Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[C:18]2[CH:19]=[C:20](B(O)O)[S:21][C:17]=2[CH:16]=[CH:15][CH:14]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20]2[S:21][C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[C:18]=3[CH:19]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: COc1cccc2sc(B(O)O)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc2sc(-c3ccc([N+](=O)[O-])cc3)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
To a suspension of anhydrous 1,2-dimethoxyethane (DME, 20 mL) containing a palladium tetrakis catalyst (Pd(PPh3)4 (49.7 mg, 0.043 mmol) was added 4-iodonitrobenzene (535.8 mg, 2.15 mmol), stirred at room temperature for 10 minutes, followed by adding 4-methoxybenzothiophene-2-boronic acid (95a, 470 mg, 2.26 mmol) and 2.0 M sodium carbonate aqueous solution (43 mL, 0.086 mmol). The reaction mixture was heated to reflux for 10 hours and cooled to room temperature, and ice water was added. The resulting product was extracted with ethyl acetate, evaporated after a treatment with, and purified by column chromatograph to give the target compound 2-(4-nitrophenyl)-4-methoxybenzothiophene (1-1, 560 mg, 87%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][N:14]=[C:15]=S>>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:13]([NH:14][CH3:15])[NH:2][C:3]=2[CH:7]=1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CN=C=S
Agent: Cl
Product: CNC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and methyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp >190° C. decomp.; 1H-NMR (DMSO-d6): δ 2.75 (s, 3H), 7.02 (s, 1H), 7.25 (br, 1H), 11.3 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C@@H:14]4[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[NH:9]2)=[CH:4][CH:3]=1.I[CH3:23]>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C@@H:14]4[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:23])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(O)cc3)c(=O)c12
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1ccc(O)cc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 75.4 %

Procedure:
A mixture of (4S,7R)-2-(4-hydroxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 41; 1.60 g, 5.6 mmol) and iodomethane (1.1 mL, 17.7 mmol) in dimethylformamide (50 mL) was heated in a sealed tube at about 100° C. for 2.5 h. The reaction mixture was allowed to cool to room temperature. The tube was carefully opened, and the contents were allowed to stand at room temperature over a weekend. The solvent was evaporated and dichloromethane (250 mL) was added. The solution was washed with water (100 mL), saturated sodium thiosulfate (100 mL), water (100 mL), and brine (100 mL). The organic layer was dried (magnesium sulfate), filtered, and evaporated. The residue was triturated with ethyl acetate and the solid was filtered off and washed with 20% ethyl acetate/hexanes and then hexanes, and then purified using a Biotage 40M system, eluting with 3-5% methanol/dichloromethane to give (4S,7R)-2-(4-Hydroxy-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.26 g, 75%) as a light yellow solid. APCI(+)-MS (M+H) 299.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]3[CH2:28][CH2:27][CH:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25]3)=[O:23])[C:17]=2[CH3:34])[CH:13]=[CH:14][CH:15]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:10]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]3[CH2:28][CH2:27][CH:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25]3)=[O:23])[C:17]=2[CH3:34])[CH:11]=1
Reactant: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(-c4ccccc4)c3)c2C)C1
Yield: 59 %

Procedure:
In analogy to the procedure described in example 14C] but with 2.8 eq of K3PO4, [5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and phenylboronic acid gave (5-biphenyl-3-yl-1,4-dimethyl-1H-pyrazol-3-yl)-(3-diethylamino-pyrrolidin-1-yl)-methanone in 59% yield as yellow oil. MS: 417.1 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]4[C:19]([CH3:24])=[N:20][CH:21]=[N:22][CH:23]=4)=[O:17])=[CH:11][C:10]=3[F:25])[N:7]=[C:6]([C:26]([F:29])([F:28])[F:27])[CH:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:32]I>C1COCC1>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([N:15]([CH3:32])[C:16]([C:18]4[C:19]([CH3:24])=[N:20][CH:21]=[N:22][CH:23]=4)=[O:17])=[CH:11][C:10]=3[F:25])[N:7]=[C:6]([C:26]([F:28])([F:27])[F:29])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: Cc1ncncc1C(=O)Nc1ccc(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncncc1C(=O)N(C)c1ccc(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-fluorophenyl}-4-methylpyrimidine-5-carboxamide (300 mg, 0.74 mmol) was dissolved in THF, cooled to 0° C., added sodium hydride (35 mg, 1.48 mmol) and stirred the mixture for 30 mins at the same temperature. Methyl Iodide (120 mg, 0.84 mmol) was added and heated the reaction mixture to rt. After 3 h, reaction mixture quenched with water. Work up (H2O/AcOEt) and purification afforded the title compound (120 mg) as a pale-yellow solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.99 (s, 1H), 8.41 (s, 1H), 7.46 (t, J 8.1, 1H), 7.08-7.01 (m, 2H), 6.21 (s, 1H), 3.53 (s, 3H), 2.58 (s, 3H), 1.60-1.51 (m, 1H), 0.98-0.88 (m, 2H), 0.70-0.60 (m, 2H). MS (m/z): 418.35 [M−H]−.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[ClH:14].Cl.[Cl:16][C:17]1[CH:34]=[CH:33][C:20]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][SH:32])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:16].[ClH:14].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[SH:32][CH2:31][CH2:30][CH2:29][N:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:34][CH:33]=3)[CH2:24][CH2:25]2)[OH:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N=C=O)cc1
Reactant: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(NC(O)=[SH]CCCN2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Yield: 49.7 %

Procedure:
The procedure described in Example 2 was followed, using 1.4 g of 4-n-butylphenyl isocyanate, 3.0 g of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 0.8 g of triethylamine and 50 ml of methylene chloride, to give 1.1 g (25% of theory) of N-(4-n-butylphenyl)-S-{3-[4-(4-chlorophenethyl)piperazin-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 252°-254° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.3 %

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (1.92 g, 4.53 mmol) was added to a solution of 1-(benzyloxycarbonyl)-4-(hydroxymethyl)piperidine (1.00 g, 4.01 mmol) in CH2Cl2 (20 mL) and the mixture was stirred at RT for 45 min. Ether (75 mL) and 1.3 N NaOH (25 mL) were added and stirring was continued for 15 min. The mixture was transferred to a separatory funnel with additional ether (30 mL) and 1.3 N NaOH (20 mL). The organic layer was separated, washed with saturated aq. NaCl (20 mL, dried (Na2SO4), decanted,and evaporated to give 846 mg of 1-(benzyloxycarbonyl)-4-piperidine carboxaldehyde as a colorless syrup.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[I:12]Cl.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:8]([I:12])=[C:6]([CH:5]=1)[NH2:7]
Reactant: Nc1cccc(OC(F)F)c1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cc(OC(F)F)ccc1I
Yield: 51.2 %

Procedure:
A solution of 3-[(difluoromethyl)oxy]aniline (3.16 g), iodine monochloride (3.9 g) and sodium acetate (6.5 g) in acetic acid (30 ml) was stirred for 1 hour, then partitioned between saturated sodium bicarbonate solution and ether. The ether layer was separated, washed consecutively with sodium thiosulphate solution and brine. The solvent was removed and the residue was loaded onto a silica gel and chromatographed on silica gel eluted with hexane/ethyl acetate 0-20% to give the title compound as a red oil (2.9 g). Mass Spectrum 286 M+H+
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13][CH2:12]2)=[O:8]>ClCCl>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13][CH2:12]2)=[O:8]
Reactant: CCOC(=O)N1CCCc2cc(C(=O)CCCl)ccc21
Reactant: CNC
Solvent: ClCCl
Product: CCOC(=O)N1CCCc2cc(C(=O)CCN(C)C)ccc21
Reaction time: 2 h

Procedure:
50% Aqueous dimethylamine (51 mL) was added to a solution of ethyl 6-(3-chloropropanoyl)-3,4-dihydro-1(2H)-quinoline carboxylate (15.0 g, 50.7 mmol) obtained in Reference Example 1 in dichloromethane at room temperature and then stirred for 2 hours. The reaction solution was separated, and the organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The resultant residues were purified by alumina column chromatography (developing solvent; hexane:ethyl acetate=1:1), whereby the title compound (16.3 g) was obtained as pale yellow matter.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:26])=[C:10]([N:14]3[CH2:17][C:16]([CH3:25])([NH:18]C(=O)C(F)(F)F)[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:27])[C:5]([C:28]([OH:30])=[O:29])=[CH:4]1)[CH3:2].[OH-].[Na+].C(O)C>O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:26])=[C:10]([N:14]3[CH2:15][C:16]([NH2:18])([CH3:25])[CH2:17]3)[C:11]=2[F:13])[C:6](=[O:27])[C:5]([C:28]([OH:30])=[O:29])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)(NC(=O)C(F)(F)F)C3)c(F)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)(N)C3)c(F)c21

Procedure:
A mixture of 0.65 g (1.5 mmoles) of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-methyl-3-trifluoroacetamido-1-azetidinyl)-quinoline-3-carboxylic acid (example 21) 2 ml of 10% sodium hydroxide and 3 ml of ethanol is refluxed in 10 ml of water for 3 hours. It is filtered while hot, cooled, acidified with acetic acid, and filtered. After washing with water, 0.48 g (95%) of 1-ethyl-6,8-difluoro-7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 293°-6° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[N:9]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[CH2:22][CH2:21][CH2:20]3)[CH:13]=[CH:12][N:11]=[CH:10]1.Cl.C([O-])(O)=O.[Na+]>N1CCCCC1.C(O)(=O)C>[N:9]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[C:22](=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:21][CH2:20]3)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1C(=Cc2ccccn2)CCc2cc(OCCn3ccnc3)ccc21
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 18.1 %

Procedure:
2-Pyridine carboxaldehyde (0.202 g, 1.9 mmol) was added to a mixture of 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (1) (0.322 g, 1.2 mmol) in piperidine:acetic acid (30 μL:24 μL). The reaction mixture was heated in a 130° C. oil bath with efficient stirring for 1.5 hours. After cooling to room temperature, 2 mL of 1N HCl was added and the mixture stirred overnight. The mixture was made neutral with the addition of a saturated solution of NaHCO3 and then extracted into DCM (3×50 mL). The pooled extracts were washed sequentially several times with water, then brine, dried, filtered, and concentrated in vacuo to leave a dark brown oil. Purification by flash chromatography (silica gel, 135 g, 7% MeOH in DCM) afforded 0.075 g of the title compound as a light tan solid.
Reaction SMILES: [Na].[NH:2]([C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:3].[C:13](#[N:17])[C:14]([CH3:16])=[CH2:15]>C(O)C>[NH2:17][C:13]1[CH:14]([CH3:16])[CH2:15][N:2]([C:4]2[S:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[N:3]=1
Reactant: C=C(C)C#N
Reactant: NNc1nc2ccccc2s1
Agent: [Na]
Solvent: CCO
Product: CC1CN(c2nc3ccccc3s2)N=C1N

Procedure:
A 0.5 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 16.5 g. of 2-hydrazinobenzothiazole is added followed by 6.7 g. of methacrylonitrile. The reaction mixture is refluxed for 4 hours, then is cooled. Some of the ethanol is removed in vacuo and the precipitate is collected by filtration to give 20.6 g. of the desired product as colorless prisms, m.p. 207°-209° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[BH4-].[Na+]>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19]
Reactant: Cc1ccc(-c2nc(Cc3cccc(C=O)c3)c(C)o2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2nc(Cc3cccc(CO)c3)c(C)o2)cc1
Yield: 99.3 %

Procedure:
3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzaldehyde (3.54 g) was suspended into 35 ml of methanol, and 230 mg of sodium borohydride was added thereto with stirring under ice-cooling, and stirred for 1.5 hours at room temperature. The reaction solution was poured into ice-cold water, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduce pressure to provide 3.54 g of the objective compound as colorless crystals. M.p. 97–99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH2:18]Cl)[CH:12]=2)[CH:3]=1.[CH3:20][NH2:21].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH2:18][NH:21][CH3:20])[CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1ccc(F)c(CCl)c1
Reactant: CN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: CNCc1cc(Oc2cc(Cl)ccc2C#N)ccc1F
Temperature: 25 °C
Reaction time: 240 h
Yield: 104.6 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-4-fluorophenoxy)-benzonitrile (0.14 g, 0.47 mmol) in ethanol (15 mL) was added methylamine (33% in ethanol, 4.0 mL, 32 mmol), and the reaction mixture stirred for 10 days at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (50 mg, 0.43 mmol) in methanol (3 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 4-chloro-2-(4-fluoro-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (183 mg, 95%) as a white solid.
Reaction SMILES: [Cl-].[NH3+:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[C:7](=[O:15])[NH:6]2.[CH:16]([CH:18]1[CH2:22][CH:21](OC)O[CH:19]1OC)=[O:17]>>[CH:16]([C:18]1[CH:22]=[CH:21][N:2]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:12]=2[Cl:13])[NH:9][C:8](=[O:14])[C:7](=[O:15])[NH:6]3)[CH:19]=1)=[O:17]
Reactant: [NH3+]c1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Reactant: COC1CC(C=O)C(OC)O1
Agent: [Cl-]
Product: O=Cc1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2Cl)c1

Procedure:
16.5 mmol of 6-ammonio-7-chloro-2,3(1H,4H)-quinoxalinedione chloride were reacted with 16.5 mmol of 3-formyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[CH2:30]([N:14]1[CH2:15][CH2:16][CH:11]([N:8]2[C:9]3[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:5]=3[CH:6]=[N:7]2)[CH2:12][CH2:13]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCNCC2)c(=O)[nH]1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCN(Cc3ccccc3)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(piperidin-4-yl)-1H-indazole-4-carboxamide (1 equiv.) and benzaldehyde (1.5 equiv.) in methanol (5 mL per 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 5 h. Then NaBH3CN (1 equiv.) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the residue purified by column chromatography (27%). LCMS: 548.10 (M+1)+; HPLC: 99.16% (@ 254 nm) (Rt; 5.349); 1H NMR (DMSO-d6, 400 MHz) δ 11.51 (s, 1H), 8.59 (t, 1H, J=4.8 Hz), 8.36 (s, 1H), 8.25 (s, 1H), 7.69 (d, 1H, J=1.2 Hz), 7.34 (d, 4H, J=4.4 Hz), 7.27-7.24 (m, 1H), 5.87 (s, 1H), 4.70 (m, 1H), 4.33 (d, 2H, J=4.8 Hz), 3.55 (s, 2H), 2.93 (d, 2H, J=10 Hz), 2.30-2.20 (m, 2H), 2.19 (s, 3H), 2.12 (s, 3H), 2.09 (m, 2H), 1.87 (m, 2H).
Reaction SMILES: N[C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[I:12].N(OC(C)(C)C)=O.C(O)(=O)C1C=CC=CC=1.Cl>CN(C=O)C.C(OCC)C>[I:11][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([I:12])[CH:2]=1)[C:6]([OH:8])=[O:7]
Reactant: Nc1c(I)cc(C(=O)O)cc1I
Agent: CC(C)(C)ON=O
Agent: Cl
Agent: O=C(O)c1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(I)cc(I)c1
Temperature: 50 °C

Procedure:
The titled compound was prepared according to previously reported synthetic procedures under modified conditions (see e.g., Mak et al., J. Org. Chem. 2001, 66, 4476-4486). 4-amino-3,5-diiodobenzoic acid (2.0 g, 5.4 mmol) was added portion-wise to a stirred solution of t-butyl nitrite (1.07 g, 10.4 mmol) in DMF (10 mL) heated at 50° C. in a 3-neck round bottom flask equipped with a reflux condenser. Additional DMF (10 mL) was added halfway through the addition. Gas evolution was observed after each addition of the benzoic acid. Upon completion of the addition the reaction mixture was heated at 60° C. for 30 minutes and then allowed to cool to room temperature. The brown solution was diluted with diethyl ether (60 mL) and poured over dilute HCl (100 mL, 3N). The ethereal layer was removed and washed with 3N HCl (2×20 mL), water (3×20 mL) and brine (1×20 mL) then dried over anhydrous MgSO4. Removal of diethyl ether in vacuo and subsequent recrystallization in methanol afforded the desired compound in 77% yield (1.5 g, 4.0 mmol); mp 234-236° C. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 13.49 (s, 1H), 8.31 (s, 1H), 8.17 (s, 2H)13C-NMR (75 MHz, DMSO-d6) δ (ppm): 165.1, 148.6, 137.5, 134.7, 96.6 HRMS (m/z): [M−H]− calc. for C7H3I2O2, 372.8222. found 372.8231.
Reaction SMILES: [CH:1]1([C@H:4]([O:26][CH2:27][C:28](OCC)=[O:29])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:33]([NH2:35])[CH3:34]>CO>[CH:1]1([C@H:4]([O:26][CH2:27][C:28]([NH:35][CH2:33][CH3:34])=[O:29])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCN
Reactant: CCOC(=O)CO[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Solvent: CO
Product: CCNC(=O)CO[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reaction time: 20 h

Procedure:
A solution of ethyl ({(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}oxy)acetate (40-1, 16 mg, 0.036 mmol) and ethylamine (10 equiv) in methanol (1 mL) was heated in a sealable tube at 75 deg C. for 20 h. The reaction mixture was concentrated, then purified by reverse-phase liquid chromatography (acetonitrile/H2O with 0.1% TFA present) to provide 2-({(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}oxy)-N-ethylacetamide (40-2) as a light yellow oil. LRMS m/z (M+H) 441.5 found, 441.5 required.
Reaction SMILES: C([BH3-])#N.[Na+].[I:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[C:11]3[CH2:18][NH:17][CH2:16][CH2:15][N:12]3[C:13]=2[CH:14]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[I:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH:11]3[CH2:18][NH:17][CH2:16][CH2:15][N:12]3[C:13]=2[CH:14]=1
Reactant: Ic1ccc2cc3n(c2c1)CCNC3
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Ic1ccc2c(c1)N1CCNCC1C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
Sodium cyanoborohydride (95%, 1.6 g, 24 mmol) was added over 3 mm to a stirred solution of 7-iodo-1,2,3,4-tetrahydropyrazino-[1,2-a]indole (2.2 g, 7.4 mmol) in acetic acid (50 mL) at 10° C. under Ar. After complete addition the reaction was allowed to warm to room temperature and stirred for 18 h. The mixture was cautiously poured into a mixture of saturated aqueous sodium hydrogen carbonate solution (150 mL) and ethyl acetate (100 mL). The mixture was partitioned and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (1×100 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)] to give the product as a yellow oil (1.74 g, 79%) which was used immediately.