Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:22]5[CH:27]=[CH:26][C:25]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)=[CH:24][CH:23]=5)[CH:19]=4)[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)[C:6]([O:35][CH3:36])=[CH:5][C:4]=1[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38].[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:22]5[CH:23]=[CH:24][C:25]([N:28]6[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]6)=[CH:26][CH:27]=5)[CH:19]=4)[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)[C:6]([O:35][CH3:36])=[CH:5][C:4]=1[CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]
Reactant: COc1cc(-c2ccnc3[nH]c4ccc(-c5ccc(N6CCN(C)CC6)cc5)cc4c23)c(OC)cc1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(O)c2ccccc2)c(OC)cc1-c1ccnc2[nH]c3ccc(-c4ccc(N5CCN(C)CC5)cc4)cc3c12
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of (2,5-dimethoxy-4-(6-(4-(4-methylpiperazin-1-yl)phenyl)-9H-pyrido[2,3-b]indol-4-yl)phenyl)(phenyl)methanone (example 50, 39.8 mg, 0.0683 mmol) in CH2Cl2/MeOH 5:2 (2 mL), NaBH4 (6 mg, 2.3 eq) was added. After stirring for 1 h20 at r.t., the reaction mixture was quenched with sat. aq. NH4Cl (5 mL), diluted with CH2Cl2 (25 mL) and washed with water (30 mL) The organic layer was collected and the aqueous layer washed four times with CH2Cl2 (20 mL) The combined organic layers were washed with brine and dried over MgSO4, filtered and evaporated to dryness. A white solid was obtained in 66% yield (26.3 mg) after trituration of the crude product in DCM and filtration. 1H NMR (300 MHz, DMSO, 80° C.) δ 11.61 (s, 1H), 8.41 (d, J=5.0 Hz, 1H), 7.63 (dd, J=8.4, 1.9 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.49-7.41 (m, 4H), 7.35-7.15 (m, 5H), 7.08 (d, J=5.0 Hz, 1H), 7.02 (s, 1H), 6.98-6.79 (m, 2H), 6.11 (d, J=4.9 Hz, 1H), 5.67 (d, J=5.4 Hz, 1H), 3.69 (s, 3H), 3.62 (s, 3H), 3.24-3.14 (m, 4H), 2.54-2.47 (m, 4H), 2.27 (s, 3H); 13C NMR (75 MHz, DMSO, 80° C.) δ 152.2 (C), 150.2 (C), 149.6 (C), 149.2 (C), 145.2 (CH), 144.8 (C), 140.6 (C), 137.6 (C), 135.1 (C), 131.0 (C), 131.0 (C), 127.5 (CH), 126.3 (CH), 126.2 (CH), 126.1 (CH), 125.9 (C), 124.3 (CH), 121.8 (C), 120.7 (C), 118.6 (CH), 116.1 (CH), 115.3 (CH), 113.4 (CH), 111.0 (CH), 110.6 (CH), 68.1 (CH), 55.9 (OCH3), 55.8 (OCH3), 54.3 (2CH2), 47.8 (2CH2), 45.3 (NCH3); MS (ESI) m/z: 585.5 [M+H]+; 1170.1 [2M+H]+; 567.3 [M-OH]+; HRMS calcd for C37H37N4O3 [M+H]+ 585.2860 found 585.2868.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@:13]2([CH2:15][OH:16])[C@@H:11]([CH2:12]2)[N:10]1[C:17](=[O:31])[CH2:18][N:19]1[C:23]2=N[CH:25]=[CH:26][CH:27]=[C:22]2[C:21]([C:28](=[O:30])[CH3:29])=[CH:20]1)=[O:8].[C:36](C1C2C(=CC=CC=2)N(CC(O)=O)C=1)(=O)C>CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@:13]2([CH2:15][OH:16])[C@@H:11]([CH2:12]2)[N:10]1[C:17](=[O:31])[CH2:18][N:19]1[C:23]2[C:22](=[CH:27][CH:26]=[CH:25][CH:36]=2)[C:21]([C:28](=[O:30])[CH3:29])=[CH:20]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)c2ncccc12
Reactant: CC(=O)c1cn(CC(=O)O)c2ccccc12
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)c2ccccc12

Procedure:
The title compound was prepared in 2 steps according to the procedure described for the preparation of Example 610 (1R,3S,5S)-2-[2-(3-acetyl-pyrrolo[2,3-b]pyridin-1-yl)-acetyl]-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide using (3-acetyl-indol-1-yl)-acetic acid instead of (3-acetyl-pyrrolo[2,3-b]pyridin-1-yl)-acetic acid. White powder. TLC, Rf (EtOAc)=0.05; MS (LC/MS): 498/500 [M+H]+, 520/522 [M+Na]+; tR (HPLC conditions f): 1.84 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([CH3:30])[CH:24]=2)=[CH:21][NH:20][N:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([CH3:30])[CH:24]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Br)cc4)nc23)cc(C)n1
Yield: 41.6 %

Procedure:
Reaction of 1-(4-bromo-phenyl)-4,4,4-trifluoro-butane-1,3-dione (148 mg, 0.5 mmol), prepared from commercially available 4-bromo-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (93 mg, 42%). MS (ISP) 447.2 [(M+H)+]; mp 258° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:15][CH2:16][C:17]#[N:18]>O1CCOCC1.Cl>[C:16]([CH2:17][NH:18][S:9]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:13])[F:1])(=[O:11])=[O:10])#[N:15]
Reactant: N#CCN
Reactant: O=S(=O)(Cl)c1cnccc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: N#CCNS(=O)(=O)c1cnccc1C(F)(F)F
Reaction time: 8 h
Yield: 28.8 %

Procedure:
4-Trifluoromethyl-pyridine-3-sulfonyl chloride (0.45 g) was dissolved in dioxane (3 ml), and ami-noacetonitrile (1.0 g) was added to the mixture and allowed to stand at ambient temperature overnight. The reaction was diluted with 0.5% HCl and 37% HCl was added dropwise until the mixture became acidic. This was extracted three times with ethyl acetate. The ethyl acetate portions were combined, washed with saturated sodium bicarbonate and dried with magnesium sulfate. The drying agent was filtered away and the solvent evaporated to give 0.14 g of crude 4-Tri-fluoromethyl-pyridine-3-sulfonic acid cyanomethyl-amide, which was chromatographed an silica gel using methylene chloride to yield 0.06 g of purified 4-Trifluoromethyl-pyridine-3-sulfonic acid cyanomethyl-amide. LC/ms analysis with RT=1.12 min yielded a purity of 99% m+/m− of 265.87/263.88. Melting point of the purified compound tested as 158-159° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:5]=2[C:25](O)=[O:26])[CH2:3][CH2:2]1.Cl.Cl.[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:40][CH2:39][CH2:38][C@H:37]2[CH2:41][OH:42])[CH2:32][CH2:31]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=3)[N:7]=[C:6]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:5]=2[C:25]([N:30]2[CH2:31][CH2:32][CH:33]([N:36]3[CH2:40][CH2:39][CH2:38][C@H:37]3[CH2:41][OH:42])[CH2:34][CH2:35]2)=[O:26])[CH2:2][CH2:3]1
Reactant: O=C(O)c1c(-c2ccncc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Agent: Cl
Product: O=C(c1c(-c2ccncc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1)N1CCC(N2CCC[C@H]2CO)CC1
Yield: 54 %

Procedure:
In analogy to the procedure described in Example 160E), 5-cyclopropyl-3-pyridin-4-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid (Example 165B]) and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol dihydrochloride (Example 161A]) gave the title compound as a light yellow solid (54%). MS: 539.8 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:38])[CH2:13][N:14]=1
Reactant: COc1ccc(CCc2cc3c(s2)NC(=O)CN=C3c2ccccc2Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCc2cc3c(s2)NC(=S)CN=C3c2ccccc2Cl)cc1
Yield: 132.6 %

Procedure:
A suspension of 7 g of 5-(2-chlorophenyl)-7-[2-(4-methoxyphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 196°-198° C. and 5 g of Lawesson reagent in 100 ml of toluene is stirred at 45°-48° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 7 g of 5-(2-chlorophenyl)-7-[2-(4-methoxyphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 185°-186° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([N:14]1[CH:19]=[CH:18][C:17](=[O:20])[CH2:16][C@H:15]1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:13])[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[N:6]=[C:5]2[CH3:38].FC(F)(F)C(O)=O>CSC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([N:14]1[CH:19]=[CH:18][C:17](=[O:20])[CH2:16][C@H:15]1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:13])[NH:7][N:6]=[C:5]2[CH3:38]
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(NC(=O)N4C=CC(=O)C[C@H]4c4ccc(F)cc4)cc32)cc1
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2cc(NC(=O)N3C=CC(=O)C[C@H]3c3ccc(F)cc3)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
(S)-2-(4-Fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid [5-bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-yl]-amide (40 mg, 0.07 mmol) was dissolved in dimethylsulfide (5 ml) at room temperature. Trifluoroacetic acid (1 ml) was added and the mixture was allowed to stir at room temperature overnight. The solution was concentrated in vacuo, and the residue was purified by flash chromatography (gradient 9:1 to 1:1 Hexanes/Ethyl Acetate) to give (S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (5-bromo-3-methyl-1H-indazol-6-yl)-amide 30 mg (90.0%) of an off-white foam. MS (ES+) m/z 443 (M+H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]2[CH2:7][N:8]([C@H:10]3[CH2:15][N:14]([CH3:16])[C@H:13]([C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[F:24])[C@@H:12]([NH:25]C(=O)OC(C)(C)C)[CH2:11]3)[CH2:9][C:3]=12.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].C(Cl)Cl>>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH2:25][C@@H:12]1[C@@H:13]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[N:14]([CH3:16])[CH2:15][C@H:10]([N:8]2[CH2:9][C:3]3[C:4](=[N:5][NH:6][C:2]=3[NH2:1])[CH2:7]2)[CH2:11]1
Reactant: CN1C[C@H](N2Cc3n[nH]c(N)c3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@H](N2Cc3n[nH]c(N)c3C2)C[C@H](N)[C@H]1c1cc(F)ccc1F

Procedure:
The product from step B was treated with 1:1 TFA/CH2Cl2 for 1 h. The solvent was removed by evaporation under diminished pressure and residue dried under vacuum to give the title compound. LC-MS: 349.0 (M+1).
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[OH:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[C:39]=1[C:46](=O)[CH3:47].[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:46]([C:39]2[C:40]([O:44][CH3:45])=[CH:41][CH:42]=[CH:43][C:38]=2[OH:37])[CH:47]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COc1cccc(O)c1C(C)=O
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(O)c1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 69 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(2-hydroxy-6-methoxy-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (75 mg, 69% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[O:15]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:26][C:25]1[CH:24]=[CH:23][C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:28][CH:27]=1)=[O:11]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Oc2ccccc2)cc1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-phenoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I:13]I>C(O)(=O)C.OS(O)(=O)=O>[I:13][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@@H:2]([C:10]([OH:12])=[O:11])[NH2:1])=[CH:5][CH:6]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccc(I)cc1)C(=O)O
Temperature: 35 °C
Yield: 132.8 %

Procedure:
Into a solution of 40.15 gm (0.243 mol) of phenylalanine in a mixture of 220 mL of acetic acid and 29 mL of concentrated H2SO4 was added 24.65 gm (0.097 mol) of powered iodine and 10.18 gm(0.051 mol) of powered NaIO3 while stirring. The reaction mixture was stirred at 70° C. for 21 h, during this time, two portions of 1 gm of NaIO3 were added. The mixture was cooled and the acetic acid was removed by using rotavapor while temperature was maintained at 35° C. and the residue oil was diluted by adding 400 mL of water. The aqueous solution was extracted once with 100 mL ether and once with 100 of dichloromethane. After decolorization with 5 gm of Norit, the aqueous solution was neutralized by adding solid NaOH to precipitate the crude product, which, after chilling, was filtered and rinsed with 800 mL of water and 300 mL of ethanol. The wet product was recrystallized from 200 mL of acetic acid to produce 37.5 gm of 4-iodo-L-phenylalanine.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([N:13]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:15]=[C:14]1[CH2:28]Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C.O>CN(C)C=O>[C:1]([O:4][CH2:28][C:14]1[N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1nc(CBr)n(Cc2ccccc2)c1C(=O)OCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1nc(COC(C)=O)n(Cc2ccccc2)c1C(=O)OCC
Temperature: 40 °C
Yield: 60.1 %

Procedure:
1.11 g of sodium acetate were added to a solution of 2.67 g of diethyl11-benzyl-2-bromomethylimidazole-4,5-dicarboxylate [prepared as described in Preparation 42(ii)] in 30 ml of dimethylformamide, and the resulting mixture was heated at 40° C. for 5 hours. At the end of this time, the reaction solution was mixed with ethyl acetate and water, and then the ethyl acetate layer was separated. The resulting ethyl acetate extract was washed with an aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.52 g of the title compound as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:15]1[C:19](=[S:20])N=NN1.[Na]>>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][S:10]([CH2:13][CH3:14])(=[O:11])=[O:12])=[CH:4][C:3]=1[N:15]=[C:19]=[S:20]
Reactant: CCS(=O)(=O)Nc1cc(-n2[nH]nnc2=S)c(F)cc1Cl
Agent: [Na]
Product: CCS(=O)(=O)Nc1cc(N=C=S)c(F)cc1Cl

Procedure:
1-[2-fluoro-4-chloro-5-(ethylsulfonylamino)phenyl]-5H-tetrazol-5-thione and its sodium salt;
Reaction SMILES: [C:1]1([C:7]2[C:16]([NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]([O:28]C)=[O:27])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:32]I.Cl>C1COCC1>[CH3:32][N:17]([C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:16]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:26]([OH:28])=[O:27])=[CH:11][CH:10]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N[C@H](C)c3ccccc3)nc2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (R)-methyl 2-phenyl-3-(1-phenylethylamino)quinoxaline-6-carboxylate (141 mg, 0.37 mmol, 1.00 equiv) in THF (20 mL), sodium hydride (294.5 mg, 7.36 mmol, 20.00 equiv, 60%). The resulting solution was stirred for 1 h at room temperature in an ice/salt bath. This was followed by the addition of a solution of CH3I (522.8 mg, 3.68 mmol, 10.00 equiv) in THF (1 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 20° C. The pH value of the solution was adjusted to 3-4 with 1N aqueous hydrogen chloride. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 57 mg (39%) of (R)-3-(methyl(1-phenylethyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]1[S:15]/[C:4](=[C:5]2/[N:6]=[C:7]3[C:13]([S:14]/2)=[CH:12][C:10](=[O:11])[CH:9]=[CH:8]3)/[NH:3][C@H:2]1[C:16]([OH:18])=[O:17].[O-2:19].[Mg+2].[O:21]=[P:22](Cl)(Cl)Cl.[OH2:26]>C(Cl)(Cl)(Cl)Cl>[CH2:1]1[S:15]/[C:4](=[C:5]2/[N:6]=[C:7]3[C:13]([S:14]/2)=[CH:12][C:10](=[O:11])[CH:9]=[CH:8]3)/[NH:3][C@H:2]1[C:16]([OH:18])=[O:17].[O-:19][P:22]([O-:21])([O-:11])=[O:26]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O
Reactant: [O-2]
Agent: O=C1C=Cc2n/c(=C3\N[C@@H](C(=O)O)CS3)sc2=C1
Agent: [Mg+2]
Solvent: ClC(Cl)(Cl)Cl
Product: O=P([O-])([O-])[O-]
Reaction time: 0.5 h

Procedure:
50 mg (180 μmole) D-luciferin is dissolved in 2 ml water and mixed with 350 mg (8.75 mmole) magnesium oxide. To the cooled suspension, slowly and drop by drop a solution of 92 mg (600 μmole) phosphoroxychloride in 1 ml carbon tetrachloride is added. It is then allowed to stand for 30 min at room temperature, filtered and neutralized with acetic acid. After concentration, it is purified with HPLC as in Example 3. The yield is 29% of theoretical.
Reaction SMILES: CO.[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:23][O:22][CH:21]([C:24]#[C:25][Si](C)(C)C)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[C:8]([F:30])[C:7]=1[F:31])[CH3:4].[OH-].[Na+].Cl>ClCCl>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:23][O:22][CH:21]([C:24]#[CH:25])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[C:8]([F:30])[C:7]=1[F:31])[CH3:4]
Reactant: CCOc1ccc(C2CCC(C3CCC(C#C[Si](C)(C)C)OC3)CC2)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: C#CC1CCC(C2CCC(c3ccc(OCC)c(F)c3F)CC2)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
40 mL of methanol and 30 mL of dichloromethane were added to 3.7 g of (5-[4-(4-ethoxy-2,3-difluorophenyl)cyclohexyl]-tetrahydropyran-2-ylethynyl) trimethylsilane obtained in the seventh step, and the mixture was cooled to 0° C., to which 5 mL of a sodium hydroxide aqueous solution (1M) was added. The temperature of the reaction solution was increased to room temperature, and the reaction solution was stirred for 2 hours, neutralized with hydrochloric acid, and the solvent was concentrated to about 30 mL under reduced pressure. The residue was extracted three times with 20 mL of diethyl ether, and the mixture including the organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography to provide 2.6 g of 5-[4-(4-ethoxy-2,3-difluorophenyl)cyclohexyl]-2-ethynyltetrahydropyran.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[OH:9])[NH2:5].Cl[C:12]1[C:17]([Cl:18])=[CH:16][C:15]([O:19][CH:20]([F:22])[F:21])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:18][C:17]1[C:12]([O:9][C:8]2[C:2]([Cl:1])=[CH:3][C:4]([NH2:5])=[CH:6][C:7]=2[Cl:10])=[N:13][CH:14]=[C:15]([O:19][CH:20]([F:22])[F:21])[CH:16]=1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: FC(F)Oc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(Cl)c(Oc2ncc(OC(F)F)cc2Cl)c(Cl)c1

Procedure:
9.26 g (52 mmol) of 3,5-dichloro-4-hydroxyaniline, 10.1 g (50 mmol) of 2,3-dichloro-5-difluoromethoxypyridine and 10.4 g of anhydrous potassium carbonate were stirred for 15 hours at 105° C. under argon in 50 ml of anhydrous dimethyl sulfoxide. The dimethyl sulfoxide was then removed by distillation, and the residue was taken up in 100 ml of ether, washed twice with 30 ml of 5% strength potassium carbonate solution and with water until neutral and concentrated by evaporation.
Reaction SMILES: [F:1][C:2]([F:81])([O:66][C:67]1[CH:72]=[CH:71][C:70]([O:73][CH2:74][CH2:75][CH2:76][C:77]([F:80])([F:79])[F:78])=[CH:69][CH:68]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][C:15]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-])=O)=[CH:59][CH:58]=2)([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-])=O)=[CH:49][CH:48]=2)[CH2:16][O:17][C:18](=[O:45])/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:44])([F:43])[O:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)=[O:12])=[CH:5][CH:4]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:81])([O:66][C:67]1[CH:72]=[CH:71][C:70]([O:73][CH2:74][CH2:75][CH2:76][C:77]([F:79])([F:80])[F:78])=[CH:69][CH:68]=1)[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][C:15]([CH2:46][C:47]2[CH:48]=[CH:49][C:50]([NH2:53])=[CH:51][CH:52]=2)([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=2)[CH2:16][O:17][C:18](=[O:45])/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:43])([F:44])[O:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:40])([F:41])[F:42])=[CH:33][CH:34]=3)=[CH:23][CH:22]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCC(COC(=O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)(Cc1ccc([N+](=O)[O-])cc1)Cc1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(CC(COC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)(COC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)Cc2ccc(N)cc2)cc1
Yield: 87.4 %

Procedure:
9.57 g (8.38 mmol) of 2,2-bis(4-nitrobenzyl)-3-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoyl]oxy}propyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 400 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 7.93 g of 2,2-bis(4-aminobenzyl)-3-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoyl]oxy}propyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate as yellow crystals.