Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7]([CH:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](OCC)=[NH:24])=[CH:17][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])[CH3:5].[CH2:28](N)[CH2:29][NH2:30].Cl>O>[CH2:13]([O:12][C:10]([CH:9]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[NH:24][CH2:28][CH2:29][N:30]=2)=[CH:19][CH:20]=1)[C:7]([O:6][CH2:4][CH3:5])=[O:8])=[O:11])[CH3:14]
Reactant: CCOC(=N)COc1ccc(C(C(=O)OCC)C(=O)OCC)cc1
Reactant: NCCN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OCC2=NCCN2)cc1
Yield: 54.8 %

Procedure:
With ice cooling and stirring, 40 ml of ethanol solution containing 3.6 g of ethyl 2-ethoxycarbonyl-2-[4-(2-ethoxy-2-iminoethoxy)phenyl)acetate obtained in the above step b) was added dropwise to a 10 ml ethanol solution containing 0.6 g of ethylenediamine, and the resulting mixture was stirred at room temperature for 1.5 hours, followed by refluxing under heating for 0.5 hours. After cooling, the resulting reaction solution was adjusted to an acidic pH with ethanol containing 13% (w/v) of hydrochloric acid, and then concentrated to dryness. The residue thus obtained was dissolved in water and washed with diethyl ether. Thereafter, the resulting water layer was adjusted to pH 9-10 with dilute sodium hydroxide aqueous solution, and crystals thus precipitated were collected by filtration. In this way, 1.83 g of the title compound was obtained in the form of colorless crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][C:18](B(O)O)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[NH:13][CH:14]=[CH:15]4)[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nccc2ccc(-c3ccc4[nH]ccc4c3)cc12
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A mixture of 7-bromo-1-chloroisoquinoline (0.50 g, 2.1 mmol), 5-indoleboronic acid (0.40 g, 2.5 mmol), tetrakis(triphenylphosphene)palladium (0.035 g, 0.08 mmol), potassium carbonate (2.1 mL, 2 M, 4.1 mmol), N,N-dimethylformamide (11 mL) was stirred while purging the headspace with argon for 30 min. The mixture was then brought to reflux for 16 h before being allowed to cool to RT. The mixture was filtered through a bed of silica gel, diluted with water (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was separated and washed with NaOH (2×20 mL, 10% aq.), water (5×30 mL, until refractive changes were no longer seen at the organic-aqueous interface), and ammonium chloride (20 mL, sat.). The organic layer was then adsorbed onto silica gel and flash-chromatographed (ethyl acetate/hexanes) to afford 0.14 g (25%) of a yellow solid. MS (ESI): calculated for C17H11ClN2, 278.1. Found 301.0 [M+Na]+. 1H NMR (300 MHz, DMSO-d6) δ 6.56-6.58 (m, 1H), 7.44 (t, J=2.77 Hz, 1H), 7.57-7.59 (m, 2H), 7.93 (m, 1H), 8.04 (s, 1H), 8.13-8.20 (m, 1H), 8.27-8.31 (m, 2H), 8.43 (m, 1H), 11.25 (brs, 1H).
Reaction SMILES: N12CCCN=C1CCCCC2.[O:12]=[C:13]1[CH2:19][CH:18](S(C2C=CC=CC=2)(=O)=O)[C:17]2[CH:29]=[C:30]([C:33]([O:35][CH3:36])=[O:34])[CH:31]=[CH:32][C:16]=2[O:15][CH2:14]1.O.Cl>ClCCl>[O:12]=[C:13]1[CH:19]=[CH:18][C:17]2[CH:29]=[C:30]([C:33]([O:35][CH3:36])=[O:34])[CH:31]=[CH:32][C:16]=2[O:15][CH2:14]1
Reactant: COC(=O)c1ccc2c(c1)C(S(=O)(=O)c1ccccc1)CC(=O)CO2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(c1)C=CC(=O)CO2

Procedure:
0.084 ml (1.05 equivalents) of 1,8-diazabicyclo[5.4.0]undec-7-ene is added at ambient temperature to 217 mg (0.6 mmol) of methyl 3-oxo-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate, prepared according to example 2, in suspension in 20 ml of dichloromethane. From the addition of the base, the medium becomes translucent and slightly yellow. After addition of water and 1N hydrochloric acid, the phases are separated by settling and then the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with a saturated sodium hydrogencarbonate solution and then with brine. After drying and then concentrating under vacuum, 90 mg (68%) of methyl 3-oxo-2,3-dihydro-1-benzoxepin-7-carboxylate are obtained in the form of a white solid; M.p.=89–93° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Br:1][C:2]1[CH:7]=[C:6]([S:16]([Cl:15])(=[O:18])=[O:17])[CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:11])[F:12]
Reactant: O=C(Nc1ccccc1Br)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=C(Nc1ccc(S(=O)(=O)Cl)cc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
3.0 g N-(2-Bromo-phenyl)-2,2,2-trifluoro-acetamide was added in three portions to 3.74 mL (5.0 equiv.) chlorosulfonic acid under cooling in an ice-bath. The ice-bath was removed, the mixture was warmed to room temperature, and subsequently stirred for 1 hour at 80° C. After cooling, the clear brown reaction mixture was poured into ice and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness to give 3.36 g (80%) of an oil that solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J=9.0, 2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.69 (d, J=9.0 Hz, 1H), 8.71 (br.s., 1H).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:7]=3[C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[NH:22][CH3:23]>>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[N:22]([CH3:23])[C:15]([C:13]1[S:14][C:7]2[C:6]3[CH:5]=[C:4]([F:18])[CH:3]=[C:2]([F:1])[C:11]=3[O:10][CH2:9][C:8]=2[CH:12]=1)=[O:17]
Reactant: CNc1ccccc1Cl
Reactant: O=C(O)c1cc2c(s1)-c1cc(F)cc(F)c1OC2
Product: CN(C(=O)c1cc2c(s1)-c1cc(F)cc(F)c1OC2)c1ccccc1Cl

Procedure:
Following the procedure of Example 70 and General Procedure B, 142bp was prepared from 6,8-difluoro-4H-thieno[3,2-c]chromene-2-carboxylic acid and 2-chloro-N-methylaniline. MS: (ESI+)=392.1
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:31][CH:30]([CH2:32][C:33](OC)=[O:34])[CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH:30]5[CH2:31][O:28][CH2:29]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: COC(=O)CC1COC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1COC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (99 mg, 92%), MS (ISP) m/z=429.4 [(M+H)+], mp 195° C., was prepared in accordance with the general method of example 2 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl 2-(oxetan-3-yl)acetate.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[CH3:12])(=[O:3])[CH3:2].O.C[C:15]([N:17](C)C)=O>[C-]#N.[Zn+2].[C-]#N.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:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]#[N:17])=[CH:7][C:6]=1[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Br)cc1C
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(=O)Oc1ccc(C#N)cc1C
Temperature: 100 °C
Yield: 99 %

Procedure:
A solution of 4-bromo-2-methylphenyl acetate (6.9 g, 30 mol) in 75 mL of anhydrous dimethyl acetamide was treated with zinc cyanide (3 g, 25.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.5 g, 3.9 mmol). The reaction mixture was heated at 100° C. for 2 hours, cooled to room temperature, and treated with 300 mL of cold water. The resulting precipitate was filtered, washed with water, and air dried. Chromatography on SiO2 (100% dichloromethane) afforded 5.2 g of 4-cyano-2-methylphenyl acetate as a colorless oil (99% yield), which solidified on standing.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:11]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[F:40])([C:31]#[N:32])[CH:10]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH:9]1)=[O:7])(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:11]2([C:31]#[N:32])[CH:10]([CH2:41][C:42]([CH3:43])([CH3:44])[CH3:45])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH2:22][OH:23])=[C:34]([F:40])[CH:35]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(Cl)ccc2OCCO[Si](C)(C)C(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cc(Cl)ccc2OCCO)C1(C#N)c1ccc(Cl)cc1F
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 84b (1.0 g, 1.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-[5-chloro-2-(2-hydroxy-ethoxy)-phenyl]-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 98%).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[C:8]([OH:29])([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[C:7]1=[O:30])[CH3:2].[OH-:33].[K+]>C(O)(C)(C)C>[CH2:31]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:17]([F:18])([F:19])[F:20])[CH:11]=[C:12]([C:15](=[O:33])[NH2:16])[CH:13]=2)[C:8]([OH:29])([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[C:7]1=[O:30])[CH3:32]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc(Cl)cc2Cl)c2c1cc(C#N)cc2C(F)(F)F
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc(Cl)cc2Cl)c2c1cc(C(N)=O)cc2C(F)(F)F
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-cyano-3-hydroxy-3-(2,4-dichlorophenyl)oxindole (315 mg, 0.648 mmol) in t-butanol (5 mL) was added powdered KOH (ca. 300 mg) at 50° C. The mixture was stirred for 30 min at the same temperature and passed through a celite pad. The celite was washed with THF and the filtrate was concentrated. The residue was dispersed between water and ethyl acetate and the organic layer was separated. The organic layer was dried over MgSO4 and concentrated to give the title compound (248 mg, 66%). The compound was dissolved in dioxane (2.5 mL) and 4 N HCl in dioxane (0.5 mL) was added. The solvent was evaporated azeotropically with toluene to dryness to give the hydrochloride (331 mg, 94%).
Reaction SMILES: CO[N:3](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:4]1[NH:5][C:6](=[O:20])[C:7]2[N:8]=[CH:9][N:10]([CH2:13][CH2:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])[C:11]=2[N:12]=1.[C:40](Cl)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]>N1C=CC=CC=1>[C:40]([O:19][CH2:18][CH:15]([CH2:16][O:17][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:14][CH2:13][N:10]1[CH:9]=[N:8][C:7]2[C:6](=[O:20])[NH:5][C:4]([NH2:3])=[N:12][C:11]1=2)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]
Reactant: CON(c1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCC(CCn1cnc2c(=O)[nH]c(N)nc21)COC(=O)C(C)(C)C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
To a solution of N2-monomethoxytrityl-9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (0.47 g, 0.9 mmol) in pyridine (4.5 ml) was added pivalyl chloride (0.55 ml, 4.5 mmol) and the solution was stirred for 45 minutes. The mixture was precipitated in water (45 ml) and the resulting precipitate was stirred in 80% acetic acid (10 ml) at 80° for 20 minutes. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with chloroform-methanol (10:1) to afford 9-(4-pivalyloxy-3-pivalyloxymethylbut-1-yl)guanine (0.22 g, 58%), m.p. 225-237° C.; νmax (KBr) 3430, 2980, 1730, 1690, and 1620 cm−1; δH [(CD3)2SO] 1.11 (18H, s, 2×C(CH3)3), 1.81 (2H, q, J 6.8 Hz, 2′-H), 1.93 (1H, m, 3′-H), 4.0-4.1 (6H, m, 1′-H and 2×4′-H), 6.38 (2H, s, 2-NH2), 7.69 (1H, s, 8-H), and 10.58 (1H, br.s, 1-H); (Found: C, 56.58; H, 7.26; N, 16.14%; C20H31N5O5 requires: C, 56.99; H, 7.41; N, 16.62%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([CH3:17])[CH:15]=1)[CH3:12]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: Cc1cccc(C[Mg]Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)Cc1cccc(C)c1
Temperature: -78 °C

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (1.80 mL, 10.1 mmol) in THF (20 mL) was added slowly a THF solution of (72) prepared above at −78° C. After stirring at −78° C. for an hour, to this was added 20% aqueous solution of ammonium chloride (10 mL) and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=9/1) to give 1,1-diethoxy-3-(3-methylphenyl)propan-2-one (73) as a colorless oily substance (1.38 g, 5.84 mmol, 58.0%).
Reaction SMILES: Cl(O)(=O)(=O)=O.CO[CH:8]=[C:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1.Cl.[O:18]([NH2:20])[CH3:19]>C(Cl)(Cl)Cl.O.CO>[CH3:19][O:18][N:20]=[CH:8][CH:9]1[CH:14]2[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]2)[CH2:10]1
Reactant: CON
Reactant: COC=C1CN2CCC1CC2
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CON=CC1CN2CCC1CC2

Procedure:
11 cm3 of a 70% aqueous solution of perchloric acid is added at ambient temperature to 4.6 g of 3-methoxy methylidene quinuclidine (Heterocycles 244, 4-971 (1986)) in solution in 46 cm3 of chloroform. After one hour of contact, 2.5 g of methoxylamine hydrochloride in 10 cm3 of water and 10 cm3 of methanol is added and the reaction medium is maintained in this way for one night, and is then concentrated, alkalized with 2N sodium hydroxide, extracted with ethyl acetate; the solvents are evaporated, and the residue is taken up in ethyl ether and filtered. The filtrate is distilled at 150° C. under 0.08 mbar and 3.2 g of expected product is obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[NH2:24]>>[CH3:20][O:21][C:22](=[O:27])[C:23]([NH:24][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:26])[CH3:25]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(-c2cc[nH]n2)c(OCC2CC2)n1
Product: COC(=O)C(C)(C)NC(=O)c1ccc(-c2cc[nH]n2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(1H-pyrazol-3-yl)-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 359.1 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(OCN1C2N=CN=C(C3C=NN([CH:29]([O:31][CH2:32][CH3:33])[CH3:30])C=3)C=2C=C1)(=O)C(C)(C)C.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:29]([O:31][CH2:32][CH2:33][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[CH3:30]
Reactant: Ic1cn[nH]c1
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOCCn1cc(I)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A 22 L 4-neck flask equipped with an mechanical stirrer, thermowell, N2 inlet and condenser was charged with 4-iodo-1H-pyrazole (14, 1.00 Kg, 5.16 mol) and toluene (10 L) and ethyl vinyl ether (18, 557 g, 740 mL, 7.73 mol, 1.5 equiv) was added. To the suspension 4 M HCl in dioxane (32 mL, 0.128 mol, 0.025 equiv) was added over 5 min with formation of a slightly thicker white suspension. The mixture was heated carefully to 35-40° C. at which point a mild exotherm to about 40° C. occurred with rapid dissolution of all solids to give a clear light yellow solution. The reaction mixture was heated at about 40° C. for an additional 0.5 hr until the GC analysis indicated the reaction was complete. The solution was allowed to cool to 25-30° C. and solid NaHCO3 (108 g, 1.29 mol, 0.25 equiv) was added. The suspension was stirred for 1 hr at room temperature to ensure the complete neutralization of HCl. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residual liquid was fractionally distilled to afford 1-(ethoxyethyl)-4-iodo-1H-pyrazole (20, 1.346 Kg, 1.373 Kg theoretical, 98%) as a pale yellow liquid (bp 89-93° at about 1 torr). For 20: 1H NMR (CDCl3, 250 MHz) δ ppm 7.61 (s, 1H), 7.47 (s, 1H), 5.46 (q, 1H, J=6.0 Hz), 3.48-3.23 (m, 2H), 1.60 (d, 3H, J=6.0 Hz), 1.11 (t, 3H, J=7.0 Hz); C7HHIN2O (MW, 266.08), LCMS (EI) m/e 267 (M++H).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:18]1([C@H:16]([N:11]2[C@@H:10]3[C@@H:13]([CH2:14][CH2:15][NH:8][CH2:9]3)[CH2:12]2)[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H](c1ccccc1)N1CC2CCN(C(=O)OC(C)(C)C)CC21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccccc1)N1C[C@@H]2CCNC[C@@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the minor isomer product of Example 3E (9.3 g, 29.4 mmol) in 40 mL CH2Cl2 at 0° C. was added 20 mL trifluoroacetic acid. The ice bath was removed after the addition and the mixture stirred at ambient temperature for 3 h then was concentrated under reduced pressure and the residue was purified via column chromatography (SiO2, 1% NH4OH:9% CH3OH:90% CH2Cl2) to give the title compound. MS (DCl/NH3) m/z 217 (M+H)+.
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:29])=[NH:6]>[Ni].CO.O>[ClH:28].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[N:19]=[C:18]1[NH2:29])(=[NH:4])[NH2:6]
Reactant: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccc(Cl)cc2)nc1N
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CO
Product: N=C(N)c1cccc2c1CCC2=Nn1cc(-c2ccc(Cl)cc2)nc1N

Procedure:
Analogously to Example 2, 0.2 g of Raney nickel is added to a solution of 1.0 g (2.024 mmol) of 1-[4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-4-(4-chlorophenyl)-irnidazole dihydrochloride in 35 ml of methanol and 20 ml of water, and hydrogenation is carried out at room temperature and under normal pressure until the absorption of hydrogen has ceased. The reaction mixture is then diluted with 50 ml of methanol and filtered. The filtrate is adjusted to pH 3 with a small amount of 3N methanolic hydrochloric acid and is concentrated to a volume of approximately 30 ml. After cooling in an ice-bath, the product that has crystallized out is filtered off, washed with a small amount of methanol and diethyl ether and dried under a high vacuum at 120° C. The title compound is obtained in the form of the monohydrate, m.p. 245°-250° C. (decomp.), 1H-NMR (DMSO/D2O): δ=8.33 (d, 1H); 8.12 (s, 1H); 7.79-7.87 (m, 3H); 7.67 (t, 1H); 7.57 (d, 2H); 3.38 (s, 4H).
Reaction SMILES: B(Br)(Br)Br.Cl.[CH:6]1([CH2:9][N:10]2[CH2:29][CH2:28][C@:17]34[C:18]5[C:19]6[O:27][C@@:16]3([CH3:30])[C:15](=[O:31])[CH2:14][CH2:13][C@@:12]4([O:32][CH2:33][CH2:34][CH3:35])[C@H:11]2[CH2:24][C:23]=5[CH:22]=[CH:21][C:20]=6[O:25]C)[CH2:8][CH2:7]1.[NH4+].[OH-]>C(Cl)Cl>[CH:6]1([CH2:9][N:10]2[CH2:29][CH2:28][C@:17]34[C:18]5[C:19]6[O:27][C@@:16]3([CH3:30])[C:15](=[O:31])[CH2:14][CH2:13][C@@:12]4([O:32][CH2:33][CH2:34][CH3:35])[C@H:11]2[CH2:24][C:23]=5[CH:22]=[CH:21][C:20]=6[OH:25])[CH2:7][CH2:8]1
Reactant: CCCO[C@@]12CCC(=O)[C@]3(C)Oc4c(OC)ccc5c4[C@@]31CCN(CC1CC1)[C@@H]2C5
Agent: BrB(Br)Br
Agent: Cl
Agent: [NH4+]
Solvent: ClCCl
Product: CCCO[C@@]12CCC(=O)[C@]3(C)Oc4c(O)ccc5c4[C@@]31CCN(CC1CC1)[C@@H]2C5
Temperature: 2.5 °C
Reaction time: 0.83 h
Yield: 70.9 %

Procedure:
A 1 M solution of boron tribrornide in CH2Cl2 (7.3 ml) was added at once to an ice-cooled solution of the compound 16 (480 mg, 0.97 inmol) in 50 ml of CH2Cl2. After 50 min stirring at 0-5° C., a mixture of 13 g ice and 3 ml conc. NH4OH was added. The resulting mixture was stirred at room temperature for 30 min and the extracted with CH2Cl2 (3×30 ml). The combined organic layers were washed with brine (45 ml), dried over Na2SO4 and evaporated. The residue (204 mg slightly brown foam) was treated with 0.5 ml hot MeOH to afford 302 mg (55%) of 17-(cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-5-methyl-14-n-propyloxymorphinan-6-one (compound 17). M.p. 184-186° C. IR (KBr): 3390 (OH), 1720 (CO)cm-1. CI-MS: m/z 397 (M+ +1). 1H-NMR (CDCl3): δ 10.24 (broad s, OH), 6.73 (d, J=8.2 Hz, 1 arom. H), 6.65 (d, J=8.2 Hz, 1 arom. H)1.62 (s, CH3 --C(5)), 1.00 (t,J=7.3 Hz, CH3). Analysis calculated for C24H31NO4. 0.6 MeOH (416.74): C 70.90, H 8.08, N 3.36; found: C 70.76, H 7.73, N 3.52.