Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].[Br:15][C:16]1[CH:17]=[C:18]2[C:29](=[CH:30][CH:31]=1)[O:28][C:21]1[C:22]([F:27])=[N:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:19]2=[N:32]S(C(C)(C)C)=O.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:15][C:16]1[CH:17]=[C:18]2[C:19]3([C:7]4=[N:14][CH:13]=[CH:12][CH:11]=[C:8]4[C:9]([NH2:10])=[N:32]3)[C:20]3[CH:25]=[C:24]([Cl:26])[N:23]=[C:22]([F:27])[C:21]=3[O:28][C:29]2=[CH:30][CH:31]=1
Reactant: N#Cc1cccnc1Br
Reactant: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC1=NC2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2ncccc21
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-butyllithium (102 μL, 0.164 mmol, Aldrich) was added dropwise to a solution of 2-bromonicotinonitrile (30 mg, 0.164 mmol, Aldrich) in THF (2 mL) at −95° C. under N2 atmosphere. After 1 min a solution of N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide (55 mg, 0.127 mmol, example 1b) in THF (1 mL) was added. After 2 min aqueous, saturated NH4Cl solution was added and the reaction mixture was allowed to warm to RT. EtOAc was added and the organic phase was separated. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The remaining residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min to obtain the title compound as a light-yellow solid. MS m/z=432.8 [M+H]+. Calculated for C18H9BrClFN4O: 431.65
Reaction SMILES: [CH3:1][C@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@@H:15]1[CH2:14][C@H:13]1[C@@H:4]([CH2:5][CH2:6][C@H:7]3[C@@H:12]1[CH2:11][CH2:10][C:9](=[O:20])[CH2:8]3)[CH2:3]2.Cl>C1COCC1>[OH:20][CH:9]1[CH2:8][C@@H:7]2[C@@H:12]([C@@H:13]3[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@@:2]2([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16][C@@H:15]2[CH2:14]3)[CH2:11][CH2:10]1
Reactant: C[C@@]12C[C@@H]3CC[C@@H]4CC(=O)CC[C@@H]4[C@H]3C[C@H]1CCC2=O
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@]12C[C@@H]3CC[C@@H]4CC(O)CC[C@@H]4[C@H]3C[C@H]1CCC2=O
Reaction time: 2 h

Procedure:
To a solution of compound 54 (110 mg, 0.4 mmol) in THF (10 mL) was added LiAl(OtBu)3H at 40° C. After 2 h, 3 N HCl, was added and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) to give compound 55 (4aR separated from 4aS diastereomer, 65 mg, 56% from compound 36) as a white solid: mp 174-176° C.; [α]D25 −36.2 (c 0.21, CHCl3); 1H NMR (CDCl3) δ 3.65-3.55 (m, 1H), 0.82 (s, 3H); 13C NMR (CDCl3) δ 221.1, 71.4, 47.9, 45.7, 40.1, 39.1, 38.8, 38.4, 36.2, 35.6, 35.5, 31.7, 29.6, 29.3, 28.4, 25.5, 24.0, 13.5; IR νmax 3460, 1738 cm−1. Anal. Calcd for (C18H28O2): C, 78.21; H, 10.21. Found: C, 78.37; H, 10.20.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC=CC=1.[Mg].[S:17]([C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)C#N>C1COCC1>[C:1]1([S:17][C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CSc1ccc[nH]1
Reactant: Br[Mg]c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Brc1ccccc1
Product: c1ccc(Sc2ccc[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of phenyl magnesium bromide (prepared from bromobenzene (0.75 ml) and magnesium chips (0.19 g, 7.8 mmol) in anhydrous THF (20 ml), cooled to 0° C., was slowly added a solution of 2-thiocyanopyrrole 11 (0.5 g, 4.0 mmol) in anhydrous THF (20 ml). After stirring at 0° C. for 30 min, the mixture was poured into crushed ice and extracted with ethyl acetate. The organic phase was washed with 20% NH4Cl, anhydrified and evaporated. The residue was purified by chromatography (35% hexane in chloroform) to give 0.6 g (93% yield) of 12 as colourless prisms: melting point 86-87° C. (hexane); IR (CHCl3) 3420 cm−1; 1H NMR (CDCl3) δ8.20 (br s, 1H), 7.25-6.85 (m, 5H), 6.92 (m, 1H), 6.55 (m, 1H), 6.31 (m, 1H). Anal. (C9H9NS): C, H, N.
Reaction SMILES: C([N:7]1[CH2:10][CH:9]([NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:8]1=[O:22])(C(OC)=O)=O.C[O-].[Na+]>CO>[CH2:15]([O:14][C:12]([NH:11][CH:9]1[CH2:10][NH:7][C:8]1=[O:22])=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C(=O)N1CC(NC(=O)OCc2ccccc2)C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC1CNC1=O)OCc1ccccc1
Yield: 73 %

Procedure:
1-Methoxalyl-3-benzyloxycarbonylamino-2-azetidinone (240 mg.) was dissolved in methanol (10 ml.), and sodium methylate (6 mg.) was added to said solution, and then the mixture was heated under reflux for 45 minutes. The methanol was distilled off from the reaction mixture, and the residue was washed with ether to give crude 3-benzyloxycarbonylamino-2-azetidinone (126 mg.). Furthermore, this product was recrystallized from acetone to give the purified compound (50 mg.). And, the purified same compound (54 mg.) was recovered from the mother liquor. Total yield was 104 mg. Mp 164° to 165° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12].[ClH:14]>O>[ClH:14].[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12])[NH2:8]
Reactant: CC(C)c1ccc([N+](=O)[O-])cc1Br
Agent: Cl
Solvent: O
Product: CC(C)c1ccc(N)cc1Br
Temperature: 0 °C
Yield: 99.8 %

Procedure:
2-Bromo-1-isopropyl-4-nitrobenzene (XI) (50 g, 0.192 mol, 93.5 GC-% by area), 100 ml of water, ironpowder (40.71 g, 0.718 mol) were heated to 70° C. and hydrochloric acid (193.7 g, 1.647 mol, 31% in water) was added over a period of 2 hours. The mixture was then cooled to 0° C. and the suspension was filtered with suction. The solvent obtained was dried overnight at 50° C. in a vacuum drying oven. 3-Bromo-4-isopropylaniline hydrochloride (48 g, purity: 88.7%, contains: 8.6% of iron, 88.7% of theory) was obtained as a light-brown solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]3[C:5]([O:24][CH3:25])=[CH:4][CH:3]=[C:2]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:10]=3[N:9]=2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: OB(O)c1ccccc1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)ccc(OC)c21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(-c3ccccc3)ccc(OC)c21
Temperature: 100 °C
Reaction time: 9 h
Yield: 52.9 %

Procedure:
A mixture of 100 mg (0.25 mmol) 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole, 45 mg (0.424 mmol) sodium carbonate, 34 mg (0.275 mmol) phenyl-boronic acid and 10 mg tetrakis(triphenylphosphine) palladium in 10 ml toluene/water (3:1) is stirred at 100° C. for 9 hours. Then the reaction mixture is cooled to room temperature and poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=4:1) to afford 53 mg of the title compound as a white crystalline solid.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=4)=[CH:23][C:16]=3[N:15]=2)=[CH:9][CH:8]=1.[CH2:33](N)[CH2:34][NH2:35]>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[NH:35][CH2:34][CH2:33][N:32]=5)[CH:26]=4)=[CH:23][C:16]=3[N:15]=2)=[CH:9][CH:8]=1
Reactant: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(C#N)c3)ccc21
Reactant: NCCN
Agent: O=S(=O)(O)O
Product: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(C4=NCCN4)c3)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
H2SO4 (454 mg) was added cautiously to a suspension of 4-[2-(4-chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbonitrile (60.0 mg) in ethylenediamine (0.50 mL). The system was shaken at room temperature for 72 hrs, then poured onto ice/NaHCO3. The solid product was collected, washed (H2O) air-dried 59.8 mg. M/z=419 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=O)[N:20]=2)=[CH:11][CH:10]=1.[CH:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[C:27]1=O)[CH2:33]2.O>C1COCC1.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-].C(OCC)(=O)C>[CH:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[C:27]1=[C:19]1[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[O:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=3)=[N:20]1)[CH2:33]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: COc1ccc(-c2nc(=O)c3ccccc3o2)cc1
Agent: [Ti+4]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2=NC(=C3C4CC5CC(C4)CC3C5)c3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21 mmol lithium aluminium hydride is carefully added to a suspension of 40 mmol titanium chloride in 100 ml absolute THF while stirring vigorously. After stirring for 1 hour at room temperature, a mixture of 15 mmol 2-(4'-methoxyphenyl)-4H-1,3-benzoxazine-4-one and 11 mmol adamantanone is added while cooling on ice. It is heated to boiling for 60 min under reflux. After cooling to room temperature it is poured onto 200 ml water. The mixture is shaken out twice with 200 ml ethyl acetate each time. The combined organic phases are washed once with water and separated. After drying over sodium sulfate it is filtered and the solvent is removed by distillation. The oily residue is separated by column chromatography (silica gel: ethyl acetate/petroleum ether 1:9).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>>[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][N:36]([C:29]([CH:25]2[CH2:24][N:23]([C:20]3[CH:19]=[CH:18][C:17]([C:15]([N:12]4[CH2:13][CH2:14][N:9]([C:3]5[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=5[CH3:1])[CH2:10][CH2:11]4)=[O:16])=[CH:22][CH:21]=3)[C:27](=[O:28])[CH2:26]2)=[O:31])[CH2:35]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)O)CC4=O)cc3)CC2)c(C)c1
Reactant: CN(C)[C@H]1CCNC1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)N5CC[C@H](N(C)C)C5)CC4=O)cc3)CC2)c(C)c1
Yield: 39.2 %

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid (100 mg) described in Example 333 and (S)-3-(dimethylamino)pyrrolidine (27 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (48 mg) was obtained.
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H:5]([OH:6])[C@H:3]1[OH:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].S([O-])([O-])(=O)=O.[Mg+2]>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
25g of lactose was added to 0.05M potassium phosphate buffer solution (pH 7.0) and heated to solution for a total quantity of 45 ml. Then, bacteria suspension (300 units as β-galactosidase) of streptococcus thermophilus YIT2046 obtained from a culture, 5 g of immobilized glucose isomerase GODO-AGI, and 0.25 ml IM-magnesium sulfate were added before addition of water so as to make the total quantity 50 ml. The thus-prepared liquid was reacted at 50° C. over night while being shaken. 1g of activated carbon was added to liquid to be reacted from which immobilized glucose isomerase and bacteria of streptococcus thermophilus had been filtered, and then the liquid was subjected to a decoloring processing. As a result, a colorless sugar liquid was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:24]1([C:30]2[O:31][C:32]([C:38]([F:41])([F:40])[F:39])=[C:33]([C:35](O)=[O:36])[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[C:1]([O:5][C:6](=[O:23])[CH2:7][O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:35]([C:33]3[N:34]=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:31][C:32]=3[C:38]([F:40])([F:41])[F:39])=[O:36])=[CH:16][N:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)COC1CCN(c2ccc([N+](=O)[O-])cn2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COC1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1
Yield: 36.9 %

Procedure:
[1-(5-Nitro-pyridin-2-yl)-pyrrolidin-3-yloxy]-acetic acid tert-butyl ester (280 mg, 0.866 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (245 mg, 0.953 mmol), Et3N (486 uL, 3.46 mmol) and BOP (402 mg. 0.909 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield (1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yloxy)-acetic acid tert-butyl ester as a solid (170 mg). ES-MS calcd for C26H27F3N4O5 (m/e) 532.52, obsd 533.1 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:21])[NH:16][CH:17]([CH3:20])[CH2:18][OH:19])[CH:10]=1.[NH3:23]>O>[C:3]([CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][CH:17]([CH3:20])[CH2:18][OH:19])=[O:21])(=[O:2])[NH2:23]
Reactant: COC(=O)CCCC=Cc1cccc(C(=O)NC(C)CO)c1
Reactant: N
Solvent: O
Product: CC(CO)NC(=O)c1cccc(C=CCCCC(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
21 (0.030 g, 0.10 mmol) was dissolved in 2 mL of ammonia 33% solution in water and stirred at room temperature for 8 h. The solvent was removed and the product was purify by reverse-phase HPLC chromatography (18% acetonitrile/82% water 20 min isocratic program) to give 19 (7 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH2:6][CH2:5][N:4]([CH:9]([C:11]([OH:13])=[O:12])[CH3:10])[C:3]1=[O:14].O=[C:16]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:11]([CH:9]([N:4]1[C:3](=[O:14])[CH:2]([NH:1][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:8][S:7][CH2:6][CH2:5]1)[CH3:10])([OH:13])=[O:12]
Reactant: CC(C(=O)O)N1CCSCC(N)C1=O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(CCc1ccccc1)NC1CSCCN(C(C)C(=O)O)C1=O
Yield: 74.8 %

Procedure:
6-Amino-4-N-(1-carboxyethyl)perhydro-1,4-thiazepin-5-one (0.05 g) is suspended in 1 ml of methanol. Ethyl 2-keto-4-phenylbutyrate (0.24 g) and acetic acid (0.02 g) are added. A 1M solution of sodium cyanoborohydride (0.75 ml) is added dropwise over a period of twenty hours. After removal of methanol, the reaction mixture is taken up in water and loaded onto a column of Dowex-50 (on the proton cycle). After thorough washing with water, the column is developed with 5% pyridine solution. Lyophilization of the eluent afforded the crude product (0.08 g), which is purified by preparative thin layer chromatography on silica gel (9:1 chloroform-methanol containing 5% formic acid). The product is obtained as an oil (0.07 g). The NMR spectrum is consistent with the assigned structure.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[O-:23][Bi](=O)=O.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>CO.O>[O:23]=[C:12]1[C:4]2[C:3]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)=[N:2][NH:1][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: O=[Bi](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2n[nH]c3c2C(=O)c2ccccc2-3)cc1

Procedure:
A mixture of methyl 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoate (6.3 g, Example 7), sodium bismuthate (31 g), glacial acetic acid (180 ml) and water (60 ml) was boiled under reflux for about 3.5 hours. A further amount of sodium bismuthate (33 g) was added and the mixture boiled under reflux for about 24 hours, then cooled. The pH of the reaction mixture was adjusted to 8-9 by addition of saturated sodium bicarbonate solution. The reaction mixture was filtered through a celite pad and the residue solid washed with ethyl acetate. The organic layer was separated, dried, filtered and evaporated to give a brown solid. The solid was boiled up in methanol (50 ml), cooled and the solid was filtered off, then dried to give methyl 4-(4-oxo-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoate, m.p. dec. 235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]1)[CH2:7][CH2:6]2>CC(C)=O.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]1)[CH:7]=[CH:6]2
Reactant: COc1cc2c(cc1OC)N(CCn1cc(N)cn1)CC2
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: COc1cc2ccn(CCn3cc(N)cn3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(2-(5,6-dimethoxyindolin-1-yl)ethyl)-1H-pyrazol-4-amine (1.36 g, 4.70 mmol) in acetone (10 mL) was added dropwise to a suspension of MnO2 (817 mg, 9.41 mmol) in aceton (10 mL). The resulting dark reaction mixture was stirred at rt overnight, then filtered over celite, washed with acetone and the filtrate was concentrated under reduced pressure. Purification was performed by FC (DCM/MeOH 98:2→95:5) to yield the title compound as a brown oil. LC-MS conditions B: tR=0.41 min, [M+H]+=287.18.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[NH:23]([C:20](=[O:22])[CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:10]=2)=[CH:17][CH:16]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNC(=O)c1cc(Oc2ccc(CCC(=O)O)cc2)ccn1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(CCC(=O)Nc3ccccc3)cc2)ccn1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
A mixture of 3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-propanoic acid (100 mg, 0.33 mmol), aniline (0.033 mL, 0.36 mmol), and TBTU (117 mg, 0.36 mmol) in DCM (5 mL) was stirred at rt. To this slurry was added DIPEA (0.20 mL, 1.16 mmol). The mixture was allowed to stir at rt overnight and then diluted with water. The aqueous phase was separated and extracted with DCM. The organic solutions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The resulting solid was treated with MeOH and filtered to give 45 mg of a white solid. 1H NMR (400 MHz, d6-DMSO) δ: 9.90 (br s, 1H), 8.71-8.78 (m, 1H), 8.48 (d, J=5.6 Hz, 1H), 7.55-7.60 (m, 2H), 7.36-7.40 (m, 2H), 7.36 (d, J=2.4 Hz, 1H), 7.25-7.31 (m, 2H), 7.12-7.16 (m, 2H), 7.11 (dd, J=5.2, 2.4 Hz, 1H), 6.99-7.04 (m, 1H), 2.93-2.98 (m, 2H), 2.77 (d, J=4.8 Hz, 3H), and 2.64-2.69 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].[P:7](Cl)([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:7]([O:12][CH2:13][CH3:14])(=[O:8])[O:9][CH2:10][CH3:11]
Reactant: [Li]c1cccs1
Reactant: CCOP(=O)(Cl)OCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cccs1

Procedure:
A solution of 1.0 mmol 2-thienyl lithium in THF was treated with 1.0 mmol diethyl chlorophosphate at −78° C. for 1 h. Extraction and chromatography gave diethyl 2-thiophenephosphonate as a clear oil.
Reaction SMILES: [OH:1][C@@H:2]([C@H:6]1[CH2:10][N:9]([C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH3:12])[C:8](=[O:21])[CH2:7]1)[CH2:3][CH:4]=[CH2:5].[H-].[Na+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][O:1][C@@H:2]([C@H:6]2[CH2:10][N:9]([C@@H:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH3:12])[C:8](=[O:21])[CH2:7]2)[CH2:3][CH:4]=[CH2:5])=[CH:28][CH:27]=1
Reactant: COc1ccc(CCl)cc1
Reactant: C=CC[C@@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@H](OCc1ccc(OC)cc1)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the alcohol 1.08 (480 mg 1.7 mmol) in 8 mL of DMF at 0° C. was added NaH (166 mg, 60% dispersion in oil, 4.2 mmol) and their reaction was stirred for 30 minutes at 0° C. p-Methoxybenzyl chloride (0.36 mL, 2.7 mmol) was added and the resulting mixture stirred at room temperature for 3 hr. The reaction was quenched with water, and the mixture was extracted with EtOAc. The combined organics were dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography (30-70% EtOAc in hexanes) to afford (R)-4-((R)-1-(4-methoxybenzyloxy)but-3-enyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.25.
Reaction SMILES: [Na+:1].[Na+].[Na+].[Na+].[N+:5]([C:8]1[CH:9]=[C:10]([C:35]([NH:37][C:38]2[CH:39]=[C:40]3[C:45](=[CH:46][CH:47]=2)[C:44]([S:48]([O-:51])(=[O:50])=[O:49])=[CH:43][C:42]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:41]3)=[O:36])[CH:11]=[C:12]([C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:22][C:21]([S:31]([O-:34])(=[O:33])=[O:32])=[CH:20]3)=[O:15])[CH:13]=1)([O-])=O.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].C(O)(=O)C>O>[Na+:1].[Na+:1].[Na+:1].[Na+:1].[NH2:5][C:8]1[CH:9]=[C:10]([C:35]([NH:37][C:38]2[CH:39]=[C:40]3[C:45](=[CH:46][CH:47]=2)[C:44]([S:48]([O-:51])(=[O:49])=[O:50])=[CH:43][C:42]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:41]3)=[O:36])[CH:11]=[C:12]([C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:22][C:21]([S:31]([O-:34])(=[O:33])=[O:32])=[CH:20]3)=[O:15])[CH:13]=1
Reactant: O=C(Nc1ccc2c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc2c1)c1cc(C(=O)Nc2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(C(=O)Nc2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2)cc(C(=O)Nc2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2)c1

Procedure:
To a solution of 13.49 g of 6,6'-[5-nitro-1,3-phenylenebis(carbonylimino)]bis[1,3-naphthalenedisulfonic acid] tetrasodium salt in 200 ml of water at 65° C. is added 6.42 g of sodium sulfide nonahydrate. After heating on the steam bath at 70° to 75° C. the solution is cooled, acidified with acetic acid and filtered. The filtrate is adjusted to pH 6 with 5N sodium hydroxide solution and concentrated to small volume. The solution is diluted with absolute ethanol and filtered to give the title compound.