CH3:33]
Reactant: CC(=O)OCI
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCOC(=O)C1=C(CSc2nnnn2C)CSC2C(NC(=O)Cc3csc(=O)s3)C(=O)N12
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
The sodium salt of 2-carboxy-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (5.08 g.) is dissolved in dimethylformamide (100 cc.) at 5° C. A solution of iodomethyl acetate (2 g.) in dimethylformamide (10 cc.) is added to this solution and the reaction mixture is stirred for 10 minutes at 5° C. It is then poured into water (500 cc.) and extracted twice with ethyl acetate (200 cc.). The combined organic phases are washed with water (100 cc.), saturated sodium bicarbonate solution (100 cc.), a 5% sodium bisulphite solution (100 cc.) and a saturated sodium chloride solution (100 cc.). The organic phase is dried over magnesium sulphate, filtered in the presence of decolourising charcoal and concentrated to dryness under reduced pressure (15 mm Hg). This gives a white product (5 g.) which is recrystallised from acetonitrile (50 cc.). 2-Acetoxymethoxycarbonyl-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (3 g.) is thus obtained as white crystals m.p. 154° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)C(OCC)=O)[CH3:2].[Cl-].[Na+].CS(C)=O>O>[CH2:1]([O:3][C:4](=[O:37])[CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][CH:17]=1)[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][CH:30]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)Cc1ccc(C(=O)C(C)(C)C)cc1

Procedure:
A mixture of 50.0 g. (0.100 mole) bis(p-pivaloylbenzyl)malonic acid diethylester, 6.0 g. (0.103 mole) sodium chloride, 200 ml. dimethylsulfoxide and 3.5 ml. water is heated at 180° for 22 hours. The resulting mixture is then cooled and poured into water. The water mixture is extracted twice with methylene chloride and the methylene chloride washed with water and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting oil is crystallized from pentane to give bis(p-pivaloylbenzyl) acetic acid ethyl ester; m.p. 60°-63° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:23]C)[N:13]2[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:9]([NH2:25])[N:8]=1)[CH3:2].Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: CCOCCOc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCOCCOc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 2-(2-ethoxyethoxy)-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (240 mg) in dry methanol (10 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (4.0 ml). The reaction was left to stir at room temperature for 3 hours. The reaction was neutralised by the addition of 2.0M sodium hydroxide solution and concentrated in vacuo. The residue was taken up in water (15 ml) and the solid filtered and washed with water (2×5 ml). The solid was dried en vacuo (60° C.) for 30 minutes. This afforded the title compound as an off-white solid (129 mg).
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][C:9]2[C:4](=[C:5]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:34]=[CH:33][S:32][CH:31]=1>C(C(C)=O)C>[O:1]=[C:2]1[CH:11]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][C:9]2[C:4](=[C:5]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:29][C:30]1[CH:34]=[CH:33][S:32][CH:31]=1
Reactant: CC(=O)NC1Cc2cccc(N3CCCC3=O)c2NC1=O
Reactant: BrCc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 79 °C
Reaction time: 20.5 h

Procedure:
Methyl ethyl ketone (5 mL) was added to a mixture of N-(2-oxo-8-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (500 mg) and potassium carbonate powder (265 mg), and 3-(bromomethyl)thiophene was added thereto. The mixture was stirred at an internal temperature of 79° C. for 20.5 hours, and then left to stand at room temperature. The mixture was partitioned between saturated aqueous sodium chloride solution (2 mL) and ethyl acetate (1 mL), and the aqueous layer was extracted with ethyl acetate (2 mL+1 mL). The organic layers were combined, and the solvent was evaporated under reduced pressure. Ethyl acetate (1.5 mL) and toluene (2.5 mL) were added to the thus-recovered residue, and the precipitated crystals were recovered through filtration. The container of the reaction mixture was washed with a mixture of ethyl acetate and toluene (3:5) (0.5 mL×2). The thus-recovered crystals were washed with a mixture of ethyl acetate and toluene (3:5) (1.0 mL×2), and then dried under reduced pressure at 60° C., whereby ethyl acetate solvates of the title compound (510 mg) were yielded.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[CH3:13][C:14](C)(C)C([O-])([O-])[O-]>S(=O)(=O)(O)O.CO>[CH3:13][C:14]1[O:12][C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[N:1]=1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc2nc(C)oc2c1
Temperature: 160 °C
Yield: 61.9 %

Procedure:
In a 50 ml round-bottomed three-necked flask equipped with a 12-inch Vigraux column and a Dean Stark trap assembly were placed methyl 4-amino-3-hydroxybenzoate (10.0 g, 60 mmole), trimethylorthoacetate (10.8 g, 90 mmole), and concentrated sulfuric acid (0.25 g, 2.6 mmole). The resulting well-stirred mixture was heated at 115° C. until approximately 8 ml of methanol were collected in the Dean Stark trap. The reaction mixture was heated at 160° C. for another 60 minutes. The reaction mixture was cooled to room temperature and dissolved in ethyl acetate. The resulting organic solution was extracted sequentially with saturated aqueous sodium bicarbonate (1×100 ml), water (2×50 ml), brine, and dried over anhydrous magnesium sulfate. The solvent was removed in the rotary evaporator yielding 7.1 g of the expected methyl 2-methylbenzoxazole-6 carboxylate used as such in the next step.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH:17]([CH3:19])[CH3:18])[C:13](=[O:16])[CH2:14][CH3:15])=O)C1C=CC=CC=1>O1CCCC1.[Pd]>[NH2:11][C@@H:12]([CH:17]([CH3:19])[CH3:18])[C:13](=[O:16])[CH2:14][CH3:15]
Reactant: CCC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(=O)[C@@H](N)C(C)C

Procedure:
4-(S)-Benzyloxycarbonylamino-5-methyl-3-oxohexane (61 mg), prepared in Referential Example 15, was dissolved in tetrahydrofuran (2.0 ml) and catalytically reduced by stirring for 40 minutes under an atmosphere of hydrogen in the presence of 10% palladium on charcoal (6 mg). After the catalyst had been filtered off, the filtrate was concentrated under reduced pressure to yield 4-(S)-amino-5-methyl-3-oxohexane as a crude product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N+:12]=1[O-:18].C(=O)(O)[O-].[Na+]>>[Br:10][C:11]1[CH:16]=[C:15]([N+:1]([O-:4])=[O:2])[CH:14]=[C:13]([CH3:17])[N+:12]=1[O-:18]
Reactant: Cc1cccc(Br)[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])cc(Br)[n+]1[O-]
Temperature: 70 °C
Yield: 40 %

Procedure:
Concentrated nitric acid (4 mL) was added to cold concentrated sulfuric acid (7 mL). 2-Bromo-6-methyl-pyridine 1-oxide (820 mg, 4.36 mmol) was added to this and then heated at 70° C. for 4 h. The mixture was cooled and poured slowly into ice-cold water (100 mL) and basified to pH ˜8 with sodium bicarbonate solution. This was extracted with ethyl acetate (4×50 mL) then the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a residue which was purified by washing with pentane (50 mL) to afford 2-bromo-6-methyl-4-nitro-pyridine 1-oxide (0.41 g, 40%) as a free flowing yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl.CN(C)C=O.C(OCC)(=O)C.CCCCCC>[N:28]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])=[N:13][CH:14]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1ccc(CO)cn1)c1cc(F)ccc1F
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
In a mixture of carbon tetrachloride (4 ml) and N,N-dimethylformamide (16 ml) was dissolved the 2-[(4-chlorophenylsulfonyl) (2,5-difluorophenyl)methyl]-5-(hydroxymethyl)pyridine (471 mg, 1.15 mmol) obtained in Example 331. Sodium azide (112 mg, 1.72 mmol) and triphenylphosphine (451 mg, 1.72 mmol) were added and the mixture was stirred at 90° C. for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then washed successively with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to chromatography on a silica gel column. A fraction obtained from the elution portion with hexane:ethyl acetate=3:1 was concentrated under reduced pressure, whereby the title compound (244 mg, 0.561 mmol, 49%) was obtained as a colorless amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11][CH2:10]2.[CH2:20]([O:22][CH2:23][CH2:24]Br)[CH3:21]>>[CH2:20]([O:22][CH2:23][CH2:24][N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=3)[CH:8]=2)[CH2:13]1)[CH3:21]
Reactant: CCOCCBr
Reactant: Fc1cccc(COc2ccc3c(c2)CCNC3)c1
Product: CCOCCN1CCc2cc(OCc3cccc(F)c3)ccc2C1

Procedure:
As described for example 44, 6-(3-fluoro-benzyloxy)-1,2,3,4-tetrahydro-isoquinoline (0.100 g, 0.39 mmol) was converted to the tide compound (0.075 g, 59%) using 2-bromoethyl ethyl ether (0.072,g, 0.47 mmol) instead of 2-bromopropionamide. MS: m/e=330.4 (M+H+).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)n2C)c1ccccn1
Yield: 64 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and benzyl chloroformate. Yield: 64% of theory, C35H35N7O5 (633.6) Rf value: 0.60 (silica gel; dichloromethane/methanol=9:1) ##EQU131##
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O>CN(C)C=O>[NH2:1][C:2]1[S:3][C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:4]=1
Reactant: O=C1CCCCC1Cl
Reactant: NC(N)=S
Solvent: CN(C)C=O
Product: Nc1nc2c(s1)CCCC2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Thiourea (123.3 g., 1.62 moles) was combined with 400 ml. of dimethylformamide and heated on a steam bath. After dissolution of the thiourea was complete, 2-chlorocyclohexanone (195.1 g., 1.47 moles) was added dropwise over 20 minutes, during which the temperature began to rise above 100° C., and external heating was discontinued. The temperature rose to a maximum of 128° C. After addition was complete, heating on the steam bath was resumed and was continued for 30 minutes. The reaction mixture was cooled to 5° C. and crude product recovered by filtration. The crude was partially dried to 242.4 g., and then dissolved by warming in a mixture of 1.4 l. of water, 100 ml. of methanol and 50 ml. of concentrated hydrochloric acid. The acidic solution was added dropwise to a stirred mixture of 150 ml. of concentrated ammonium hydroxide and ice and partially purified product (167.6 g.) recovered by filtration. Recrystallization from 1400 ml. of cyclohexane gave purified 2-aminio-4,5,6,7-tetrahydrobenzthiazole (150 g., m.p. 86°-87° C.).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][OH:32])[CH2:26]2)=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:18]([CH3:19])=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1[CH3:20])=[O:7].CO>C1COCC1>[F:3][C:4]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][OH:32])[CH2:26]2)=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:10]([CH3:20])=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][C:18]=1[CH3:19])=[O:7]
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2F)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc(C)c1NC(=O)c1cc(N2CCCC(CO)C2)ccc1F
Reaction time: 16 h
Yield: 69.7 %

Procedure:
A solution of aqueous 2N NaOH (2.00 ml) is added to a stirred solution of methyl 4-[[2-fluoro-5-[3-(hydroxymethyl)-1-piperidyl]benzoyl]amino]-3,5-dimethyl-benzoate (0.18 g, 0.43 mmol) in THF:MeOH (3 ml:1 ml). After 16 h at 50° C., the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with 1N HCl and extracted with CH2Cl2. The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as a white solid (0.12 g, 69%). Mass spectrum (m/z): 401.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[C:5]([CH3:16])([CH3:15])[C:4]1=[O:17])[CH3:2]>CO.O1CCCC1>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([CH3:15])([CH3:16])[C:4](=[O:17])[N:3]2[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: CCN1C(=O)C(C)(C)c2ccc([N+](=O)[O-])cc21
Solvent: CO
Solvent: C1CCOC1
Product: CCN1C(=O)C(C)(C)c2ccc(N)cc21

Procedure:
To a solution of 1-ethyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (5.9 g, 25.19 mmol) in methanol/tetrahydrofuran (THF) palladium on charcoal (10%) was added and the mixture hydrogenated at room temperature. After filtration and evaporation of the solvents 5.05 g (98%) 6-amino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one was isolated as white solid.
Reaction SMILES: [Li+].C[O-].[CH3:4][C:5]1([CH3:14])[C@H:7]([CH:8]=O)[C@H:6]1[C:10]([O:12][CH3:13])=[O:11].[C:15]1([C:21]2(C3C=CC=CC=3)COC(C3C=CC=CC=3)(CBr)[O:22]2)C=CC=CC=1.CN(C)C=O>CO>[CH3:4][C:5]1([CH3:14])[C@H:7](/[CH:8]=[CH:15]/[CH:21]=[O:22])[C@H:6]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@@H]1[C@@H](C=O)C1(C)C
Reactant: BrCC1(c2ccccc2)OCC(c2ccccc2)(c2ccccc2)O1
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@@H](/C=C/C=O)C1(C)C
Temperature: 75 °C
Reaction time: 5 h
Yield: 68.9 %

Procedure:
A solution of 17.1 ml of lithium methylate in methanol was added over 21/2 hours at ≃75° C. to a solution of 46.8 g of methyl (1R,trans) 2,2-dimethyl-3-formyl-cyclopropane-1-carboxylate, 193.2 g of the product of Step A and 750 ml of dimethylformamide and the mixture was stirred at ≃75° C. for 5 hours and then stood overnight at room temperature. The mixture was poured with stirring into an ice-water mixture and the resulting mixture was extracted with ether. The organic phase was washed with aqueous saturated sodium chloride solution and dried under reduced pressure at 50° C. The residue was dissolved in a solution of 750 ml of tetrahydrofuran and 750 ml of N hydrochloric acid and the solution was stirred at room temperature for 3 hours and was poured into water. The mixture was extracted with ether and the organic phase was washed with aqueous solution bicarbonate solution, with aqueous saturated sodium chloride solution, was dried and evaporated to dryness. The residue was taken up in an 8-2 petroleum ether (b.p.=60°-80° C.)-ethyl acetate mixture and the mixture was vacuum filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with an 8-2 petroleum ether-ethyl acetate mixture yielded 37.6 g of methyl (1R,trans) 2,2-dimethyl-3[(E)-2-formylethenyl]-cyclopropane-1-carboxylate with a refractive index of nD28 =1.5018.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([C:16]([O:18]CC)=[O:17])[CH:7]=1)(=[O:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[N:9]=[C:8]([C:16]([OH:18])=[O:17])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(COC(C)=O)nc(C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCc1cc(C(=O)O)nc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl 6-[(acetyloxy)methyl]-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.95 g, 3.2 mmol, from Step B) in tetrahydrofuran (8.7 mL) at 0° C. was treated with Lithium hydroxide, monohydrate (140 mg, 3.2 mmol) in water (1.3 mL). The reaction was stirred for 15 minutes, then was treated with 1N HCl to pH˜4 while still in the ice bath. THF was removed from the mixture in vacuo. The product was extracted first with ethyl acetate, then with several portions of 10% isopropanol in CHCl3, including periodic adjustment of pH as necessary. The extracts were combined and dried over sodium sulfate, filtered and concentrated to afford a yellow oil, which was used without further purification.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[Br:41][CH2:42][CH2:43]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:41][CH2:42][CH2:43][O:38][C:35]1[CH:36]=[CH:37][C:32]([N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:24]=[CH:25][C:20]4[N:21]([C:17]([C:16]([F:15])([F:39])[F:40])=[N:18][N:19]=4)[N:22]=3)[CH2:31][CH2:30]2)=[CH:33][CH:34]=1
Reactant: OCCBr
Reactant: Oc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4ccc(OCCBr)cc4)CC3)nn12
Temperature: 20 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
DIAD (1.625 mL, 8.25 mmol) was added to 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenol (obtained as described in Example 514, preparation of starting materials) (3.01 g, 8.25 mmol), 2-bromoethanol (0.645 mL, 9.08 mmol) and triphenylphosphine (2.165 g, 8.25 mmol) in THF (150 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 16 hours. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM to afford 6-[4-[4-(2-bromoethoxy)phenyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.765 g, 19.67%) as a pale yellow solid.