Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.N1C=CC=C(C)C=1.[Cl:29][C:30]1[CH:41]=[C:40]([CH3:42])[C:33]2[NH:34]C(=O)[O:36][C:37](=O)[C:32]=2[CH:31]=1>C(#N)C.O>[Br:6][C:7]1[CH:11]=[C:10]([C:12]2[O:14][C:37](=[O:36])[C:32]3[CH:31]=[C:30]([Cl:29])[CH:41]=[C:40]([CH3:42])[C:33]=3[N:34]=2)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: Cc1cccnc1
Solvent: CC#N
Solvent: O
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: -2.5 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a solution of methanesulfonyl chloride (5.0 mL, 7.4 g, 65 mmol) in acetonitrile (55 mL) at −5° C. was added dropwise a solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see WO 03/015519 for preparation) (93.6% purity, 16.16 g, 50.0 mmol) and 3-picoline (8.3 mL, 7.9 g, 85 mmol) in acetonitrile (50 mL) over five minutes while maintaining the temperature at about −5 to 0° C. A slurry formed during the addition. The mixture was stirred for 5 minutes at this temperature, and then 6-chloro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (99.0% purity, 11.22 g, 52.5 mmol) was added all at once, and the residue was rinsed with acetonitrile (10 mL). To the reaction mixture was added 3-picoline (8.3 mL, 7.9 g, 85 mmol) dropwise in 5 minutes at −5 to 0° C. After stirring for 15 minutes at −5 to 0° C., the reaction mixture was heated to 50° C. and stirred 4 hours. Then the reaction mixture was cooled to room temperature, water (30 mL) was added dropwise and the mixture was stirred 15 minutes. The mixture was filtered, and the solids were re-slurried sequentially with 4:1 acetonitrile-water (2×40 mL) and acetonitrile (3×40 mL), and then dried under nitrogen to afford the title product as a light yellow powder, 20.95 g (93.6% purity by HPLC, 86.7% yield calculated based on the purity).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Br:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]1.C[O-].[Na+].[C:20](=O)(O)[O-:21].[Na+]>O1CCCC1>[CH3:20][O:21][CH2:2][C:3]1[C:8]([Br:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]1
Reactant: Cn1nnn(-c2cccc(Br)c2CBr)c1=O
Reactant: O=C([O-])O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1c(Br)cccc1-n1nnn(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(2-bromomethyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 45.0 g, sodium methoxide 37.4 g and tetrahydrofuran 600 ml was stirred at room temperature for three hours. To the reaction mixture was added aqueous saturated sodium bicarbonate solution and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and was dried over anhydrous magnesium sulfate. The resulting mixture was concentrated under reduced pressure to give 1-(2-methoxymethyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 36.2 g.
Reaction SMILES: [C:1]([CH:3]([CH:8]([C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10](OC)=[O:11])[C:4]([O:6][CH3:7])=[O:5])#[N:2].[H][H]>CO.C(Cl)(Cl)Cl.CC(O)C.[Pt](=O)=O>[O:11]=[C:10]1[NH:2][CH2:1][C@@H:3]([C:4]([O:6][CH3:7])=[O:5])[C@H:8]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:9]1
Reactant: COC(=O)CC(c1cc(F)c(F)cc1F)C(C#N)C(=O)OC
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CO
Product: COC(=O)[C@@H]1CNC(=O)C[C@H]1c1cc(F)c(F)cc1F
Reaction time: 0.08 h

Procedure:
To a solution of 26.4 g (83.8 mmol) of dimethyl 2-cyano-3-(2,4,5-trifluorophenyl)pentanedioate from Step B in 120 mL of methanol was added 5.0 g (22 mmol) of platinum(IV) oxide. The reaction mixture was shaken under 50 psi of hydrogen for 16 h at which point the reaction was diluted with 400 mL of a 3:1 mixture of chloroform and 2-propanol to dissolve the desired white solid, and filtered through a pad of Celite. The filter cake was successively washed with three portions of 400 mL of the above solvent mixture. The combined filtrate and washings were concentrated and then taken up in 150 mL of ethyl acetate, stirred for 5 min, then 150 mL of hexanes was added and stirred for 5 min. The white precipitate was filtered to afford the title compound which was used without further purification. LC/MS 288.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][C@@H:12]2[CH3:30])=[O:10])=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33].CO>C(O)(C)C>[ClH:1].[CH3:31][N:32]([CH3:33])[C:2]1[CH:3]=[CH:4][C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][C@@H:12]2[CH3:30])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(Cl)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Reactant: CNC
Solvent: CO
Solvent: CC(C)O
Product: Cc1nc(N(C)C)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Product: Cl
Temperature: 120 °C

Procedure:
(2S)-1-[(6-Chloro-2-methyl-3-pyridinyl)carbonyl]-2-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Example 24) (65 mg, 0.14 mmol) was weighed into a microwave vial, and suspended in isopropanol (0.7 ml). Dimethylamine, 2M in methanol (0.7 ml, 1.40 mmol) was added, and the mixture was stirred briefly to give a clear solution. This was heated in the microwave to 120° C. for 4 h with stirring. The reaction mixture was concentrated to give the crude material as a yellow gum, which was purified by MDAP to give the free base of the title compound as a colourless gum (47 mg).
Reaction SMILES: C1COCC1.C(NC(C)C)(C)C.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].[CH3:19][O:20][C:21]([C:23]1[C:24]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=2[F:42])=[C:25]([F:33])[C:26]2[N:27]([C:29](I)=[CH:30][N:31]=2)[CH:28]=1)=[O:22]>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][O:20][C:21]([C:23]1[C:24]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=2[F:42])=[C:25]([F:33])[C:26]2[N:27]([C:29]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:30][N:31]=2)[CH:28]=1)=[O:22]
Reactant: COC(=O)c1cn2c(I)cnc2c(F)c1Nc1ccc(C)cc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cn2c(C#C[Si](C)(C)C)cnc2c(F)c1Nc1ccc(C)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
THF (1.0 mL), diisopropylamine (95 μL, 0.68 mmol) and trimethylsilylacetylene (38 μL, 0.27 mmol) were added to a mixture of 8-fluoro-7-(2-fluoro-4-methylphenylamino)-3-iodo-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (100 mg, 0.23 mmol), CuI (4.0 mg, 0.023 mmol) and PdCl2(PPh3)2 (16 mg, 0.023 mmol). The solution was stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate, washed with saturated NaHCO3 (3×), brine (2×), dried over Na2SO4 and concentrated to a dark brown solid. Flash column chromatography (40:1 dichloromethane/MeOH) provide desired product (30 mg, 32%) as a yellow liquid. MS APCI (+) m/z 414 (M+1) detected. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.61 (s, 1H), 7.80 (s, 1H), 6.90 (m, 3H), 4.00 (s, 3H), 2.32 (s, 3H), 0.33 (s, 9H). 19F NMR (376 MHz, CDCl3)−129.12 (s, 1F), −141.99 (s, 1F).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1B(O)O)([CH3:9])[CH3:8].Br[C:22]1[CH:51]=[CH:50][C:25]([CH2:26][NH:27][C:28](=[O:49])[C:29]2[CH:34]=[CH:33][C:32]([C:35]3[O:36][C:37]4[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:42][C:41]([C:47]#[N:48])=[CH:40][C:38]=4[N:39]=3)=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:47]([C:41]1[CH:42]=[C:43]([CH:44]([CH3:46])[CH3:45])[C:37]2[O:36][C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([NH:27][CH2:26][C:25]4[CH:50]=[CH:51][C:22]([C:12]5[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=5[O:10][CH:7]([CH3:9])[CH3:8])=[CH:23][CH:24]=4)=[O:49])=[CH:30][CH:31]=3)=[N:39][C:38]=2[CH:40]=1)#[N:48]
Reactant: Cc1ccc(OC(C)C)c(B(O)O)c1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCc4ccc(Br)cc4)cc3)oc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(OC(C)C)c(-c2ccc(CNC(=O)c3ccc(-c4nc5cc(C#N)cc(C(C)C)c5o4)cc3)cc2)c1
Temperature: 150 °C

Procedure:
Sodium carbonate (100 μl of a 2M aqueous solution), (2-isopropoxy-5-methylphenyl)boronic acid (19 mg), and N-(4-bromobenzyl)-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (24 mg, EXAMPLE 1) were dissolved in toluene (2.1 ml), water (0.6 ml) and ethanol (0.3 ml). To this solution was added tetrakis(triphenylphosphine)palladium(0) (9 mg). The mixture was heated to 150° C. for 25 min via microwave. Upon cooling, the mixture was concentrated in vacuo and then dissolved in dichloromethane (5 ml). The sample was transferred to a Biotage 40M column and purified via flash chromatography, eluting 1 column volume of 100% hexanes followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volume, followed by 100% ethyl acetate for 4 column volumes, to provide the title compound. Mass spectrum (ESI) 544.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.35 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.2 Hz, 2H), 7.94 (s, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.52 (s, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.13 (s, 1H), 7.09 (d, J=8.2 Hz, 1H), 6.90 (d, J=8.4 Hz, 2H), 6.47 (t, J=4.6 Hz, 1H), 4.73 (d, J=5.5 Hz, 3H), 4.40 (sept, J=6.2 Hz, 1H), 3.48 (sept, J=7.1 Hz, 1H), 2.32 (s, 3H), 1.46 (d, J=6.9, 6H), 1.24 (d, J=5.9, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=[O:13])[CH3:12])=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O>CC#N>[C:25]([O:24][C:22](=[O:23])[CH2:21][N:8]1[C:5]2=[CH:6][N:7]=[C:2]([CH3:1])[CH:3]=[C:4]2[C:10]([C:11](=[O:13])[CH3:12])=[N:9]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(=O)c1n[nH]c2cnc(C)cc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1nn(CC(=O)OC(C)(C)C)c2cnc(C)cc12

Procedure:
To a solution of 1-(5-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)-ethanone (1 g, 5.71 mmol) in CH3CN (30 mL) were added potassium carbonate (1.81 g, 13.13 mmol) and tert-butyl bromoacetate (0.927 mL, 6.28 mmol). The reaction mixture was stirred at reflux for 1 h, then poured into water and extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 3:2). TLC, Rf (c-hexane/EtOAC 1:1)=0.25; MS (UPLC/MS): 290 [M+H]+; tR (HPLC conditions f): 1.50 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]=4[NH2:41])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:24])[CH2:18][N:19](C)[C:20](=O)O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.CCOC(C)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]=4[NH2:41])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:24])[CH2:18][NH:19][CH3:20])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CN(CC(=O)N1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1)C(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC(=O)N1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a suspension of (2-(4-[4-Amino-5-(3-amino-2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-piperidin-1-yl)-2-oxo-ethyl)-methyl-carbamic acid tart-butyl ester (30 mg, 0.049 mmol) in anhydrous DCM (1.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction mixture was stirred at rt. After 1 h, the mixture was poured into EtOAc (75 mL), and the organic phase was washed with aqueous, saturated NaHCO3 solution (3×25 mL), water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Trituration with DCM-hexane afforded the title compound (24.7 mg, 98.5%) as a pink solid. 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.71 (d, 1H), 7.34 to 7.29 (m, 2H), 7.27 to 7.21 (m, 3H), 7.15 (s, 1H), 6.73 (dd, 1H), 6.54 (s, 1H), 6.37 (broad s, 2H), 5.38 (s, 2H), 4.50 (d, 1H), 3.90 (d, 1H), 3.42 to 3.27 (m, 3H), 3.13 (t, 1H), 2.76 to 2.66 (m, 1H), 2.26 (s, 3H), 2.05 to 1.99 (m, 3H), 1.68 to 1.49 (m, 2H); ES-MS m/z 510.1 [M+H]+, RT (min) 1.56.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.C([C:20]([O:22][CH3:23])=[O:21])#N>ClCCl>[CH3:23][O:22][C:20]([C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1)=[O:21]
Reactant: COC(=O)C#N
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: COC(=O)c1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 21 h
Yield: 88.9 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (4.0 g, 16.2 mmole) and methyl cyanoformate (2.75 g, 32.4 mmole) in 30 mL of dichloromethane was stirred at room temperature for 21 h. The precipitate was filtered and washed with dichloromethane to give 3.36 g (84%) of 3-(methoxycarbonyl)-1,2,4-thiadiazolo [4,5-a]benzimidazole as a colourless solid: mp 208°-209° C.; 1H NMR (CDCl3) δ8.61 (d, 1H), 7.82 (d, 1H), 7.51 (t, 1H), 7.31 (t, 1H), 4.17 (s, 3H) ppm; 13C NMR (CDCl3) δ164.02, 156.51, 150.67, 140.89, 129.34, 125.93, 122.41, 119.48, 115.41, 54.04 ppm; IR (KBr) ν1733 cm-1 ; HRMS calcd for C10H7N3O2S 233.0259, found 233.0262. Anal. Calcd. for C10H7N3O2S: C, 51.50; H, 3.02; N, 18.02. Found: C, 51.41; H, 2.89; N, 18.16.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2].Cl.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[C:22]([Cl:24])[CH:23]=1.[CH2:31](O)C>>[ClH:17].[Cl:24][C:22]1[CH:21]=[C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:2][C:1]([C:4]3[CH:5]=[N:6][N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=4)[C:8]=3[CH3:9])=[O:3])[CH2:27][CH2:26]2)[CH:19]=[C:18]([Cl:17])[CH:23]=1
Reactant: CC(=O)c1cnn(-c2ccccn2)c1C
Reactant: CCO
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Agent: Cl
Product: Cc1c(C(=O)CCN2CCN(c3cc(Cl)cc(Cl)c3)CC2)cnn1-c1ccccn1
Reaction time: 24 h

Procedure:
In 150 ml of absolute ethanol was dissolved 2.26 g of 4-acetyl-1-(2-pyridyl)-5-methylpyrazole, and 2.94 g of 1-(3,5-dichlorophenyl)piperazine hydrochloride and 0.9 g of p-formaldehyde were added to the solution, followed by refluxing for 6 hours. To the reaction mixture was further added 0.40 g of p-formaldehyde, and the refluxing was continued for an additional 24 hour period. About a half of the ethanol was removed by evaporation, and the precipitate was collected by filtration. The precipitate was dissolved in chloroform, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and the residue was subjected to column chromatography on silica gel using a mixture of chloroform-methanol (50:1 by volume) as a developing solvent. The fraction containing the desired compound was concentrated. A 1N hydrochloric acid/ethanol solution was added to the residue, followed by concentration. The residue was recrystallized from ethanol to yield 2.90 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>ClCCl.CN(C)C=O>[CH2:1]([N:8]([CH2:9][CH2:10][Cl:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCCl)Cc1ccccc1
Yield: 79.1 %

Procedure:
33 g of N-benzyl-N-methyl-2-aminoethanol were dissolved in 300 ml of dichloromethane. 48 g of thionyl chloride and 2 drops of dimethylformamide were added to the solution at 0° C. The reaction mixture was then heated under reflux for 6 hours. The reaction mixture was worked up by evaporating it to dryness and taking up the residue three times in 300 ml portions of toluene and again evaporating to dryness. The remaining residue was dissolved in dichloromethane and the N-benzyl-N-(2-chloroethyl)-N-methylamine hydrochloride was crystallized by addition of diethyl ether to the solution. The crystals (m.p. 142° C.-145° C.) were filtered out and dissolved in ice water. The solution was adjusted to alkaline pH 9 by addition of aqueous sodium hydroxide solution and then extracted with toluene. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. 29 g of N-benzyl-N-(2- chloroethyl)-N-methylamine were obtained as a residue.
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=O.O>CC(C)=O>[C:2]1([C:1]2[N:8]=[C:18]([C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NC(=NO)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: c1ccc(-c2noc(-c3cccs3)n2)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
Benzamide oxime (5.00 g, 36.7 mmol) was dissolved in acetone (50 mL) at 0° C. The solution was stirred and 50% aqueous sodium hydroxide (4.5 mL) added. An exotherm was noted and a precipitate formed in the reaction mixture. The exotherm lasted for about 15 minutes and the slurry became thick. The solution was warmed to 20° C. and external cooling was added. The 2-thiophenecarbonyl chloride (5.36, 36.7 mmol) was added over 15 minutes maintaining the reaction mixture below 30° C. The reaction was maintained at 30° C. for 15 minutes and the slurry became thinner. The reaction mixture was cooled to room temperature and stirred for 20 additional minutes. Water (50 mL) was added and the resulting solids were stirred for 1 hour. The solids were collected by vacuum filtration, washed with water (2×50 mL) and dried on a Buchner funnel with air flow from vacuum overnight. 3-Phenyl-5-(2-thienyl)-1,2,4-oxadiazole (6.94 g, 30.4 mmol) was obtained as a white solid (83% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH:10]=[C:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:1][C@H:2]2[CH2:21][CH2:20][C@@:19]3([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]4[C@@H:18]3[C:17](=[O:23])[CH2:16][C@@:15]3([CH3:24])[C@H:8]4[CH2:9][CH:10]=[C:11]3[C:12](=[O:14])[CH3:13])[CH2:3]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 97.6 %

Procedure:
A solution of 3β-hydroxy-5α-pregn-16-ene-11,20-dione (39.6 g) in dry pyridine (165 ml.) was treated with toluene-p-sulphonyl chloride (43.9 g.) to give 3β-toluene-p-sulphonyloxy-5α-pregn-16-ene-11,20-dione (56.7 g.) m.p. 147°-151°. A portion (10.7 g.) of this material was crystallised from ethyl acetate-petrol to give the pure toluenesulphonate (9.2 g.) as plates m.p. 154°-155°, [α]D + 42.8° (c 1.2).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)#[N:2].C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O.O>[C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)(=[O:22])[NH2:2]
Reactant: COC(=O)c1ccc2c(c1)-c1nc(C#N)cn1CCO2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
Methyl 2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate (220 mg, 0.82 mmol) was dissolved in 4.0 ml of dimethyl sulfoxide and treated with a solution of potassium carbonate (136 mg, 0.980 mmol) in water (1.60 mL, 88.8 mmol). After cooling at 0° C., hydrogen peroxide (0.751 mL, 9.80 mmol) was added slowly. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with 20 ml of water and extracted with ethyl acetate (3×20 ml). The oprganic extracts were washed with 5% sodium thiosufate, sat. NaHCO3, brine, dried over sodium sulfate and concentrated to give 180 mg (77%) of crude methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate. MS (ESI+): 288.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O-:3])=[O:2].C(O[C:49]1[CH:57]=[CH:56][C:52](C(O)=O)=[CH:51][CH:50]=1)CCCCCCCCCCCCC.OC1C=CC(C(OC[C@@H](C)CC)=O)=CC=1.ClC1C=C(O)C=CC=1C(OC[C@@H](C)CC)=O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:49]3[CH:57]=[CH:56][CH:52]=[CH:51][CH:50]=3)=[O:32])=[CH:27][CH:26]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: CC[C@H](C)COC(=O)c1ccc(O)cc1
Agent: CC[C@H](C)COC(=O)c1ccc(O)cc1Cl
Product: CCCCCCCCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccccc3)cc2)cc1[N+](=O)[O-]

Procedure:
The procedure of Example 1 was followed except using 3'-nitro-4'-tetradecyloxybiphenyl-4-carboxylic acid instead of said 4-tetradecyloxybenzoic acid and (S)-2-methylbutyl 4-hydroxybenzoate instead of said (S)-2-methylbutyl 2-chloro-4-hydroxybenzoate. There resulted (S)-2-methylbutyloxycarbonyl]phenyl 3'-nitro-4'-tetradecyloxybiphenyl-4-carboxylate].
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6]([NH:12][CH3:13])([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:10][C:9]([C:6]1([NH:12][CH3:13])[CH2:7][CH2:8][N:3]([O:2][CH3:1])[CH2:4][CH2:5]1)=[O:11]
Reactant: CNC1(C(=O)O)CCN(OC)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CNC1(C(=O)OC)CCN(OC)CC1

Procedure:
To a suspension of 1-methoxy-4-methylamino-piperidine-4-carboxylic acid (2.0 g, 10.63 mmol) in methanol (50 ml) at 0-10° C. was added thionyl chloride (2.29 ml, 3.76 g, 31.57 mmol) and the reaction mixture was heated at reflux overnight. After cooling, the mixture was concentrated, the residue diluted with ice water (20 ml) and neutralised with aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (4×25 ml) and dichloromethane (4×50 ml), the combined organic layers washed with aqueous sodium bicarbonate (15 ml) and brine (15 ml), dried over sodium sulfate and concentrated. Yield: 0.76 g of 1-methoxy-4-methylamino-piperidine-4-carboxylic acid methyl ester (compound P5.4) as a viscous, orange oil. The spectral data of this crude material were identical to those described above under preparation example 6, step 2.