Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([C@@H:7]2[O:11][C@H:10]([CH2:12][O:13][P:14]([O:17][P:18]([O:21][CH2:22][C@H:23]3[O:27][C@@H:26]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH2:37])[C:31]=5[N:30]=[CH:29]4)[C@H:25]([OH:38])[C@@H:24]3[OH:39])([OH:20])=[O:19])([OH:16])=[O:15])[C@@H:9]([OH:40])[C@H:8]2[OH:41])[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH:2]=1.P([O-])([O-])([O-])=O.[OH-].[Na+]>>[CH:34]1[N:35]=[C:36]([NH2:37])[C:31]2[N:30]=[CH:29][N:28]([C@@H:26]3[O:27][C@H:23]([CH2:22][O:21][P:18]([O:17][P:14]([O:13][CH2:12][C@H:10]4[O:11][C@@H:7]([N:5]5[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH2:2][CH:1]=[CH:6]5)[C@H:8]([OH:41])[C@@H:9]4[OH:40])([OH:16])=[O:15])([OH:20])=[O:19])[C@@H:24]([OH:39])[C@H:25]3[OH:38])[C:32]=2[N:33]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Temperature: 23 °C
Reaction time: 17 h
Yield: 24.2 %

Procedure:
NAD+ (34.0 mg, 38.0 μmol) was placed in 2 mL of a 0.1 M phosphate buffer. The pH of this solution was adjusted to 8.1 with NaOH and then placed in an 80 mL Fisher-Porter bottle. The Fisher-Porter bottle was evacuated and refilled with argon three times then [Cl2Ru(TPPTS)2]2 (6.9 mg, 2.6 μmol) was added under a flow of argon. The Fisher-Porter bottle was evacuated and filled with 70 psi of H2 and stirred to 23° C. for 17.0 hr. The volatiles were removed under reduced pressure and a sample dissolved in D2O To this was added 20 μl of trimethylsilylpropionate standard solution. 1H NMR integration shows that 9.2 μmole of NADH have been produced under these conditions.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.CO.[H][H]>[C].[Pd].C(OCC)(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CCOc2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(CCOc2ccc(N)cc2)n1
Yield: 90.5 %

Procedure:
To a solution of 2.8 g of 4-[2-(6-methyl-2-pyridyl)ethoxy]nitrobenzene in the mixture consisting of 30 ml of methanol and 20 ml of ethyl acetate is added 0.5 g of 10% palladium carbon, and then the mixture is shaken in a stream of hydrogen. After absorption of hydrogen ceased, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with water, dried over anhydrous magnesium sulfate and then concentrated to give 2.24 g of 4-[2-(6-methyl-2-pyridyl)ethoxy]aniline as yellowish brown powder.
Reaction SMILES: [O:1]([C:8]([N:10]([CH:21]([C:23]#[CH:24])[CH3:22])[O:11]C(OC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.[OH-].[NH4+:26]>CO>[CH3:22][CH:21]([N:10]([OH:11])[C:8]([NH2:26])=[O:1])[C:23]#[CH:24]
Reactant: C#CC(C)N(OC(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: C#CC(C)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 28 %

Procedure:
A mixture of N,O-Bis(phenoxycarbonyl)-N-(3-butyn-2-yl)hydroxylamine (3.14 g,9.7 mmol), methanol (20 mL), and ammonium hydroxide (20 mL) was stirred for 17 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. Chromatography on silica gel (2% methanol, methylene chloride) afforded N-(3-butyn-2-yl)N-hydroxyurea (340 rag, 28%). 1H NMR (DMSO-26, 300 MHz) δ1.25 (d, 3H, J=7.5 Hz), 3.05 (d, 1H, J=3.0 Hz), 4.85 (dq, 1H, J=7.5, 3.0 Hz), 6.50 (br s, 1H), 9.25 (S, 1H). MS (DCI/NH3) m/e 129 (M+H)+, 146 (M+NH4)+. Anal calcd for C5H8N2O2 : C, 46.87; H, 6.29; N, 21.86. Found: C, 47.03; H, 6.27; N, 21.98.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:15]=[C:16]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)[CH2:17]2.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH2:37][CH2:36]2)[CH:15]=[C:16]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:25][CH:24]=1)[CH2:17]2
Reactant: O=C1c2c(Cl)cc(CC3CCNCC3)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(CN2CCC(Cc3cc(Cl)c4c(c3)CN(Cc3ccc(OC(F)(F)F)cc3)C4=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.3 %

Procedure:
To a mixture of 4-Cyano-benzyl bromide (12 mg, 0.06 mmol), 7-chloro-5-piperidin-4-ylmethyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (30.0 mg, 0.06 mmol) and potassium carbonate (42 mg, 0.3 mmol) was added acetonitrile (3.0 mL). The mixture was allowed to stir at room temperature overnight. Water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography provided the title compound as a brown oil (39.0 mg, 99%). 1H NMR (300 MHz, CDCl3): δ 7.60 (d, 2H), 7.27-7.59 (m, 4H), 7.17-7.20 (m, 3H), 7.05 (s, 1H), 4.77 (s, 2H), 4.22 (s, 2H), 3.53 (s, 2H), 2.80-2.84 (m, 2H), 2.58-2.60 (m, 2H), 1.91 (t, 21, 1.56-1.62 (m, 3H), 1.27-1.34 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][CH:16]=[O:17].S(=O)(=O)(O)O>CO>[CH3:12][C:13]([CH3:19])([CH3:18])[CH2:14][C:15]([CH:16]=[O:17])=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)CCC=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)CC(C=O)=Cc1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
134 g (0.95 mol) of 4-chlorobenzaldehyde are added to a solution of 15.8 g of 50% strength sodium hydroxide solution in 500 ml of methanol, after which 90 g (0.79 mol) of 4,4-dimethylpentanal are added dropwise at 35° C. in the course of 3 hours. Stirring is carried out for three hours, after which the mixture is neutralized with dilute sulfuric acid and evaporated down and the residue is distilled.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Br)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-bromo-5-methyl benzoic acid (1.0 g, 0.00465 mole) in dry dichloromethane (10 mL) was added oxalylchloride (1.22 mL, 0.013 mole) dropwise at 0° C. followed by 1-2 drops of N,N-dimethyl formamide. The reaction mixture was then stirred for 2 hours at room temperature and the solvents were evaporated and the product dried under vacuum to yield 2-bromo-5-methylbenzoyl chloride which was used for the next step. To a precooled solution of 2-bromo-5-methyl benzoyl chloride in toluene (5 mL) was slowly added a pre-cooled solution of triethylphosphite (1.05 mL, 0.00604 mole) in toluene. The reaction was then left at room temperature for overnight. The solvents were then evaporated on a rotovap. The resultant product was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate (NaHCO3, 25 mL), and then dried over magnesium sulfate (MgSO4). Filtration and solvent evaporation provided 1.1 g of product. Flash chromatography on silica gel using 0%-5% ethyl acetate/dichloromethane followed by drying of the product under high vacuum afforded 0.900 g of (2-bromo-5-methylbenzoyl)phosphonic acid diethyl ester. B. The material from A above was used to prepare [2-bromo-5-methylbenzoyl)difluoromethyl]phosphonic acid diethyl ester following a procedure similar to Example 80C. This material was used to prepare Compound 82 following a procedure similar to Example 40. 1H NMR: (DMSO-d6, 400 MHz) δ 7.56 (d, 1H, J=8.4 Hz), 7.40 (s, 1H), 7.19 (d, 1H, J=8.0 Hz), 2.28 (s, 3H). MS (ion spray): m/z 300.15/301.05 (M−H)
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[N:45]=[C:44]([CH3:46])[CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:41]=[CH:42][CH:43]=[C:44]([CH3:46])[N:45]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Cc1cccc(Br)n1
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: COCCOC
Solvent: O
Product: Cc1cccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)n1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 6-bromo-2-picoline (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (425 mg, 82%) as a yellow oily substance.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N+:5]([O-:43])[CH:6]=[C:7]([Cl:42])[C:8]=1[CH2:9][C@@H:10]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)[O:11][C:12](=[O:26])[CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl.Cl>[Cl:42][C:7]1[CH:6]=[N+:5]([O-:43])[CH:4]=[C:3]([Cl:2])[C:8]=1[CH2:9][C@@H:10]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:40][CH2:41]2)[CH:28]=1)[O:11][C:12](=[O:26])[CH2:13][N:14]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:45]([CH3:44])(=[O:47])=[O:46]
Reactant: COc1ccc(CNCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CN(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)S(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxybenzylamino)acetoxy)ethyl)pyridine 1-oxide hydrochloride (42 mg, 0.064 mmol) was dissolved in DCM (1.5 ml). Py (500 μl, 6.18 mmol) and methanesulfonyl chloride (5.96 μl, 0.076 mmol) were added, and the reaction was stirred at RT for 2 hours to achieve completion. The reaction mixture was diluted with HCl 1M and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative reverse-phase HPLC to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(N-(3,4-dimethoxybenzyl)methylsulfonamido)-acetoxy)ethyl)pyridine 1-oxide (20 mg, 44.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:17][CH:16]2[OH:31])=[CH:11][CH:10]=1.Cl[CH2:38][C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][O:51][Si:52]([CH:59]([CH3:61])[CH3:60])([CH:56]([CH3:58])[CH3:57])[CH:53]([CH3:55])[CH3:54])[C:43]=2[CH:62]=1>>[F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:17][CH:16]2[O:31][CH2:38][C:39]2[CH:40]=[CH:41][C:42]3[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][O:51][Si:52]([CH:53]([CH3:55])[CH3:54])([CH:56]([CH3:58])[CH3:57])[CH:59]([CH3:61])[CH3:60])[C:43]=3[CH:62]=2)=[CH:11][CH:10]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(OCCCOc3cc(F)ccc3F)cc2)C(O)C1
Reactant: CC(C)[Si](OCCN1C(=O)COc2ccc(CCl)cc21)(C(C)C)C(C)C
Product: CC(C)[Si](OCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21)(C(C)C)C(C)C

Procedure:
Analogously to Method D, 1.34 g of benzyl 4-{4-[3-(2,5-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 1.43 g of 6-chloromethyl-4-(2-triisopropylsilanyloxyethyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.55 (1:1 EtOAc-heptane); Rt=7.03.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)Cc1ccc(OCCCBr)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-hydroxyphenyl)propan-2-one (1 g, 6.67 mmol), 1,3-dibromopropane (0.74 mL, 7.3 mmol) and potassium carbonate (1.84 g, 13 3 mmol) in 2-butanone (30 mL) was heated to reflux for 16 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with additional ethyl acetate. The organic extracts were combined, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 10% ethyl acetate/hexanes to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 2.14 (s, 3H), 2.36-2.27 (m, 2H), 3.60 (t, J=6.4 Hz, 2H), 3.63 (s, 2H), 4.09 (t, J=5.8 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H); MS (DCI/NH3) m/z 288 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.[C:17]1([CH:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][OH:32])[CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>O1CCCC1>[C:33]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][O:32][C:2]3[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)[N:3]=3)[CH2:28][CH2:29]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COc1ccc(-c2nc(C)cc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(C)cc(OCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.4 %

Procedure:
0.6 g of 4-chloro-2-(4-methoxyphenyl)-6-methylpyrimidine and 0.76 g of 1-diphenylmethyl-4-(2-hydroxyethyl)piperazine were dissolved in 20 ml of dried tetrahydrofuran. After addition of 0.1 g of 60% sodium hydride, the mixture was stirred for 20 hours at room temperature. The reaction mixture was poured into ice-water and was extracted with ethyl acetate. After the extract was washed with water and was dried with anhydrous magnesium sulfate, then was evaporated in vacuo. The resulting residue was purified with column chromatography with silica gel (Wako gel C-200, elution with chloroform and then chloroform:ethyl acetate=8:1). The desired fraction was crystallized by evaporating the solvent under reduced pressure. The crystals were recrystallized with the solvent mixed with chloroform and ether, resulting to obtain 0.6 g of crystals. Melting point is 132° to 133° C.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8](F)[C:7]([F:13])=[CH:6][C:3]=1[C:4]#[N:5].[OH:14][C:15]([C@H:18]1[CH2:22][CH2:21][NH:20][C@H:19]1[CH3:23])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Li+].[Li+]>>[F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([N:20]2[CH2:21][CH2:22][C@H:18]([C:15]([OH:14])([CH3:17])[CH3:16])[C@@H:19]2[CH3:23])[C:7]([F:13])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1c(F)c(F)cc(C#N)c1F
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: COc1c(F)c(C#N)cc(F)c1N1CC[C@H](C(C)(C)O)[C@@H]1C

Procedure:
Using 2,4,5-trifluoro-3-methoxybenzonitrile (347 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (409 mg) and lithium carbonate (328 mg), the title compound was obtained as a pale-yellow oil (yield: 175 mg) by an operation similar to that in Example 3.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]2[C:15]=1[C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[NH:12][C:11](=O)[CH2:10]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C(=O)(O)[O-].[Na+].O>COCCOCCOC>[Cl:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]2[C:15]=1[C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[NH:12][C:11](=[S:22])[CH2:10]2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Cn2c(c(Cl)c3ccccc32)-c2ccccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: S=C1Cn2c(c(Cl)c3ccccc32)-c2ccccc2N1
Temperature: 110 °C
Yield: 15.7 %

Procedure:
A mixture of 12.5 g 13-chloroindolo[1,2-d][1,4]benzodiazepin-6(7H)-one, 22.6 g phosphorus pentasulfide and 8.6 g sodium bicarbonate in 240 ml diglyme was heated at 110° C. for two hours. The resulting mixture was cooled and poured into 2.5 L water to precipitate a solid. The solid was collected, washed with water and dried (P2O5) to give 11.9 g crude product. Recrystallization of 3.3 g from toluene (300 ml) gave 2.08 g fluffy solid, m.p. 280°-282° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].O1CCOCC1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C(OCC)(=O)C>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(F)cc1Cl
Yield: 85 %

Procedure:
Combine 4-fluoro-3-nitroaniline (1.0 g, 6.4 mmol) with dioxane (20 mL). Treat mixture with 2-chloro-4-fluorobenzoyl chloride (1.6 g, 8.3 mmol). Stir the reaction overnight at room temperature. Transfer the reaction mixture into ethyl acetate (220 mL), then wash successively with aqueous HCl (1N, 50 mL), aqueous NaOH (1N, 50 mL), saturated aqueous NaCl (50 mL). Dry the organic layer over anhydrous sodium sulfate, then evaporate the solvent under reduced pressure. Further purify the residue by chromatography on silica gel, using a gradient of 10-30% ethyl acetate in hexanes to obtain the title intermediate (1.7 g, 85% yield): mass spectrum (ion spray): m/z=313.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[F:8][C:9]([F:31])([F:30])[C:10]([N:12]([CH2:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>>[F:8][C:9]([F:30])([F:31])[C:10]([N:12]([CH2:19][C:20]1[CH:25]=[C:24]([N:3]2[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]2[CH3:1])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11]
Reactant: CCOC(=O)CN(Cc1cc(F)ccc1[N+](=O)[O-])C(=O)C(F)(F)F
Reactant: Cc1c[nH]c(C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)CN(Cc1cc(-n2cc(C)nc2C)ccc1[N+](=O)[O-])C(=O)C(F)(F)F

Procedure:
A mixture of 2,4-dimethylimidazole (6.25 g), ethyl N-trifluoroacetyl-N-(5-fluoro-2-nitrobenzyl)glycinate (22.0 g) and sodium carbonate (6.62 g) was stirred and heated at 130° for 2 hours. Volatile material was removed from the cooled mixture in vacuo and the residue was partitioned between ethyl acetate (200 cm3) and water (100 cm3). The organic phase was washed with water (2×25 cm3), dried (MgSO4), and evaporated in vacuo to give an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate:methanol, 1:19. Combination and evaporation of the appropriate fractions gave an oil which crystallised on trituration with ether to afford the title compound, m.p. 172.5°-176° (3.1 g). Analysis %: Found: C,50.7; H,4.8; N,12.7; Calculated for C18H19F3N4O5 : C,50.5; H,4.5; N,13.1.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([NH2:14])=[CH:11][CH:10]=[CH:9]2)=[N+:2]=[N-:3].N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>CCOCC>[C:21]([NH:14][C:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N:1]=[N+:2]=[N-:3])[CH:9]=[CH:10][CH:11]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: [N-]=[N+]=Nc1cccc2cccc(N)c12
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)Nc1cccc2cccc(N=[N+]=[N-])c12

Procedure:
To a stirred solution of 8-azido-1-naphthylamine (1.84 g., 0.01 mole) in 70 ml. of pyridine was added a solution of acetyl chloride (0.784 g., 0.01 mole) in 10 ml. of ether. The mixture was warmed on a steam bath for 30 minutes. The solvents were removed in vacuo and the residue washed with water and dried. Recrystallization from hexane provided 1-acetamido-8-azidonaphthalene in the form of colorless, long needles having a yield of 2.1 g., 93 percent, m.p. 148°C.-149°C., Lit. m.p. 147°C.-148°C. and an analysis of: Calcd. for C12H10N4C: C, 63.70; H, 4.46; N, 24.77 Found: C, 63.90; H, 4.14; N, 24.66
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][OH:16].O>CS(C)=O>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1
Reactant: OCCBr
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: OCCn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
KOH (571 mg, 10.2 mmol) was stirred in 5 mL of anhydrous DMSO at room temperature. 6-Bromoindole (500 mg, 2.55 mmol) was added as solid. After 30 min, 2-bromoethanol (181 μL, 2.55 mmol) was added to the green solution, which was then stirred at room temperature overnight. Water was then added and the reaction mixture was extracted with ethyl acetate (2×25 mL). The organic layer was then washed with water and brine, dried over Na2SO4, evaporated in vacuo. MPLC purification of the crude product provided the titled compound as a light brown oil (344 mg, 56% yield).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]([OH:15])=O)[NH:10]2)=[CH:6][CH:5]=1)[CH3:3].[CH3:16][CH:17]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18].C(N=C=NCCCN(C)C)C>>[CH3:18][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:9]2[NH:10][C:11]3[CH:12]=[C:4]([N:2]([CH3:1])[CH3:3])[CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:16]
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Reactant: CN(C)c1ccc2cc(C(=O)O)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3ccc(N(C)C)cc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 6-(N,N-dimethylamino)indole-2-carboxylic acid (PREPARATION 89, 0.40 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.43 g) and 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.45 g), the title compound is obtained, mp 153°-154°.