Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[Br:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][O:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2/[CH:24]=[CH:23]/[CH:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:35][CH:34]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(Br)cc2)CCc2ccc(C#N)cc2)cc1
Yield: 87.5 %

Procedure:
A solution of 230 mg (0.56 mmol) of methyl E-4-[2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-enyl]benzoate from Example 17A in 5 ml of dry acetonitrile is mixed with 209 mg (0.84 mmol) of 4-bromobenzyl bromide and 116 mg (0.84 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The resulting organic phase is concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane). 286 mg (0.49 mmol, 88% yield) of a solid are obtained.
Reaction SMILES: [I-].[Na+].[C:3]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([NH:22][C:23](=[O:26])[CH2:24]Cl)[CH:11]=1)(=[O:5])[CH3:4].[Cl-].[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[O:32][CH:33]1[CH2:38][CH2:37][NH2+:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>C1COCC1.C(#N)C>[C:3]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([NH:22][C:23](=[O:26])[CH2:24][N:36]2[CH2:35][CH2:34][CH:33]([O:32][C:31]3[CH:39]=[CH:40][CH:41]=[C:29]([Cl:28])[CH:30]=3)[CH2:38][CH2:37]2)[CH:11]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)NCCNc1cc(NC(=O)CCl)nc(-c2ccccc2)n1
Reactant: Clc1cccc(OC2CC[NH2+]CC2)c1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)NCCNc1cc(NC(=O)CN2CCC(Oc3cccc(Cl)c3)CC2)nc(-c2ccccc2)n1

Procedure:
Large scale reaction: Sodium iodide (2.45 g; 16.3 mmol) was added to a suspension of chloroacetamide 6 (5.67 g; 16.3 mmol), piperidinium chloride 7.5 (4.85 g; 19.5 mmol) and DIPEA (7.0 mL; 40.2 mmol) in 3:1 acetonitrile:THF (480 mL). After 19.5 h the reaction was concentrated on a rotary evaporator. EtOAc (250 mL) was added and the suspension was washed with 50% saturated NaHCO3 (1×50 mL), water (2×25 mL) and saturated NaCl (2×35 mL). The orange-brown solution was dried over MgSO4; charcoal (0.86 g) was added and this was filtered then concentrated leaving a light orange foam. The crude material was purified on silica gel (850 mL) with 12-9:1 EtOAc:i-PrOH. Product was obtained as a pale yellow/off-white hard foam (7.82 g; 92%).
Reaction SMILES: [Mg].BrCC.II.Cl[CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.[C:15]([O:19][C:20](=[O:32])[NH:21][C@H:22]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][CH:25]=1)[CH3:23])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>O1CCCC1>[C:15]([O:19][C:20](=[O:32])[NH:21][C@H:22]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]([OH:31])[CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:28][CH:29]=1)[CH3:23])([CH3:16])([CH3:17])[CH3:18]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Reactant: CN1CCC(Cl)CC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C2CCN(C)CC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a mixture of 975 mg of magnesium, 100 μL of bromoethane, and 20 μL of tetrahydrofuran, a catalyst amount of iodine was added, and the mixture was stirred for about 10 minutes until the brown color from iodine disappears. Thereto, 20 mL of a tetrahydrofuran solution containing 5.9 g of 4-chloro-1-methylpiperidine was added, and heated for 2.5 hours under reflux. Thus produced white suspension was cooled to 0° C., and 10 mL of a tetrahydrofuran solution containing 2 g of the compound [15-1] was added thereto. After the overnight stirring under gradually heating back to room temperature, a saturated aqueous solution of ammonium chloride was added thereto, and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0-90/10), to obtain 2.27 g of tert-butyl((1S)-1-{4-[hydroxy(1-methylpiperidin-4-yl)methyl]phenyl}ethyl)carbamate [23-1] (hereinafter, referred to as the compound [23-1]).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)=[O:12]
Reactant: O=C(Cl)CCCCCBr
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (1.3 g) was added to a solution of 6-bromohexanoyl chloride (2 g) in chlorobenzene (20 ml) under ice-cooling and the mixture was stirred at room temperature for 2 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.38 g of 6-bromo-1-(4-chlorophenyl)-1-hexanone.
Reaction SMILES: CN([CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[O:8][C:7]([CH3:13])([CH3:12])[C:6]1=O)C.C(O)(=O)C.[NH2:19][C:20]([NH2:22])=[NH:21].C[O-].[Na+]>C(O)C>[CH3:10][C:9]1([CH3:11])[C:5]2[CH:4]=[N:19][C:20]([NH2:22])=[N:21][C:6]=2[C:7]([CH3:13])([CH3:12])[O:8]1
Reactant: CN(C)C=C1C(=O)C(C)(C)OC1(C)C
Reactant: N=C(N)N
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)OC(C)(C)c2nc(N)ncc21
Temperature: 100 °C
Yield: 67.3 %

Procedure:
To a solution of 4-dimethylaminomethylene-2,2,5,5-tetramethyl-dihydro-furan-3-one (1.97 g, 10.0 mmol, 1.0 equiv) and guanidine acetate (1.19 g, 10.0 mmol, 1.0 equiv) in ethanol (40 mL) was added sodium methylate (0.54 g, 10.0 mmol, 1.0 equiv) and the reaction mixture heated to 100° C. for 3 h. The solvent was removed under reduced pressure and the reaction product purified by crystallization from a mixture of hot heptane/ethyl acetate to yield 1.3 g (67% yield) of the title compound. MS (EI): 193 [M]+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[N:26]1([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH:30]=[CH:29][N:28]=[CH:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)=[CH:37][CH:36]=3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: Nc1ccc(-n2ccnc2)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)Nc3ccc(-n4ccnc4)cc3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 4-(1H-imidazol-1-yl)aniline and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:35])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[CH:18]=2)[CH2:14][C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7]1)=[O:5])C.[OH-].[Li+]>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:7]2)=[O:35])=[CH:18][C:19]=1[O:25][CH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)Cc2cccnc2C1
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3cccnc3C2)cc1OCCc1cccc(C)c1

Procedure:
The compound of step 1 was hydrolyzed with lithium hydroxide in analogy to step 3 of example 94 to give 5 mg of the title compound.
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl[C:24]1[CH:42]=[CH:41][C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[CH:32]=2)=[O:29])=[CH:26][N:25]=1.C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([NH:30][C:28]([C:27]2[CH:41]=[CH:42][C:24]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)=[N:25][CH:26]=2)=[O:29])[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=1
Reactant: COc1cc(NC(=O)c2ccc(Cl)nc2)cc(OC)c1
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: COc1cc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)cc(OC)c1

Procedure:
4-{4-[5-(3,5-Dimethoxy-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and 6-chloro-N-(3,5-dimethoxy-phenyl)-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C25H26N4O5 [M+H]+: 463.1976. Found: 463.1977
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:36][CH2:37][C:38](Br)=[O:39]>ClCCl.O>[Br:36][CH2:37][C:38]([NH:24][C:23]1[CH:25]=[CH:26][C:20]([C:17]2[N:16]=[C:15]([C:4]3[CH:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]4[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=4)[N:5]=3)[O:19][N:18]=2)=[CH:21][CH:22]=1)=[O:39]
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N)cc4)no3)cc2C)cc1
Reactant: O=C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(NC(=O)CBr)cc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}-aniline (Step 1, 150 mg, 0.434 mmol) and N,N-diisopropylethylamine (113 μL, 0.651 mmol) in dichloromethane (5 mL) was added bromoacetyl bromide (46 μL, 0.521 mmol) dropwise at a temperature of 0° C. After 5 minutes, the reaction mixture was allowed to warm to rt. After a further 2 h, the reaction mixture was diluted with an equal volume of dichloromethane, and 20 mL water were added. After separation of the organic from the aqueous layer, the organic phase was dried over anhydrous sodium sulfate. Subsequent filtration and evaporation of the solvent yielded the title compound which was obtained in pure form after stirring with cyclohexane (195 mg, 96%): 1H NMR (400 MHz, DMSO-d6) 10.70 (s, 1H), 8.03 (d, 2H), 7.80 (d, 2H), 7.18 (d, 2H), 7.10 (d, 2H), 6.90 (s, 1H), 5.44 (s, 2H), 4.09 (s, 2H), 2.32 (s, 3H), 2.28 (s, 3H); ES-MS m/z 466/468, HPLC RT (Method F) 2.45 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]([OH:11])=[CH:9][C:8]([CH2:12][CH3:13])=[C:7]([CH3:14])[N:6]=1.Cl[CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CN(C)C=O.C(OCC)C>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[CH2:16][O:11][C:10]1[C:5]([O:4][CH3:3])=[N:6][C:7]([CH3:14])=[C:8]([CH2:12][CH3:13])[CH:9]=1
Reactant: ClCc1nc2ccccc2o1
Reactant: CCc1cc(O)c(OC)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCc1cc(OCc2nc3ccccc3o2)c(OC)nc1C
Temperature: 60 °C
Yield: 33.5 %

Procedure:
A quantity of 60% sodium hydride in mineral oil (24 mg, 0.6 mmol) was added to a solution of 2-methoxy-3-hydroxy-5-ethyl-6-methylpyridine (77 mg, 0.46 mmol) in dry dimethylformamide (2 mL). After gas evolution ceased, 2-(chloromethyl) benzoxazole (100 mg, 0.6 mmol) was added and the reaction mixture warmed at 60° C. for one hour. The reaction was then cooled, diluted with diethyl ether, the ether extract washed with water, dried (Na2SO4), filtered and evaporated to give 151 mg of crude mixture. This mixture was flash chromatographed on silica gel, eluting with 0.5% methanol/chloroform. Combined appropriate fractions gave 46 mg (32%) of oily product.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([NH:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:35]([OH:37])=[O:36])=[CH:39][CH:40]=3)[CH2:28][CH2:29]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC2CCN(CCCN(C(=O)C3CCN(C(C)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Nc3ccc(C(=O)O)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
To a solution of the compound obtained in Example 210 (51.8 mg, 0.09 mmol) in ethanol (2 mL) was added aqueous solution of 1N-sodium hydroxide (0.53 mL, 0.53 mmol), and the mixture was stirred at 90° C. for 5 hours. To the mixture was added dropwise aqueous solution of 1N-hydrochloric acid (0.53 mL, 0.53 mmol) under ice cooling, and the mixture was concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 5 g, ethyl acetate/methanol=1/0 to 1/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (28 mg, 0.05 mmol, Yield 55%) as white amorphous substance.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC1C=C(Cl)C=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Agent: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2Cl)cc1
Product: CS(=O)(=O)c1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Yield: 8.8 %

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-4′-(methylsulfonyl)benzhydryloxy]azetidine (170) (6.9 mmol) using the procedure described for compound (4). After basic aqueous workup, purification by flash column chromatography [SiO2; ethyl acetate-methanol (90:10)→ethyl acetate-methanol—ammonium hydroxide (90:10:5)] afforded the desired product as a pale yellow oil (234 mg, 9% over 2 steps).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].Cl.[CH2:18]([O:25][C:26](=[O:31])[C@@H:27]([OH:30])[CH2:28][NH2:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH2:18]([O:25][C:26](=[O:31])[C@@H:27]([OH:30])[CH2:28][NH:29][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC[C@H](O)C(=O)OCc1ccccc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)SCC(Cc1ccccc1)C(=O)NC[C@H](O)C(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
Add 2(R,S)-acetylthiomethyl-3-phenylpropionic acid (0.59 g) to (S)-isoserine benzyl ester, hydrochloride (0.578 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.53 g), 1-hydroxybenzotriazole (HOBT) (0.37 g) and N-methylmorpholine (0.80 ml) in dimethylformamide (DMF) (10 ml), and stir the resulting mixture for 20 hours. Concentrate the reaction mixture in vacuo and partition the residue between dichloromethane/water. Concentrate the dried (MgSO4) dichloromethane solution in vacuo. Chromatograph the resulting residue on a column of silica gel (1 L) using chloroform:methanol 19.5:1 as eluant to give the title compound, a colorless oil, [α]D26 =+12.3° (MeOH).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.OO.O.O.O.O.O.S([O-])([O-])(=[O:33])=S.[Na+].[Na+].O>C(O)(=O)C>[CH3:23][O:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:10]=2)=[O:33])=[CH:14][CH:15]=1
Reactant: COCCOc1ccc(Sc2ccc(OCCOC)cc2)cc1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1ccc(S(=O)c2ccc(OCCOC)cc2)cc1
Reaction time: 15 h
Yield: 984.4 %

Procedure:
In 200 g of acetic acid was dissolved 28.5 g of bis[4-(2-methoxyethoxy)phenyl]sulfide obtained in Synthesis Example 1-33. While the solution was maintained at an internal temperature of 40° C., 7.87 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 15 hours, after which under ice cooling, a mixture of 2.0 g sodium thiosulfate pentahydrate and 10 g water was added dropwise to quench the reaction. The solution was concentrated in vacuum and combined with 100 g of toluene, 50 g of ethyl acetate and 50 g of water. The organic layer was separated, washed with water, and concentrated in vacuum. The concentrate was crystallized from 20 g of ethyl acetate and 300 g of hexane, obtaining 27.8 g of the target compound, bis[4-(2-methoxy-ethoxy)phenyl]sulfoxide as white crystals. Yield 91%.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1B(O)O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: OB(O)c1ccncc1Cl
Reactant: Nc1ncc(Br)c(NC2CCOCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccncc2Cl)c(NC2CCOCC2)n1
Temperature: 130 °C
Yield: 91.1 %

Procedure:
A mixture of compound 33 (2.03 g, 7.43 mmol), 3-chloropyridin-4-ylboronic acid (3.51 g, 22.3 mmol), and Pd(PPh3)2Cl2 (0.522 g, 0.743 mmol) in dioxane (44 ml) in a pressure vessel was purged with N2 for 20 minutes and to this mixture was added aq. Na2CO3 (1 M, 22 mL) by syringe. The reaction was further purged with N2 for another 20 minutes and then heated to 130° C. for 12 hours. DCM was added to the reaction and the mixture was washed with water and brine. The organic layer was dried with sodium sulfate and concentrated to provide compound 34 (2.07 g, crude, 98%) which was used in the next reaction without further purification. LCMS-ESI (POS), M/Z, M+1: Found 306.1, Calculated 306.1.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:26])[C:12]3[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=3[C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[NH2:18][C:16]1[CH:15]=[CH:14][C:13]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[C:12]([CH:17]=1)[C:11]([NH:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2)=[O:26]
Reactant: O=C(Nc1ccc2c(c1)CCC2)c1cc([N+](=O)[O-])ccc1-c1cccs1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cccs2)c(C(=O)Nc2ccc3c(c2)CCC3)c1
Reaction time: 16 h

Procedure:
A solution of the compound of Example 5, N-(indan-5-yl)-5-nitro-2-thiophen-2-yl-benzamide (0.083 g, 0.228 mmol) in ethyl acetate (10 mL) is degassed and 10% palladium on carbon added. The reaction mixture is evacuated and placed under 1 atm H2(g) for 16 h. Filtration of the reaction mixture through Celite is followed by concentration of the filtrate under reduced pressure to give 5-amino-N-(indan-5-yl)-2-(thiophen-2-yl)-benzamide as an oil which foams to a solid on treatment with diethyl ether. mp 62-67° C. MS (ES+), m/z 335 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[H-].[Na+].Cl.Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21].O>CN(C=O)C>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][N:12]1[CH2:11][CH2:10][O:9][C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]1=2
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN1CCOc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A solution of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (240 mg, 1.33 mmol) in DMF (10 mL) was treated with NaH (170 mg, 4.26 mmol, 60% wt in mineral oil) at 0° C., resulting in an orange mixture. The mixture was then treated with 2-chloro-N,N-dimethylethanamine hydrochloride (384 mg, 2.66 mmol), resulting in a dark red mixture. The reaction was stirred at room temperature for 1 hour. At this time, the reaction was then heated to 90° C. and stirred for another 45 minutes. The reaction was cooled to room temperature, water (15 mL) was added, and the reaction was extracted into EtOAc (2×12 mL). The combined organic layers were washed with brine (3×5 mL), dried (Na2SO4), filtered, and concentrated. The residue was subjected to flash chromatography on silica gel: CH2Cl2 followed by 5:95 (2M NH3 in MeOH):CH2Cl2 to give a yellow/orange solid (210 mg, 63%). 1H-NMR (DMSO-d6) δ 7.75 (dd, J=2.7, 9.0 Hz, 1H), 7.48 (d, J=2.7 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 4.18 (t, J=4.5 Hz, 2H), 3.57-3.53 (m, 4H), 2.54-2.45 (m, 2H), 2.23 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([OH:24])[N:9]=1.S(Cl)(Cl)=O.[CH2:29](Cl)Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([O:24][CH3:29])[N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2O
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC1N=C(c2ccccc2F)c2cc(I)ccc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.435 g (1 mmol) of rac-6-(2-fluorophenyl)-4-hydroxy-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine, 3 ml of thionyl chloride and 20 ml of methylene chloride was stirred at room temperature for 2 hours. After evaporation under reduced pressure, the residue was dissolved in 20 ml of methanol and the solution was :reated with 3 ml of triethylamine. After heating on the steam bath for 5 minutes, the mixture was evaporated to dryness and the residue was partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic layer was dried and evaporated and the residue was crystallized from ethyl acetate to yield colorless crystals of rac-6-(2-fluorophenyl)-8-iodo-4-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with m.p. 240°-242°. The analytical sample was recrystallized from methanol/ethyl acetate and had m.p. 243°-244°.