Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH3:52])[CH2:11][O:12][N:13]=[C:14]([C:18]1[N:19]=[C:20]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:21][CH:22]=1)[C:15](O)=[O:16].[NH2:53][CH:54]1[C:79](=[O:80])[N:56]2[C:57]([C:63]([O:65][CH:66]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[O:64])=[C:58]([CH2:61][Cl:62])[CH2:59][S:60][C@H:55]12.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>>[Cl:62][CH2:61][C:58]1[CH2:59][S:60][C@@H:55]2[CH:54]([NH:53][C:15](=[O:16])[C:14](=[N:13][O:12][CH2:11][C:10]3[CH:43]=[CH:44][C:45]([O:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH3:52])=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:9]=3)[C:18]3[N:19]=[C:20]([NH:23][C:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[S:21][CH:22]=3)[C:79](=[O:80])[N:56]2[C:57]=1[C:63]([O:65][CH:66]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1)=[O:64]
Reactant: COCCOCOc1ccc(CON=C(C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1OCOCCOC
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COCCOCOc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1OCOCCOC
Reaction time: 0.5 h

Procedure:
1.0 g (1.4 mmol) of 2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(2-tritylaminothiazol-4-yl)acetic acid (syn-isomer) and 0.56 g (1.4 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate were dissolved in 0.77 ml (6.3 mmol) of N,N-dimethylaniline at 0° C., and 0.12 ml (1.7 mmol) of phosphorus oxychloride was dropwise added thereto. The mixture was stirred for 30 minutes and the reaction solution was washed with sequentially with 1 N hydrochloric acid, a 10% sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. The water layer was further extracted with ethyl acetate, and the organic layer was added thereto. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain benzhydryl 3-chloromethyl-7-{2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(2-tritylaminothiazol-4-yl)acetamido}-3-cephem-4-carboxylate (syn-isomer), which was used for the next reaction without purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl.Cl[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].O>CN(C=O)C>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][CH2:18][O:15][C:11]1[CH:10]=[C:9]([CH2:8][OH:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCCCl
Reactant: OCc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCOc1cccc(CO)c1
Temperature: 80 °C

Procedure:
Cesium carbonate (15.4 g) was added to a solution of 3-hydroxymethyl-phenol (3 g) in DMF (80 mL). To this mixture was added (3-chloro-propyl)-dimethyl-amine hydrochloride (4 g). The mixture was heated at 80° C. for 20 hours then allowed to cool. The reaction mixture was poured into water and extracted with ethyl acetate.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:15]([N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCOC(C)=O>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][CH:25]([O:14][C:3]2[C:2]([F:1])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=2)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1cc(F)c(O)cc1OC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC

Procedure:
Methyl 5-fluoro-4-hydroxy-2-methoxybenzoate from step 4 above was coupled to N-Boc-4-piperidinol using Mitsunobu conditions as given in step 4 of Example 1. Methyl 4-(N-t-butyloxycarbonyl-4-piperidinyloxy)-5-fluoro-2-methoxybenzoate was obtained as a gum (TLC Rf = 0.19 (3:7 EtOAc:hexanes); HPLC (method A) retention time= 9.9 min).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[C:11](OC([O-])=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NCc1cccc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Yield: 102.9 %

Procedure:
A solution of 25 g (110 mmol) of 3-bromobenzylamine hydrochloride and 24.5 g (110 mmol) of tert-butyl dicarbonate in 250 mL of dichloromethane in the presence of 15.6 mL (110 mmol) of triethylamine is stirred at room temperature for 16 hours. The reaction medium is washed with water, the phases are separated by settling and the organic phase is dried over sodium sulfate. The solvent is evaporated off and 32.4 g (100%) of tert-butyl (3-bromobenzyl)carbamate are obtained in the form of crystals.
Reaction SMILES: [C:1]([O:4][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:27][Si:28]([CH3:31])([CH3:30])Cl>O1CCCC1>[C:1]([O:4][C@H:5]1[N:8]([Si:28]([CH3:31])([CH3:30])[CH3:27])[C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:14])[CH3:15])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To an ice-cooled solution of 50g (0.174 mole) of (3R, 4R)-4-acetoxy-3-[(R)-1-t-butyldimethylsilyloxyethyl]-2 -azetidinone and 24.69 (0.244 mole) of triethylamine in 500 ml of tetrahydrofuran were added 26.5g (0.244 mole) of trimethylchlorosilane under a nitrogen stream. The reaction temperature was allowed to rise to room temperature and the reaction mixture was stirred for 2 hours. The precipitate was filtered off using a Celite (trade mark) filter aid. After the precipitate had been washed with ether twice, the filtrate and the washings were combined, and the solvent was evaporated. The residue was washed with ether to filter off the insoluble materials, Evaporation of the solvent from the filtrate gave 6.23 g (yield 100%) of the title compound as a semi-solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[C:35]([C:54]([CH3:62])([CH3:61])[O:55][SiH2:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[C:36]([N:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([CH:50]4[CH2:52][CH2:51]4)[CH:46]=3)[C:41]2=[O:53])[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O.O1CCOCC1>[C:57]([SiH2:56][O:55][C:54]([CH3:62])([CH3:61])[C:35]1[C:34]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:25])=[CH:20][N:19]=3)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=2)=[CH:39][CH:38]=[CH:37][C:36]=1[N:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([CH:50]3[CH2:52][CH2:51]3)[CH:46]=2)[C:41]1=[O:53])([CH3:60])([CH3:58])[CH3:59]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c(Br)cccc1-n1ccc2cc(C3CC3)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2cccc(-n3ccc4cc(C5CC5)ccc4c3=O)c2C(C)(C)O[SiH2]C(C)(C)C)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one (99 mg, 0.22 mmol), 2-[3-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-cyclopropyl-2H-isoquinolin-1-one (120 mg, 0.248 mmol), 2 mL dioxane, and a solution of cesium carbonate in water (370 mg/420 μL) were charged into a 4 mL reaction vial fitted with a stir bar and septum. Sparged the mixture with nitrogen for 15 min. Added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with dichloromethane (12 mg, 0.015 mmol). The reaction was sparged with nitrogen for 5 min. Sealed the vial and stirred at 90° 16 hr. Cooled to room temperature, partitioned the reaction mixture between 5 mL of 5% NaHCO3 and 10 mL of EtOAc, and separated phases. Washed the organic phase with 5 mL of water and 5 mL of brine, dried over Na2SO4 and concentrated in vacuo. Purified by C18 reverse phase flash chromatography (gradient elution, 10 to 95% acetonitrile+0.1% TFA/water+0.1% TFA). Added 1 mL of saturated NaHCO3 to the pooled product fractions and concentrated in vacuo. Extracted the remaining aqueous mixture with 2×10 mL CH2Cl2, dried over Na2SO4, and concentrated in vacuo to obtain 2-(2-(tert-Butyl-dimethyl-silanyloxymethyl)-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-cyclopropyl-2H-isoquinolin-1-one as a brittle amber foam. (70 mg, 0.097 mmol). MS (ESI) 718 (M+H)+.
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][C:33]1([OH:41])[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][NH:36][CH2:37]2>>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([N:36]5[CH2:37][CH:38]6[C:33]([OH:41])([CH3:32])[CH:34]([CH2:40][CH2:39]6)[CH2:35]5)=[O:24])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27]([N:28]([CH3:29])[CH3:30])=[O:31])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(O)C2CCC1CNC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)C5(C)O)cn3)nc2n1C1CCCCCC1
Yield: 26 %

Procedure:
Following general amide formation method 3, 6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with 8-methyl-3-azabicyclo[3.2.1]octan-8-ol which gave 7-cycloheptyl-2-(5-(8-hydroxy-8-methyl-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (68 mg) in 26% yield. 1H NMR (400 MHz, CDCl3) δ ppm 9.65 (s, 1H) 8.93-8.86 (m, 1H) 8.68 (d, J=8.59 Hz, 1H) 8.55 (d, J=2.02 Hz, 1H) 7.82 (dd, J=8.84, 2.27 Hz, 1H) 6.52-6.39 (m, 1H) 4.45-4.60 (m, 1H) 4.39 (br. s., 1H) 3.96 (br. s., 1H) 3.63-3.39 (m, 2H) 3.15 (s, 6H) 2.76-2.51 (m, 3H) 2.14 (br. s., 1H) 2.07-1.93 (m, 2H) 1.85 (ddd, J=6.95, 3.41, 3.28 Hz, 3H) 1.80-1.61 (m, 7H) 1.61-1.48 (m, 2H) 1.48-1.36 (m, 1H) 1.30 (s, 3H); HR-MS (m/z MH+) 546.32 RT 3.99 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:15][S:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1)(=[O:18])=[O:17]
Reactant: COc1ccc(N)cc1C1OCCO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(NS(C)(=O)=O)cc1C1OCCO1
Reaction time: 20 h
Yield: 88.1 %

Procedure:
To a solution of 2-(5-amino-2-methoxyphenyl)-1,3-dioxolane (867 mg, 4.4 mmol) in pyridine (2 ml) was added methanesulfonyl chloride (375 μl, 4.84 mmol) and stirred for 20 hr. To the resulted reaction mixture was added water and aqueous NaHCO3, and then extracted with ether/CH2Cl2. The extract was evaporated in vacuo to give crude 2-(5-methylsulfonylamino-2-methoxyphenyl)-1,3-dioxolane (1.06 g, 88.1%) as a slight brown oil.
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH2:12].N.[CH2:14]1[CH:23]2[CH:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][C:16](=[O:28])[CH2:15]1>C(O)CO.COCCOCCOC>[CH3:11][N:17]1[C:18]2[C:7]([CH3:8])([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[CH2:22][CH:23]=2)[CH2:14][CH2:15][C:16]1=[O:28].[CH3:11][N:12]1[C@@H:18]2[C@:23]([CH3:1])([C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH2:20][CH2:19]2)[CH2:14][CH2:15][C:16]1=[O:28]
Reactant: O=C(O)Cc1ccccc1
Reactant: CN
Reactant: O=C1CCC2c3ccccc3CCC2N1
Agent: N
Solvent: COCCOCCOC
Solvent: OCCO
Product: CN1C(=O)CCC2(C)C1=CCc1ccccc12
Product: CN1C(=O)CC[C@@]2(C)c3ccccc3CC[C@H]12
Reaction time: 7 h

Procedure:
By following the procedures described in Example 40, Steps A, B, C, D, E and F using phenylacetic acid as the starting material and in Step F using methylamine rather than ammonia and diglyme rather than ethylene glycol, the compound 4-methyl-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one was prepared. This hexahydrobenzo[f]quinolin-3-one was hydrogenated by following the procedures described in Example 22 except that the reaction was carried out at 60° C. over 7 hours. The reaction mixture was filtered and solvent evaporated under vacuum. The residue was purified by chromatography on SiO2 (CHCl3 as eluent) followed by recrystallization from ethyl acetate/hexanes to afford 154 mg of the title compound. Melting point 111°-113° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1.[NH2:19][C:20]([NH:22][C:23]1[NH:24][C:25]2[C:30]([C:31]=1[C:32](=[O:34])[NH2:33])=[CH:29][CH:28]=[C:27]([C:35]([OH:37])=O)[CH:26]=2)=[O:21]>CN(C)C=O>[NH2:19][C:20]([NH:22][C:23]1[NH:24][C:25]2[C:30]([C:31]=1[C:32]([NH2:33])=[O:34])=[CH:29][CH:28]=[C:27]([C:35]([NH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)=[O:37])[CH:26]=2)=[O:21]
Reactant: NC(=O)Nc1[nH]c2cc(C(=O)O)ccc2c1C(N)=O
Reactant: NCCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Nc1[nH]c2cc(C(=O)NCCc3ccccc3)ccc2c1C(N)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.2 %

Procedure:
N,N-Diisopropylethylamine (0.20 mL, 1.14 mmol) and 2-phenethylamine (48 μL, 0.38 mmol) were added to a solution of 2-aminocarbonylamino-3-carbamoylindole-6-carboxylic acid (Compound 18-1, 0.10 g, 0.38 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate g, 0.38 mmol) in anhydrous N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 2.5 hours. After the reaction mixture was concentrated under reduced pressure, the precipitated solid was washed with saturated sodium hydrogen carbonate aqueous solution (20 mL), water (20 mL), and dried under reduced pressure to give the title compound (0.11 g) as a slightly yellow solid (yield 77%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#N)=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1.C([O-])(=[O:14])C.[Na+].CO>[Ni].O>[Cl:1][C:2]1[C:7]([CH:8]=[O:14])=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cc(C#N)c(Cl)nc1C
Agent: [Ni]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(C=O)c(Cl)nc1C
Yield: 60.5 %

Procedure:
A mixture of 2-chloro-3-cyano-5,6-dimethylpyridine (21.5 g) semicarbazide hydrochloride (24.0 g), sodium acetate (42.3 g), water (225 ml) and methanol (475 ml) was hydrogenated at 344 kPa at 50° using Raney nickel catalyst (5 g). The mixture was added to water (750 ml) and filtered. The solid filtered off was suspended in water (130 ml) and concentrated hydrochloric acid (70 ml) was added and the mixture was heated at 100° for 1 hour, formalin (40% w/w, 120 ml) was added and the mixture was heated at 100° for a further 0.5 hour and allowed to cool. Sodium acetate (95 g) and water (250 ml) were added and the mixture was extracted with ether and the extracts were washed with 5% aqueous potassium carbonate and evaporated to give 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (13.24 g, 60%) m.p. 69°-70°.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[N:7]([NH:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[CH:8]=1)#[N:2].[CH2:21]=[O:22].O>C(O)=O>[C:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[N:7]([N:9]([CH2:21][OH:22])[C:10]2[C:11]([Cl:18])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])[CH:8]=1)#[N:2]
Reactant: N#Cc1cn(Nc2c(Cl)cc(Cl)cc2Cl)c(=O)[nH]c1=O
Reactant: C=O
Solvent: O
Solvent: O=CO
Product: N#Cc1cn(N(CO)c2c(Cl)cc(Cl)cc2Cl)c(=O)[nH]c1=O
Reaction time: 8 h

Procedure:
Two grams of 5-cyano-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione is added to 1.6 ml of 35% formaldehyde in enough 95% formic acid to effect stirring. The mixture is heated to reflux and 95% formic acid is added dropwise until the solid is dissolved. The mixture is refluxed overnight, after which 3.2 ml of aqueous formaldehyde is added and refluxing is continued for another 8 hours. The reaction mixture is poured into water and the precipitate is filtered to yield the compound 5-cyano-1-(N-hydroxymethyl-2,4,6-trichloroanilino)-2,4-pyrimidinedione, m.p.>300°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:13][C:14]#N)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC(C2([CH2:27][C:28]#N)CCC2)=CC=1.[Mg].C(Br)C.CC[O:36]CC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:13][C:14](=[O:36])[CH2:27][CH3:28])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOCC
Reactant: N#CCC1(c2ccc(Cl)cc2)CCC1
Reactant: N#CCC1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: [Mg]
Solvent: CCBr
Product: CCC(=O)CC1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
A solution in ether (80 ml) of 2-[1-(3,4-dichlorophenyl)cyclobutyl]acetonitrile (23 g) prepared in a similar manner to that described in Example 1 for 2-[1-(4-chlorophenyl)cyclobutyl]acetonitrile was added to the product of the reaction between magnesium turnings (3.53 g) and ethyl bromide (10.8 ml) in dry ether (80 ml) with stirring whilst heating on a steam bath. The ether was removed and replaced with toluene and the mixture heated under reflux for one hour. Water was added and the mixture added to a mixture of ice and concentrated hydrochloric acid. The mixture was heated on a steam bath for one hour and filtered through a diatomaceous earth sold under the Registered Trade Mark CELITE. The filtrate was extracted with dichloromethane and the extract washed with water and sodium bicarbonate solution and dried. The solvent was removed by evaporation and the residue distilled to give 1-[1-(3,4-dichlorophenyl)cyclobutyl]butan-2-one (b.p. 149°-150°/1.1 mm Hg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])C)[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C=NC(N3CCN(S(CC4(C(O)=O)CC[O:58][CH2:57][CH2:56]4)(=O)=O)CC3)=NC=2)=CC=1>>[OH:28][NH:27][C:25]([C:24]1([CH2:23][S:20]([N:17]2[CH2:16][CH2:15][N:14]([C:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:9][N:10]=3)[CH2:19][CH2:18]2)(=[O:21])=[O:22])[CH2:29][CH2:31][O:58][CH2:57][CH2:56]1)=[O:26]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: O=C(O)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCOCC1
Product: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCOCC1
Yield: 92 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methyl-butyramide, from 4-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonyl-methyl}tetrahydropyran-4-carboxylic acid (0.29 g), to provide the title compound as a white solid (0.27 g, 92%).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[CH:4](O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11](O)/[CH:12]=[CH:13]/[CH3:14].[C:17]([O:23]C)([O:21][CH3:22])(OC)[CH3:18]>C(CC(O)=O)(C)(C)C>[CH3:1][CH:2](/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[CH:13]([CH3:14])[CH2:18][C:17]([O:21][CH3:22])=[O:23])[CH2:18][C:17]([O:21][CH3:22])=[O:23]
Reactant: COC(C)(OC)OC
Reactant: C/C=C/C(O)CCCCCCC(O)/C=C/C
Agent: CC(C)(C)CC(=O)O
Product: COC(=O)CC(C)/C=C/CCCCCC/C=C/C(C)CC(=O)OC
Temperature: 80 °C
Yield: 75.1 %

Procedure:
A mixture of tetradeca-2E,12E-diene-4,11-diol (5.0 g, 22.0 mmole), trimethyl orthoacetate (20 ml, 165 mmole), and t-butylacetic acid (0.1 g, 0.86 mmole) was heated to 120-140° C. for 3.0 hours with the slow distillation of the methanol formed during the reaction. The solution was cooled to 80° C. and the lower boiling materials were removed by vacuum distillation to afford dimethyl 3,14-dimethylhexadeca-4E,12E-diene-1,16-dioate (5.59 g, 75% yield) as an oil which was suitable for use in the subsequent reaction. C20H34O4 (338.49 g/mole). 1HNMR (500 MHz, CDCl3): 1.001 (d, 6H), 1.33-1.18 (m, 8H), 1.929 (dd, 4H), 2.257 (dt, 4H), 2.599 (dt, 2H), 3.634 (s, 6H), 5.32-5.27 (m, 2H), 5.43-5.36 (m, 2H) ppm. 13CNMR (125 MHz, CDCl3): 20.54, 28.99, 29.51, 32.52, 33.76, 41.89, 51.49, 129.74, 134.10, 173.22 ppm. IR (νmax(cm−1)): 2926(s), 2912(s), 2852(m), 1742(s), 1458(m), 1437(m), 1358(m), 1284(m), 1246(m), 1192(m), 1168(m), 1072(w), 1008(m), 970(m), 879(w), 839(w), 725(w). MS (m/z): 338(M+), 306, 275, 264, 257, 246, 233, 223, 215, 204, 191, 177, 163, 149, 135, 121, 108, 95, 81, 67, 55, 41.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([N:15]3[CH:19]4[CH2:20][CH2:21][CH:16]3[CH2:17][CH2:18]4)[C:11]2=O)=[CH:6][CH:5]=1)([O-])=O.B.C1COCC1.Cl>C1COCC1.O>[CH:19]12[N:15]([CH:12]3[CH2:13][CH2:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)[CH2:11]3)[CH:16]([CH2:21][CH2:20]1)[CH2:17][CH2:18]2
Reactant: O=C1C(N2C3CCC2CC3)CCN1c1ccc([N+](=O)[O-])cc1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(N2CCC(N3C4CCC3CC4)C2)cc1

Procedure:
1-(4-Nitrophenyl)-3-(7-azabicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one (0.25 g) in THF (10 ml) was mixed with borane-THF complex (1M in THF, 0.83 ml) and boiled under reflux for 3 hours. After the reaction was complete, the mixture was diluted with water and adjusted to pH 9-10 with hydrochloric acid (4N). Extraction in ethyl acetate, drying and concentration of the organic phase afforded a crude product that was hydrogenated by method B. This resulted in the product with the molecular weight of 257.38 (C16H23N3); MS (ESI): 258 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:39](=O)[CH:40]([CH3:42])[CH3:41]>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)C=O
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure F using isobutyraldehyde. The final product was obtained in 57% yield.