Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[C:8]([NH:10][C:11]1[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH2:2][CH2:3][CH3:4].[CH2:27]([O:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35])[CH2:28][CH2:29][CH3:30]>>[CH2:1]([O:5][C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[C:8]([NH:10][C:11]1[CH:21]=[C:20]([NH:22][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=2[O:31][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccccc1C(=O)Nc1cc(N)ccc1C(=O)OCC
Reactant: CCCCOc1ccccc1C(=O)Cl
Product: CCCCOc1ccccc1C(=O)Nc1ccc(C(=O)OCC)c(NC(=O)c2ccccc2OCCCC)c1

Procedure:
By the procedure similar to that described in example 21, ethyl 2-(2'-n-butoxybenzamido)-4-aminobenzoate and 2-n-butoxybenzoylchloride were reacted and treated to obtain crude crystals. Recrystallization from ethanol gave ethyl 2,4-bis(2'-n-butoxybenzamido)-benzoate having a melting point between 134° - 136°C.
Reaction SMILES: [C:1]([CH:4]([C:14]1[N:22]2[C:17]([C:18](=[O:34])[NH:19][C:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)=[N:21]2)=[C:16]([CH3:35])[N:15]=1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[O:30][CH3:31])[CH2:23][C:20]1[NH:19][C:18](=[O:34])[C:17]2=[C:16]([CH3:35])[N:15]=[C:14]([CH:4]([CH:1]([OH:3])[CH3:2])[CH2:5][CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:22]2[N:21]=1
Reactant: COc1ccc(Cc2nn3c(C(CCCc4ccccc4)C(C)=O)nc(C)c3c(=O)[nH]2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(Cc2nn3c(C(CCCc4ccccc4)C(C)O)nc(C)c3c(=O)[nH]2)cc1OC

Procedure:
110 mg (0.22 mmol) of 7-(1-acetyl-4-phenylbutyl)-2-(3,4-dimethoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one are reacted analogously to Example 12 with 20 mg (0.53 mmol) of sodium borohydride to give 2-(3,4-dimethoxybenzyl)-7-[1-(1-hydroxyethyl)-4-phenylbutyl]-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Na+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C)C=O>[CH:18]1([O:1][C:2]2[CH:3]=[C:4]([CH:10]3[O:14][C:13](=[O:15])[NH:12][CH2:11]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C2CNC(=O)O2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2CNC(=O)O2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 70 %

Procedure:
7.2 mmol of 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone is dissolved in 10 ml. of absolute dimethylformamide and stirred with 7.9 mmol of sodium hydride for 1 hour at 50°. After cooling, the mixture is combined with 8.6 mmol of cyclopentyl bromide and then agitated for 2 hours at 80°. After the reaction is terminated, the dimethylformamide is withdrawn under vacuum at 40°. The residue is taken up in 100 ml. of 2 N sodium hydroxide solution and extracted three times with 150 ml. of chloroform. The combined chloroform phases are washed with water, dried, filtered, and concentrated. The residue is recrystallized from ethyl acetate/ether, thus obtaining in a 70% yield 5-(3-cyclopentoxy-4-methoxyphenyl)-2-oxazolidinone, m.p. 111°-112°.
Reaction SMILES: C(OC1C=CC(C(F)(F)F)=CC=1CNC([C@]1(C(C)C)CC(N2C(C)=CC=C2C)C=C1)=O)(C)(C)C.C([O:42][C:43]([C@@:45]1([CH:66]([CH3:68])[CH3:67])[CH2:49][CH2:48][CH:47]([N:50]2[CH2:55][CH2:54][CH:53]([C:56]3[CH:57]=[C:58]([CH:63]=[CH:64][CH:65]=3)[C:59]([O:61][CH3:62])=[O:60])[CH2:52][CH2:51]2)[CH2:46]1)=[O:44])C1C=CC=CC=1>>[CH:66]([C@:45]1([C:43]([OH:44])=[O:42])[CH2:49][CH2:48][CH:47]([N:50]2[CH2:55][CH2:54][CH:53]([C:56]3[CH:65]=[CH:64][CH:63]=[C:58]([C:59]([O:61][CH3:62])=[O:60])[CH:57]=3)[CH2:52][CH2:51]2)[CH2:46]1)([CH3:68])[CH3:67]
Reactant: COC(=O)c1cccc(C2CCN(C3CC[C@@](C(=O)OCc4ccccc4)(C(C)C)C3)CC2)c1
Agent: Cc1ccc(C)n1C1C=C[C@@](C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)(C(C)C)C1
Product: COC(=O)c1cccc(C2CCN(C3CC[C@@](C(=O)O)(C(C)C)C3)CC2)c1

Procedure:
(1S)-1-Isopropyl-3-{4-[3-(methoxycarbonyl)phenyl]piperidin-1-yl}cyclopentane carboxylic acid was synthesized as described for INTERMEDIATE 3 (procedure A, step F) using methyl 3-(1-{(3S)-3-[(benzyloxy)carbonyl]-3-isopropylcyclopentyl}piperidin-4-yl)benzoate as starting material. The desired was obtained as a 10:1 mixture of cis: trans around the cyclopentane ring.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].I[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1.Cl>C1COCC1.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.O>[F:17][C:16]([F:18])([F:19])[O:15][C:12]1[CH:13]=[CH:14][C:9]([CH:4]([C:3]#[N:7])[C:5]#[N:6])=[CH:10][CH:11]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: N#CCC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C#N)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a suspension of sodium hydride (2.87 g, 114 mmol) in THF (15 mL), malononitrile (4.77 mL, 76 mmol) in 2 mL of THF was added dropwise at 0° C. After the gas evolution ceased, 1-iodo-4-(trifluoromethoxy)benzene (5.92 mL, 37.8 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.797 g, 1.135 mmol) were added. This mixture was then heated at reflux under nitrogen overnight. The suspension was cooled to ambient temperature, treated with water, acidified with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified on silica gel (0˜30% ethyl acetate in hexanes) to give 8.2 g of product as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.48-7.65 (m, 2H) 7.37 (d, J=8.35 Hz, 2H) 5.09 (s, 1H). MS (ESI) m/z 225.1 (M−H)−.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#[CH:13].C(N(CC)CC)C>ClCCl.O.C(OCC)(=O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[CH:13]=[C:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])[O:1][N:2]=1
Reactant: C#CC(=O)OCC
Reactant: O/N=C(\Cl)c1ccccn1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccccn2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a suspension of the (Z)—N-hydroxypicolinimidoyl chloride (Preparation 63A, 8.00 g, 51.1 mmol) in dichloromethane (75 mL) in a three neck 1000 mL flask immersed in water and equipped with an addition funnel and thermometer was added ethyl propiolate (5.21 mL, 51.1 mmol). A mixture of triethylamine (8.55 mL, 61.3 mmol) and dichloromethane (20 mL) were added to the addition funnel and then slowly added to the reaction dropwise so that the temperature remained between 20 and 28° C. (by adding ice to the water bath). After the triethylamine was completely added, the reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (350 mL), washed with water, and washed with brine. The combined aqueous layers were extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. Concentration under reduced pressure followed by purification on silica gel using a 20% mixture of ethyl acetate in hexane afforded ethyl 3-(pyridin-2-yl)isoxazole-5-carboxylate (9.90 g, 45.4 mmol, 89% yield) as an off white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (t, 3H), 4.47 (q, J=7.26 Hz, 2H), 7.39 (ddd, J=7.59, 4.84, 1.21 Hz, 1H), 7.59 (s, 1H), 7.83 (td, J=7.81, 1.76 Hz, 1H), 8.13 (dt, J=7.92, 1.10 Hz, 1H), and 8.71 (ddd, J=4.84, 1.76, 0.88 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:14]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH2:15][CH3:16]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1ccc(C(C)=O)cc1
Reaction time: 0.08 h
Yield: 75.7 %

Procedure:
To 272 g (2000 mmole) of 4'-hydroxyacetophenone dissolved in 800 ml of ethanol was added 249 g (2000 mmole) of 45% aqueous potassium hydroxide. After stirring for 5 minutes, 270 g (2200 mmole) of 1-bromopropane was added and the mixture was refluxed for 6 hours. After cooling, the precipitated potassium bromide was filtered off and washed with diethyl ether. The combined organic layers were concentrated in vacuo and then redissolved in 500 ml of diethyl ether. The resulting solution was washed with 1M aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo yielding 270 g of the expected product, an oil, bp 110° C. at 1 torr.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].[OH-].[K+]>CO>[CH2:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: C=C(Cc1ccccc1)C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
The ethyl (α-methylenebenzenepropanoate of Step 8 (4.6 g, 24.3 mmol) was dissolved in methanol (12 mL) and then reacted with 2N potassium hydroxide (24 mL) solution. The mixture was stirred at room temperature for 4 hours and concentrated by evaporation. The residue was diluted with water and washed with ether. The aqueous layer was acidified to pH 2 with 1N HCl and then extracted with ethyl acetate. The extracts were dried (MgSO4) and evaporated to give the title compound as colorless oil (2.8 g, 66% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]3[CH2:14][CH2:13][CH2:12][C:9]3=[N:10][N:11]=2)=[CH:3][CH:2]=1.O=C1[CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])CCCN1.C(NN)(=O)C1C=CN=CC=1>C(Cl)Cl.CCO>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]3[CH2:14][CH2:13][CH2:12][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:9]3=[N:10][N:11]=2)=[CH:5][CH:6]=1
Reactant: c1cc(-c2nnc3n2CCC3)ccn1
Reactant: CCOC(=O)C1CCCNC1=O
Agent: NNC(=O)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1CCCn2c(-c3ccncc3)nnc21

Procedure:
The title compound was prepared analogous to 3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole from ethyl 2-oxopiperidine-3-carboxylate (2.57 g, 15 mmol), Me3OBF4 (2.66 g, 18 mmol) and isonicotinic hydrazide (2.06 g, 15 mmol) in DCM (150 ml) and EtOH (16 ml). Recrystallization from EA afforded 1.67 g (41%). 1H NMR: 1.29 (t, 3 H), 2.03 (m, 1 H), 2.14-2.25 (m, 2 H), 2.32 (m, 1 H), 4.01-4.12 (m, 1 H), 4.16-4.27 (m, 4 H), 7.64 (d, 2 H), 8.74 (d, 2 H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH:8]=1)[NH2:7].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:9][C:5]1[CH:4]=[CH:3][C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:8][C:6]=1[NH2:7]
Reactant: C1COCCN1
Reactant: Nc1cc(Br)ccc1Cl
Agent: [Pd]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(N2CCOCC2)ccc1Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-2-chloroaniline (2.0 g, 9.74 mmol), morpholine (4.3 mL, 49 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (0.37 g, 0.79 mmol), and tris(dibenzylideneacetone)dipalladium (0) (0.37 g, 0.4 mmol) in dry THF (20 mL) was degassed by nitrogen. To this mixture was added 1.0M lithium bis(trimethylsilyl)amide in THF (54 mL) dropwise, and the resulting reaction was heated to 60° C. After 2 h, the reaction was cooled to rt then cond under reduced pressure to ˜5 mL. After pouring into water, the mixture was extracted twice with EtOAc and twice with DCM. After the combined organic layers were dried over anhydrous magnesium sulfate, filtration, and concentration, the residue was purified on silica gel (0-30% EtOAc in hexanes) to yield 2-chloro-5-morpholinoaniline. 1H NMR (400 MHz, CDCl3) δ ppm 7.19 (1H, m), 6.41 (2H, m), 4.00 (2H, br. s.), 3.93 (4H, m), 3.22 (4H, m).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:44]2[CH:53]=[N:52][C:51]3[NH:50][C:49](=[O:54])[CH2:48][O:47][C:46]=3[CH:45]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:44]4[CH:53]=[N:52][C:51]5[NH:50][C:49](=[O:54])[CH2:48][O:47][C:46]=5[CH:45]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CC1(C)OB(c2cnc3c(c2)OCC(=O)N3)OC1(C)C
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: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(c4)OCC(=O)N5)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (32.0 mg, 0.061 mmol) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (20.0 mg, 0.073 mmol) in dioxane (0.5 mL) was added Pd(PPh3)4 (3.5 mg, 0.003 mmol) and 2N K2CO3 (127 μL, 0.255 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 100° C. for 10 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H32ClN4O5S: 643.2; found: 643.3.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:29])[CH2:8][C@@H:9]([NH:18]C(=O)OCC2C=CC=CC=2)[CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1>Br.C(O)(=O)C>[NH2:18][C@@H:9]([CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:7]([N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:29]
Reactant: O=C(N[C@@H](CSc1ccccc1)CC(=O)N1CCOCC1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: N[C@@H](CSc1ccccc1)CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
A suspension of (R)-benzyl 4-morpholino-4-oxo-1-(phenylthio)butan-2-ylcarbamate (INTERMEDIATE 71, 25 g, 60 mmol) in 40% HBr in acetic acid (500 ml) was stirred at room temperature for 50 hrs. The reaction mixture became homogeneous during this time. The reaction mixture was concentrated to dryness, diluted with water (400 ml) and 5% aq. HCl (200 ml) and washed with diethyl ether (3×100 ml). The aqueous phase was brought to pH ˜8-9 with solid Na2CO3 and extracted vigorously with CH2Cl2 (5×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give the title product (16.9 g, yield: almost quantitative), which was used in the preparation of Intermediate 73 without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19]Br)=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:44]([NH2:49])[CH2:45][CH2:46][CH:47]=[CH2:48].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19][NH:49][CH2:44][CH2:45][CH2:46][CH:47]=[CH2:48])=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOc1ccc(C(CC(=O)N=C(Cc2cc(Cl)c(NC(=O)CBr)c(Cl)c2)NC(=O)OC(C)(C)C)=NOCC)cc1
Reactant: C=CCCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCNCC(=O)Nc1c(Cl)cc(CC(=NC(=O)CC(=NOCC)c2ccc(OCC=C)cc2)NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-1-(3-(4-(allyloxy)phenyl)-3-(ethoxyimino)-propanoylimino)-2-(4-(2-bromoacetamido)-3,5-dichlorophenyl)ethylcarbamate (100 mg) in dichloromethane (0.30 mL) at room temperature was added pent-4-en-1-amine hydrochloride (51 mg) and diisopropylethylamine (97 μL), and the resulting solution was stirred at room temperature for 2 h. The solvents were removed in vacuo to give the title compound as a white solid, which was used in Step B without purification. retention time: 2.14 min (method A). MS (ESI) (M+H)+ 703.24.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[Cl:1])[CH:9]=2)=[O:26])=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(Br)cc2)cc1-c1c(Cl)cnn1C
Yield: 6 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-bromophenyl isocyanate in a similar manner as described in Example 1.53, providing 2.3 mg (6%) of Compound 81: LCMS m/z (%)=437 (M+H37Cl, 100), 435 (M+H35Cl, 82). 1H NMR (400 MHz, DMSO-d6) δ: 8.97 (d, J=2 Hz, 2H), 8.80 (s, 1H), 8.70 (s, 1H), 7.61 (s, 1H), 7.53 (dd, J1=12 Hz, J2=8 Hz, 1H), 7.44 (t, J=4 Hz, 2H), 7.35 (d, J=4 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 3.74 (s, 3H), 3.58 (s, 3H).
Reaction SMILES: [S:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:4])(=[O:3])[NH2:2].Cl[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[F:36])[N:20]=1>>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][S:27][C:21]1[N:20]=[C:19]([NH:2][S:1]([N:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)(=[O:3])=[O:4])[CH:24]=[C:23]([O:25][CH3:26])[N:22]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CC(C)(C)OC(=O)N1CCN(S(N)(=O)=O)CC1
Product: COc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared from 1,1-dimethylethyl 4-sulfamoylpiperazine-1-carboxylate (the product of example 15, step i), 0.22 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography on silica gel using EtOAc/isohexane (2:8) as eluent. Yield: 0.36 g
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:18](=[O:21])([OH:20])[OH:19])[P:14](=[O:17])([OH:16])[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+:24]>CO>[Na+:24].[Na+:24].[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:18](=[O:19])([O-:20])[O-:21])[P:14](=[O:15])([OH:16])[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(O)(O)C(NCCCCOc1ccccc1)P(=O)(O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=P([O-])([O-])C(NCCCCOc1ccccc1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
4-Phenoxybutylaminomethylenebisphosphonic acid (0.54 g) was suspended in methanol (20 ml), to which was added a methanol solution of sodium methoxide (28%, 0.782 g), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate was treated with acetone to give a solid matter, which was recrystallized from water-methanol to give 4-phenoxybutylaminomethylenebisphosphonic acid disodium salt 1.5 hydrate (0.56 g, 85%), m.p.>300° C.
Reaction SMILES: C([S:14][C:15]1[N:16]=[N:17][N:18]([CH2:20][C:21]#[CH:22])[N:19]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:20]([N:18]1[N:17]=[N:16][C:15]([SH:14])=[N:19]1)[C:21]#[CH:22]
Reactant: C#CCn1nnc(SC(c2ccccc2)c2ccccc2)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C#CCn1nnc(S)n1
Temperature: 50 °C
Reaction time: 1.7 h
Yield: 62.5 %

Procedure:
A mixture of 5-benzhydrylthio-2-(2-propynyl)-2H-tetrazole (1.05 g), anisole (1.79 g) and trifluoroacetic acid (9.7 ml) was stirred at 22° C. for 1.5 hours, at 35° C. for an hour, at 50° C. for 1.7 hours and then at room temperature for a further 14 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate (10 ml) and the mixture was adjusted to pH 8.5 with 2 N aqueous solution of sodium hydroxide. The aqueous layer was separated, washed with ethyl acetate (20 ml×2) and thereto was added ethyl acetate. The resulting mixture was adjusted to pH 2.5 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated to give an oil of 2-(2-propynyl)-2H-tetrazole-5-thiol (0.3 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH:55]2[CH2:57][O:56]2)=[CH:49][CH:48]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:26][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][NH:17][C:15]([N:12]2[CH2:11][CH2:10][CH:9]([NH:8][C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:57][C@H:55]([OH:56])[CH2:54][O:53][C:50]4[CH:51]=[CH:52][C:47]([OH:46])=[CH:48][CH:49]=4)=[CH:28][CH:27]=3)[CH2:14][CH2:13]2)=[O:16])[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCCc3cccc(F)c3)CC2)cc1
Product: O=C(NCCc1cccc(F)c1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 41.4 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(3-fluorophenethyl)-1-piperidinecarboxamide (0.622 g, 1.62 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane 0.556 g, 1.40 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.46 g, 0.580 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([O:10]CC)=[O:9].CO.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C)c(C(=O)O)[nH]1
Temperature: 75 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of ethyl 3,5-dimethyl-2-pyrrolecarboxylate (Aldrich) (504 mg, 3 mmol) in THF/H20/MeOH (5:1:1, 30 ml) was added NaOH (480 mg, 12 mmol) in H20 (12 ml). The mixture was stirred at 75° C. overnight. The homogeneous mixture was washed with ether. To the aqueous layer was added a saturated aqueous KHSO4 solution until the pH was about 3. The solution was then extracted with dichloromethane. The extracts were dried over MgSO4 and evaporated. The residue was purified on silica (ethylacetate/methanol 90/10) to give the title compound (375 mg, 90%).