Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH3:3].[H-].[Na+].[CH3:6][C:7]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:12]2[C:8]=1[CH:9]=[N:10][NH:11]2>CN(C=O)C>[CH2:2]([N:11]1[C:12]2[C:8](=[C:7]([CH3:6])[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=2)[CH:9]=[N:10]1)[CH3:3].[CH2:2]([N:10]1[CH:9]=[C:8]2[C:12]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:7]2[CH3:6])=[N:11]1)[CH3:3]
Reactant: CCI
Reactant: Cc1cc([N+](=O)[O-])cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc2c(C)cc([N+](=O)[O-])cc2n1
Product: CCn1ncc2c(C)cc([N+](=O)[O-])cc21

Procedure:
Iodoethane (1.2 mL) and sodium hydride (60% in oil; 600 mg) were added to a solution of 4-methyl-6-nitro-1H-indazole (1.77 g), which can be synthesized by the method described in Patent No. WO 2009/084695, in DMF (17 mL), and the reaction solution was stirred at room temperature for 15 minutes. After dilution with ethyl acetate, the reaction solution was washed with water twice and then with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 1-ethyl-4-methyl-6-nitro-1H-indazole and 2-ethyl-4-methyl-6-nitro-2H-indazole as a light yellow solid, respectively.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C[Sn](C)(C)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[BH4-].[Na+]>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: Brc1ccc2cnccc2c1
Agent: [BH4-]
Agent: [Na+]
Product: c1ccc(-c2ccc3c(c2)CCNC3)nc1

Procedure:
In close analogy to the procedure described above, 6-Bromo-isoquinoline is reacted with 2-trimethylstannyl-pyridine and sodium borohydride to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:23]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:19][CH2:18]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: CC1(C)OB(c2cc(C(F)(F)F)ccc2OCC2CC2)OC1(C)C
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-Cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c9) the title compound is obtained as off-white solid.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[CH:9]([NH2:11])=O.C(Cl)Cl.CO.[NH4+:17].[OH-]>>[C:4]([C:3]1[NH:11][CH:9]=[N:17][CH:2]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C(=O)CBr
Reactant: NC=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cnc[nH]1
Yield: 21 %

Procedure:
Reaction of 1-bromo-3,3-dimethyl-butan-2-one (3.0 g, 16.80 mmol), and formamide (4.7 mL, 117.20 mmol), followed by chromatography (CH2Cl2/MeOH/NH4OH 94:3:3) gave the title compound (450 mg, 21%) as a yellow foam. 1H NMR (300 MHz, CDCl3) δ 1.29 (s, 9H), 6.77 (s, 1H), 7.57, (s, 1H). ES-MS m/z 125 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([NH:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:24][C:25]([C:27]2[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])=[CH:4][CH2:3]1.IC.[C:37]([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:17]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH3:37])([CH3:15])[CH3:16])[CH:11]=[CH:10][C:9]=2[NH:24][C:25]([C:27]2[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])=[CH:4][CH2:3]1
Reactant: O=C([O-])O
Reactant: CC1(C)CC=C(c2cc(C(C)(C)NCCS(C)(=O)=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCS(C)(=O)=O)C(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.1 %

Procedure:
A mixture of 4-cyano-1H-imidazole-2-carboxylic acid {2-(4,4-dimethyl-cyclohex-1-enyl)-4-[1-(2-methanesulfonyl-ethylamino)-1-methyl-ethyl]-phenyl}-amide (as prepared in Example 18, 8.0 mg, 0.017 mmol), iodomethane (25 μL, 0.40 mmol) and solid NaHCO3 (25 mg, 0.30 mmol) in 1.0 mL of THF was stirred at RT for 6 h. The solvent was removed by evaporation and the residue was purified by silica gel chromatography (0-2% MeOH/DCM) to afford the title compound (5.0 mg, 61%) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 11.90 (s, 1H), 9.63 (s, 1H), 8.31 (d, 1H, J=8.6 Hz), 7.75 (s, 1H), 7.41 (dd, 1H, J=8.6, 2.3 Hz), 7.28 (d, 1H, J=2.3 Hz), 5.77 (m, 1H), 3.11 (t, 2H, J=7.1 Hz), 2.87 (s, 3H), 2.84 (t, 2H, J=6.0 Hz), 2.29 (m, 2H), 2.24 (s, 3H), 2.11 (m, 2H), 1.60 (t, 2H, J=6.3 Hz), 1.40 (s, 6H), 1.11 (s, 6H). Mass spectrum (ESI-neg, m/z): Calcd. for C26H35N5O3S, 496.3 (M−H). found 496.1.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[NH2:15][C:14]1[CH:16]=[CH:17][C:11]([F:10])=[CH:12][C:13]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1ccccc1
Product: Nc1ccc(F)cc1C(=O)c1ccccc1
Yield: 37.9 %

Procedure:
The procedure was in the same manner as described in example 15, except that the starting material was benzoic acid instead of p-chlorobenzoic acid and 4-fluoroaniline instead of 4-chloroaniline. The title compound was obtained as yellow needle crystal, and yield 37.9%, m.p. 112-113° C.
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(O)(=O)C.C(O[C:35]1(O[Si](C)(C)C)[CH2:37][CH2:36]1)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][N:19]([CH:35]2[CH2:37][CH2:36]2)[C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=C(CNc1ccc(O)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(CN(c1ccc(O)cc1)C1CC1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-piperonylpiperazin-1-yl)-2-(4-hydroxyphenylamino)ethanone (1.00 g, 2.7 mmol) in methanol (10 mL) were added acetic acid (1.55 mL, 27 mmol), molecular sieves 3A1/16 (1.00 g), [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.653 mL, 3.2 mmol) and sodium cyanoborohydride (770 mg, 12 mmol). The resulting solution was stirred for 16 hours at 60° C. This reaction solution was filtered and concentrated, and to the residue were added ethyl acetate and water. The aqueous layer was adjusted to pH 10 using aqueous 6 N sodium hydroxide. This layer was stirred for some time, and once insoluble matter had dissolved, the ethyl acetate layer was removed, and washed with aqueous 2 N sodium hydroxide and a saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 770 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:6])[O:4][CH3:5].[H-].[Na+].[H][H].[Br:19]N1C(=O)CCC1=O>C1C=CC=CC=1>[CH3:1][O:2][P:3]([CH:7]([Br:19])[C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:6])[O:4][CH3:5]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: [H][H]
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCC(=O)C(Br)P(=O)(OC)OC
Reaction time: 0.25 h

Procedure:
A solution of 0.31 ml of dimethyl-(2-oxo-heptyl)phosphonate in 4 ml of benzene was added dropwise to a suspension of 43 mg of 80% sodium hydride in 5 ml of dry benzene until there was no more evolution of hydrogen. An hour afterwards, 0.255 g of N-bromosuccinimide was added and the mixture stirred for 15 minutes, giving the carbanion of dimethyl-(1-bromo-2-oxo-heptyl)-phosphonate. The aldehyde was then added and stirring continued for another 15 minutes. The organic phase was washed with water, a 5% aqueous solution of NaH2PO4, and again with water until the washing were neutral, and the organic phase was evaporated to dryness. The residue, 0.6 g, was chromatographed on 20 g of silica gel to give 0.335 g of dl-5β-(2'-bromo-3'-oxo-oct-1'-trans-1'-enyl)-2α,4α-dihydroxycyclopentane-1α-acetic acid-γ-lactone-4-acetate, m.p. 121°-123° C.; λmaxMeOH 241 mμε= 11,700 (72% yield), by elution with benzene-ethyl ether (90:10 ).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13]
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])c(F)c1
Reaction time: 24 h
Yield: 67 %

Procedure:
A mixture of 3-fluoro-4-nitrophenol (3.0 g, 19 mmol), 2-(dimethylamino)ethyl chloride hydrochloride (3.0 g, 21 mmol) and potassium carbonate (5.4 g, 39 mmol) in 2-butanone (75 mL) was heated to reflux for 20 hours. An additional portion of 2-(dimethylamino)ethyl chloride hydrochloride (2.0 g, 14 mmol) was added, and stirring at reflux proceeded for 24 hours. The mixture was cooled and evaporated under vacuum, and the residue was partitioned between ethyl acetate (100 mL) and water (150 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (3×150 mL) and extracted into dilute aqueous HCl (3×75 mL). The combined aqueous extracts were washed with ethyl acetate (2×100 mL) and basified (NaOH), and the resulting mixture was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (3×100 mL), dried (MgSO4), and evaporated, providing 2.9 g as a yellow oil, in 67% yield; 1H NMR (CDCl3) δ 2.34 (s, 6H), 2.76 (t, J=5.5 Hz, 2H), 4.13 (t, J=5.5 Hz, 2H), 6.72-6.81 (m, 2H), 8.09 (t, J=9.1 Hz, 1H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][CH3:3].[Br:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13](Cl)[S:14][C:10]=2[CH:9]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([CH:2]([CH3:3])[C:1]([O:5][CH3:6])=[O:4])[S:14][C:10]=2[CH:9]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: CCC(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)c1nc2ccc(Br)cc2s1
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a solution of methyl propionate (0.088 mL, 0.89 mmol) and 6-bromo-2-chlorobenzo[d]thiazole (221 mg, 0.89 mmol) in degassed toluene (5 mL) at brine/ice bath temperature was slowly added 1.0 M NaHMDS in THF (2.22 mL, 2.22 mmol). After the addition was complete, the reaction was stirred for 10 min. The mixture was then quenched with satd. NH4Cl (15 mL) then extracted with EtOAc (2×20 mL). The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexane to give Compound R3a (198 mg, 0.66 mmol, 74% yield) as a yellow solid. LCMS=1.0 min using analytical method (M), 302.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=1.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.7, 1.9 Hz, 1H), 4.30 (q, J=7.3 Hz, 1H), 3.78 (s, 3H), 1.75 (d, J=7.3 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO>[CH3:22][N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(Cc2ccccc2)CC1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reaction time: 4 h
Yield: 85 %

Procedure:
tert-Butyl 1-benzylpiperidin-4-yl(methyl)carbamate (1.0 g, 3.289 mmol, 1.0 eq.) was dissolved in MeOH (15 ml) and degassed with argon. Pd/C (300 mg) was then added and hydrogenation was carried out for 4 hours. After monitoring by TLC, the reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure. The crude product was used in the next stage without being purified further. Yield: 85% (600 mg, 2.803 mmol)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][N:16]([CH2:26][CH3:27])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]([CH2:26][CH3:27])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(C)=O)CC3)nc21
Temperature: 90 °C
Yield: 88.7 %

Procedure:
Ethyl 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-8-ethyl-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate (5.0 g) was dissolved in 35 ml of a 10% aqueous solution of sodium carbonate by heating at 90°C for 30 minutes. The resulting solution was filtered to remove the insoluble material, and the filtrate was neutralized with acetic acid to give a precipitate which was collected and recrystallized from a mixture of benzene and chloroform. There is obtained 4.1 g of the product, m.p. 298° - 300°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Br:24])[C:21]=1[O:22]C)[C:5]([N:7]1[CH2:12][CH2:11][O:10][C:9]2[N:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:8]1=2)=[O:6].[Br-].[Li+].N1CCNCC1>>[Br:24][C:20]1[CH:19]=[C:4]([CH:3]=[C:2]([Br:1])[C:21]=1[OH:22])[C:5]([N:7]1[CH2:12][CH2:11][O:10][C:9]2[N:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:8]1=2)=[O:6]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(C#N)cc32)cc1Br
Agent: C1CNCCN1
Agent: [Br-]
Agent: [Li+]
Product: N#Cc1cnc2c(c1)N(C(=O)c1cc(Br)c(O)c(Br)c1)CCO2
Yield: 78.8 %

Procedure:
By the same method as in the step f) of Example 22, 1-(3,5-dibromo-4-methoxy-benzoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-carbonitrile (12 mg, 0.026 mmol) was reacted with lithium bromide (LiBr) (4.62 mg, 0.053 mmol) and piperazine (3.4 mg, 0.0399 mmol) to obtain the target compound 47-2, i.e., 1-(3,5-dibromo-4-hydroxy-benzoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-carbonitrile as white solid (9 mg, 78%).
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[CH:30]1(O)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[F:29][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:25]=[C:24]([C:26]([O:28][CH:38]4[C:39]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:35][CH2:36][CH2:37]4)=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: OC1CCCc2ccccc21
Reactant: O=C(O)c1cccc(N2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(OC1CCCc2ccccc21)c1cccc(N2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(4-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperazin-1-yl)-pyridine-2-carboxylic acid (150 mg) in dichloromethane (5 ml) are added, at room temperature, 1,2,3,4-tetrahydronaphthalen-1-ol (70 mg), 4-dimethylaminopyridine (4.4 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (104 mg). The mixture is stirred at room temperature overnight, and then water is added. The aqueous phase is removed and extracted with ethyl acetate, and then the combined organic phases are dried over sodium sulphate. The solids are filtered off and the solvent is distilled off. The residue is purified by chromatography. This gives 1,2,3,4-tetrahydronaphthalen-1-yl 6-(4-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperazin-1-yl)pyridine-2-carboxylate (70 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:22])[CH:3]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([NH:37][C:38](=[O:40])[CH3:39])[CH2:32]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]2[CH2:36][CH2:35][CH2:34][C@H:33]([NH:37][C:38](=[O:40])[CH3:39])[CH2:32]2)=[O:7])=[C:4]([NH:11][C:12]2([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:22])[CH:3]=1
Reactant: CC(=O)N[C@H]1CCCNC1
Reactant: O=C(O)c1ccc(Br)cc1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCCN(C(=O)c2ccc(Br)cc2NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Yield: 17.6 %

Procedure:
The mixture 4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid (150 mg, 0.298 mmol), (S)-N-Piperidin-3-yl-acetamide (63 mg, 0.446 mmol), EDC.HCl (85 mg, 0.446 mmol), HOBt (60 mg, 0.446 mmol) and DIPEA (154 mg, 1.190 mmol) in dichloro-methane (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give 33 mg N-((S)-1-{4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoyl}-piperidin-3-yl)-acetamide as yellow solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:11][CH2:12][CH2:13][O:14][CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17].[NH3:24]>C(O)C>[CH2:19]([O:18][P:16]([CH2:15][O:14][CH2:13][CH2:12][O:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:24])([O:21][CH2:22][CH3:23])=[O:17])[CH3:20]
Reactant: N
Reactant: CCOP(=O)(COCCOn1cnc2c(Cl)ncnc21)OCC
Solvent: CCO
Product: CCOP(=O)(COCCOn1cnc2c(N)ncnc21)OCC
Temperature: 25 °C

Procedure:
A solution of 6-chloro-9-[2-(diethoxyphosphorylmethoxy)ethoxy]purine (1.45 g, 4 mmol) in ethanol (20 ml) saturated with ammonia gas was heated in a sealed steel vessel at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, evaporated to dryness and the residual oil chromatographed on silica gel (eluted with dichloromethane: methanol, 90:10) to give recovered starting material (0.25 g) and the title compound (0.94 g, 82%--based on used starting material), crystallised from acetone-ether, m.p. 74°-76°. UV: λmax (EtOH) 260 nm (ε 13,500); IR: νmax (KBr) 3308, 3146, 1669, 1646, 1600, 1538, 1466, 1416, 1320, 1301, 1232, 1206, 1164, 1129. 1066, 1053, 1039, 1009, 978 cm-1 ; 1H NMR: δH [(CD3)2SO]1.24 (6H,t,J=7 Hz, (OCH2CH3)2), 3.83-3.89 (2H,m,CH2OCH2P), 3.91 (2H,d,J=8 Hz, OCH2P), 4.0-4.15 (4H, dq, J=7 Hz, 7 Hz, (OCH2CH3)2), 4.48-4.51 (2H,m,N-OCH2), 7.37 (2H,br.s,D2O exchangeable NH2), 8.14 (1H,s,H-8), 8.34 (1H,s,H-2). Found: C,41.74; H: 5.49; N: 20.06%; m/z 345.1202. C12H20N5O5P requires: C,41.74; H, 5.83; N, 20.28%; m/z 345.1212.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].Cl.[C:30]([NH:34][NH2:35])([CH3:33])([CH3:32])[CH3:31]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:22])[F:20])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:34]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:35]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Reactant: CC(C)(C)NN
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C(C)(C)C

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with tert-butylhydrazine hydrochloride (CAS Reg. No. 7400-27-3) to give the title compound as brown solid. MS (ESI): m/z=474.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S)[N:5]=[C:4]([OH:9])[C:3]=1[CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>O.[Ni]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([OH:9])[C:3]=1[CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: CCOC(Cc1c(N)nc(S)nc1O)OCC
Agent: [Ni]
Solvent: O
Product: CCOC(Cc1c(N)ncnc1O)OCC
Yield: 71.5 %

Procedure:
To a suspension of 6-amino-5-(2,2-diethoxy-ethyl)-2-mercapto-pyrimidin-4-ol (1.19 g, 4.6 mmol) in water (50 ml) was added Raney nickel (Aldrich Raney 2800 nickel, 4.8 ml). The mixture was heated at reflux for 1 hour, and then the hot solution was filtered through Celite®. The nickel residue was washed with further water (100 ml), and these washings were filtered through Celite. The aqueous filtrate was evaporated to dryness to yield the title product (0.747 g, 71%).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][S:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11](/[C:12](=[N:29]/[OH:30])/[CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1)=O.[C:33]([O-:36])([O-:35])=O.[K+].[K+].C[OH:40].O>>[C:18]([OH:28])(=[O:40])/[CH:19]=[CH:21]/[C:33]([OH:36])=[O:35].[NH2:5][CH2:6][CH2:7][S:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11](/[C:12](=[N:29]/[OH:30])/[CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: C[C@]12CC[C@H](SCCNC(=O)C(F)(F)F)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CO
Agent: [K+]
Solvent: O
Product: C[C@]12CC[C@H](SCCN)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: O=C(O)/C=C/C(=O)O
Yield: 50 %

Procedure:
To a stirred solution of 3β-(2-trifluoroacetamidoethylthio)-6-(E)-hydroxyiminoandrostan-17-one (Prepn. 88, 120 mg) in MeOH/H2O 95/5 (7 mL), K2CO3 (170 mg) was added. The mixture was refluxed for 1.5 hrs and then concentrated, washed with water, extracted with CH2Cl2 and dried with Na2SO4. Fumaric acid (30 mg) was added and the resulting solution evaporated to dryness. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH3 9/1/0.1). To the concentrated fractions a stoichiometric amount of fumaric acid in MeOH was added. The solution was concentrated and the resulting mixture centrifugated. The solid was washed with Et2O/EtOH 9/1 (1 mL) to give, after centrifugation, the title compound (55 mg, 50%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.45 (1H, s), 8.10 (3H, m), 6.35 (2H, s), 3.30 (1H, dd), 3.22 (1H, m), 2.86 (2H, t), 2.67 (1H, m), 2.60 (2H, t), 2.50-0.80 (20H, m), 0.76 (3H, s), 0.67 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[NH:4][C:5](=[S:20])[N:6]([CH2:9][CH2:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]=2)[C:7]=1[NH2:8].[C:22](O)(=O)C.C(N)=N>CS(C)=O>[NH:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[CH2:10][CH2:9][N:6]1[C:7]2[N:8]=[CH:22][NH:1][C:2]=2[C:3](=[O:21])[NH:4][C:5]1=[S:20]
Reactant: CC(=O)O
Reactant: Nc1c(N)n(CCc2nc3ccccc3[nH]2)c(=S)[nH]c1=O
Agent: N=CN
Solvent: CS(C)=O
Product: O=c1[nH]c(=S)n(CCc2nc3ccccc3[nH]2)c2nc[nH]c12
Temperature: 80 °C
Yield: 11.7 %

Procedure:
To 5,6-diamino-1-[2-(1H-benzimidazol-2-yl)ethyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.29 g, 0.96 mmol, obtained from Example 12(c)) in DMSO (2 mL) was added formamidine acetate (0.15 g, 1.4 mmol) and the reaction was heated to 80° C. for 2 h. Purification of the crude product using preparative HPLC gave the title compound (0.035 g, 12% yield).