Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[Br:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]Br>O.CCOCC.C(#N)C>[CH3:1][O:2][C:3]([C@@:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([O:17][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][Br:44])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4]
Reactant: COC(=O)[C@@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: BrCCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@@]1(C)CCc2c(C)c(OCCCCCBr)c(C)c(C)c2O1

Procedure:
A mixture of 6.5 g (24.6 mmoles) of (R)-(+)-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester, 10.37 g (75.1 mmoles) of anhydrous potassium carbonate, 1.12 g of 18-crown-6, 39.3 ml (0.2 mole) of 1,5-dibromopentane, and 150 ml of acetonitrile was stirred and refluxed for 21 hours. After being cooled, the mixture was treated with ether and water. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (68 g) was purified first by column chromatography on silica gel (400 g; eluting with 49:1 toluene-ethyl acetate) and then by preparative HPLC on silica gel using 9:1 hexane-ethyl acetate as the mobile phase. There was obtained 9.71 g (95.6%) or (R)-(+)-6-[(5-brompentyl)oxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester as a solid. Recrystallization from ethanol gave a colorless solid mp 64°- 65.5° C., [α]D25 +36.37° (c 2, CHCl3).
Reaction SMILES: [N+]([O-])([O-])=O.[Ca+2:5].[N+]([O-])([O-])=O.O.N.[P:12]([O-:16])([O-:15])([OH:14])=[O:13].[NH4+].[NH4+]>O>[P:12]([O-:16])([O-:15])([O-:14])=[O:13].[Ca+2:5].[P:12]([O-:16])([O-:15])([O-:14])=[O:13].[Ca+2:5].[Ca+2:5]
Reactant: O=P([O-])([O-])O
Agent: *CC(*)C
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=P([O-])([O-])[O-]
Temperature: 80 °C
Reaction time: 48 h

Procedure:
In 7.1 l. of distilled water there was dissolved 2500 g of commercially available calcium nitrate [Ca(No3)2. 4H2O], and 7.9 l. of 28% ammonia water was slowly added to the resultant solution. The thus obtained solution was then diluted with 3 1. l. of distilled water. Separately therefrom, 840 g of commercially available ammonium hydrogen-phosphate [NH4)2HPO4 ] was dissolved in 10 l. of distilled water. 4.8 l. of 28% ammonia water and 10 l. of distilled water were then added to this solution. While keeping the former calcium nitrate aqueous solution at 20° C., the latter ammonium hydrogenphosphate aqueous solution (20° C.) was added dropwise thereto with stirring to effect reaction therebetween. After completion of the dropwise addition, the mixture described above was heated to 80° C. and maintained for 20 minutes under reflux, while continuing stirring. After cooling, the reaction mixture was allowed to settle for 2 days. Subsequently, the solution was dehydrated (2000 g) with a centrifugal dehydrator equipped with a polypropylene-made filter cloth (1000 mesh) and washed with distilled water until the system showed no alkaline property. The thus obtained calcium phosphate filtered cake was dried and then ground into powders in a mortar. The powders were passed through a sieve of 140 mesh to give 920 g of calcium phosphate powders. The calcium phosphate powders were packed in 18 pieces of polyurethane foam "Everlightscott Filter" (HR-20; cell number, 17-25 cells/25 mm; porosity, 97%) manufactured by Bridgestone Corporation, which were then each inserted in a respective rubber form as in Example 1. Three pieces each in a group were pressed with a rubber press under 6 levels of pressure as shown in Table 1. They were put in an electric furnace and calcined for 2 hours at 1100° C., after elevating the temperature to 1100° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)C(O)=O)=[CH:4][CH:3]=1.C([N:37](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C[Si](C)(C)CCO.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>O1CCOCC1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[NH2:37])=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccc(Br)cc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: CCN(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)CCO
Agent: [F-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(Cc1ccc(Br)cc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36.6 %

Procedure:
To a solution of 3-(4-bromophenyl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid (224 mg, 0.41 mmol) in dioxane (5 mL) was added 4 Å molecular sieves (appx 100 mg), triethylamine (0.068 mL, 0.49 mmol) and diphenylphosphoryl azide (0.11 mL, 0.49 mmol) and the reaction mixture was stirred for 45 minutes. 2-(Trimethylsilyl)ethanol (0.176 mL, 1.23 mmol) was added and the reaction mixture was heated at reflux for 1 h. The reaction mixture was allowed to cool to rt and concentrated under reduced pressure. The residue was diluted with Et2O (10 mL) and washed with sat. NH4Cl (5 mL), sat. NaHCO3 (5 mL) and sat. NaCl (5 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was diluted with THF (5 mL) and cooled in an ice-bath, then a 1M solution of tetrabutylammonium fluoride in THF (0.80 mL, 0.80 mmol) was added dropwise. The reaction mixture was allowed to warm to rt and stirred for 3 h. The reaction mixture was diluted with CH2Cl2 (5 mL) and washed with H2O (5 mL) and sat. NaCl (5 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified on ISCO silica chromatography with elution at 0 to 50% EtOAc/hexane to give 2-(4-bromophenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethanamine (78 mg, 37% yield) as a clear colorless oil. LCMS: RT=1.87 min [M−NH2] 505.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) δ ppm 1.68 (bs, 2H), 3.46 (s, 2H), 6.57 (d, J=8.35 Hz, 2H), 7.10 (d, J=8.35 Hz, 2H), 7.18 (s, 2H), 7.21-7.26 (m, 4H), 7.32 (t, J=8.13 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]#[CH:5].C(BC(C(C)C)C)(C(C)C)C.C[N+]([O-])(C)C.[OH-].[Na+].[I:29]I>>[I:29]/[CH:5]=[CH:4]/[CH:3]([O:2][CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: II
Reactant: C#CC(CCCCC)OC
Agent: CC(C)C(C)BC(C)C(C)C
Agent: C[N+](C)(C)[O-]
Agent: [Na+]
Product: CCCCCC(/C=C/I)OC

Procedure:
Treatment of 3-methoxy-1-octyne (Example 1877) with disiamylborane, trimethylamine oxide, sodium hydroxide and iodine by the procedure described in Example 996 furnishes the title product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][C:15]1([CH3:22])[NH:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:14][C:15]1([CH3:22])[C:16](=[O:21])[N:17]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[C:18](=[O:20])[NH:19]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Yield: 46 %

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)benzonitrile (5.67 g, 30 mmoles), 5,5-dimethyl-hydantoin (7.68 g, 60 mmoles), K2CO3 (8.28 g, 60 mmoles) in DMF (45 ml) is distributed in equal parts into three tubes to be placed in a microwave oven. Under magnetic stirring, each tube is irradiated at 140° C. for 20 minutes. The reaction masses are then combined, poured into water (200 ml) and extracted with AcOEt (2×75 ml). The organic phases are combined, washed with salt water, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue crystallizeds from Et2O (25 ml). After recrystallization from EtOH (75 ml), the powder is filtered and dried under vacuum. The expected compound is obtained in the form of a white solid with a yield of 46% (4.1 g). Melting point: 212-213° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]1[O:12][CH:11]1[CH2:13][OH:14].N1C=CC=CC=1>ClCCl>[C:1]([O:14][CH2:13][CH:11]1[CH2:10][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CO1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCC1CO1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
Benzoyl chloride (1.2 mL, 10.0 mmol) was added to a solution of glycidol (0.67 mL, 10.0 mmol) and pyridine (0.81 mL, 10.0 mmol) in anhydrous dichloromethane at 0° C. The reaction mixture was further stirred at 0° C. for 60 min. The reaction mixture was then concentrated to dryness under reduced pressure, diluted with ethyl acetate, and washed with 10% citric acid twice followed by the addition of a saturated NaHCO3 solution and brine. The organic phase was dried over MgSO4 and concentrated to dryness to yield 1.8 g (100%) of Oxiran-2-ylmethyl benzoate.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@H:20]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[C:35]([C:40]4[NH:44][C:43]([C@@H:45]6[CH2:50][C@@H:49]7[C@@H:47]([CH2:48]7)[N:46]6C(OC(C)(C)C)=O)=[N:42][CH:41]=4)[CH:34]=[N:33]5)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH2:19][C@@H:18]2[C@H:16]1[CH2:17]2)=O)(C)(C)C>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C@@H:16]12[CH2:17][C@@H:18]1[CH2:19][C@@H:20]([C:21]1[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[C:35]([C:40]4[NH:44][C:43]([C@@H:45]6[CH2:50][C@@H:49]7[C@@H:47]([CH2:48]7)[NH:46]6)=[N:42][CH:41]=4)[CH:34]=[N:33]5)[CH:28]=[CH:29][C:23]=3[N:22]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2cnc3cc(-c4ccc5nc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]c5c4)ccc3n2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2nc(-c3cnc([C@@H]4C[C@H]5C[C@H]5N4)[nH]3)cnc2cc1-c1ccc2nc([C@@H]3C[C@H]4C[C@H]4N3)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 147.5 %

Procedure:
TFA (0.25 mL, 3.24 mmol) was added to a solution of (1R,3S,5R)-tert-butyl 3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (10 mg, 0.015 mmol) in DCM (0.5 mL) and the mixture was stirred at rt for 16 h. The volatiles were removed under vacuum and the residue was triturated with Et2O. The resulting solid was rinsed with Et2O to yield a TFA salt of 6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)quinoxaline (10.5 mg) as yellow solid. LC-MS retention time 1.32 min; m/z 475 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([O:25][CH3:26])=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1>CCO.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([O:25][CH3:26])=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:28][CH:29]=1
Reactant: COc1nc2c(cc1C#CCO)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1nc2c(cc1CCCO)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
N-(4-Chlorobenzyl)-6-(3-hydroxy-1-propynyl)-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide (180 mg) is suspended in EtOH (50 mL) and PtO2 is added. The mixture is shaken under an atmosphere of H2 (45 psi) for 2 h. The solution is filtered through Celite, and concentrated in vacuo. The residue is purified by silica gel chromatography (CH2Cl2/MeOH 1/0, 45/1, 19/1) and recrystallyzed from MeOH to afford 55 mg of N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide. Physical characteristics are as follows: 1H NMR (CDCl3) δ10.49-10.46, 8.82, 7.35-7.30, 4.66, 4.12, 4.00, 3.71, 2.81, 1.98-1.88; IR (diffuse reflectance) 2350, 2317, 1940, 1921, 1916, 1663, 1617, 1568, 1550, 1516, 1456, 1397, 1385, 1283, 809, cm−1; MS (El) m/z 414 (M+), 415, 276, 275, 249, 248, 246, 140, 84, 77, 57.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=4)[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH2:4][CH2:3]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:27])=[CH:22][CH:21]=4)[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: C1COCCN1
Reactant: CN1CCN(c2ccnc(-c3cccc(-c4ccc(C(=O)O)cc4)c3)c2)CC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(c2ccnc(-c3cccc(-c4ccc(C(=O)N5CCOCC5)cc4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3′-[4-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-biphenyl-4-carboxylic acid (30 mg, 0.08 mmol) in DMF (2 mL) was added morpholine (16 mg, 0.16 mmol), EDC (20 mg, 0.1 mmol), and Et3N (10 mg, 0.1 mmol). The resulting mixture was stirred at room temperature overnight, and then was poured into water and extracted with CH2Cl2. The organic layer was washed with 1 N HCl, 2 M aqueous Na2CO3, dried, and concentrated, and the resulting residue was purified by preparative TLC (MeOH/CH2Cl2) to yield the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]([O:54][C@@H:55]1[C@@H:61]([O:62][C:63](=[O:65])[CH3:64])[C@H:60]([O:66][C:67](=[O:69])[CH3:68])[CH2:59][S:58][CH:56]1O)(=[O:53])[CH3:52]>C1COCC1>[C:51]([O:54][C@@H:55]1[C@@H:61]([O:62][C:63](=[O:65])[CH3:64])[C@H:60]([O:66][C:67](=[O:69])[CH3:68])[CH2:59][S:58][C@H:56]1[O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:12][CH:13]=1)(=[O:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(O)cc21
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(O)[C@@H]1OC(C)=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc2ccn(C(=O)OC(C)(C)C)c2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 3 %

Procedure:
A solution of 2.66 g (11.41 mM) of 6-hydroxy-1H-indole-1-carboxylic acid tert-butyl ester in 50 ml of THF, 4.16 g (20.6 mM) of diisopropylazodicarboxylate and 5.39 g (20.6 mM) of triphenylphosphine are added to a solution of 4.34 g (14.84 mM) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranose in 150 ml of THF. The reaction mixture is stirred at 50° C. for 4 hours and then concentrated under reduced pressure. The evaporation residue is solubilized in ethyl acetate and the organic phase is washed with a 1N solution of sodium hydroxide and then with a concentrated aqueous solution of ammonium chloride. The organic phase is subsequently dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by silica gel chromatography, elution being carried out with a methylcyclohexane/ethyl acetate mixture (gradient of 9/1 to 7/3; v/v). The residue obtained is subsequently purified by C18-grafted silica chromatography, elution being carried out with an acetonitrile/water mixture (6/4; v/v). The desired product is obtained in the form of a white solid with a yield of 3%.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH3:16])(=[O:6])=[O:5].C[N:18](C=O)C>>[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([NH2:18])[CH:11]=[C:10]2[CH3:16])(=[O:6])=[O:5]
Reactant: Cc1c[nH]c2ccc(S(C)(=O)=O)cc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cn(N)c2ccc(S(C)(=O)=O)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of NaH (1.06 g, 26.6 mmol, 60% in mineral oil) in DMF (15 mL) at 0° C. is treated with 5-methanesulfonyl-3-methyl-1H-indole (370 mg, 1.77 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (1 g, 8.85 mmol) portion wise and warmed to rt overnight. The mixture is then poured over ice, and extracted with EtOAc (3×100 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 5-methanesulfonyl-3-methyl-indol-1-ylamine, which is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:5][C:4]=1[CH:16]=O.[C:18]1([C@H:24]2[C@@H:29]([NH2:30])[CH2:28][CH2:27][CH2:26][NH:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:5][C:4]=1[CH2:16][NH:30][C@H:29]1[CH2:28][CH2:27][CH2:26][NH:25][C@H:24]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc2c(cc1C=O)C(C)(C)C(=O)N2C
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)C(C)(C)C(=O)N2C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To 6-Methoxy-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5-carbaldehyde (936 mg, 4.0 mmol) in 50 mL of toluene was added (2S,3S)-2-Phenyl-piperidin-3-ylamine (1.0 g, 4.0 mmol) and 3 mL of methanol. The solution was heated to reflux with azeotropic water removal for 48 h. The solution was then concentrated and the residue was dissolved in CH2Cl2. Sodiumtriacetoxyborohydride (1.0 g, 4.7 mmol) was added and the mixture was stirred overnight. The mixture was then quenched with satd NaHCO3 and the layers were separated. The aqueous portion was extracted with CH2Cl2 (2×20 mL). The combined organic portions were washed successively with brine and water and concentrated. Silica gel chromatography (10:1 EtOAc/MeOH) gave 1.27 g (81%) of the title compound as an orange oil. Treatment of the oil with ethereal HCl gave 1.44 g of the dihydrochloride salt as an off-white solid.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@:10]23[NH:50][C:49](=[O:51])[C@@H:48]4[CH2:52][C@@H:45]5[CH2:46][N:47]4[C:53](=[O:54])[C@@H:20]([NH:21][C:22](=[O:55])[O:23][C@H:24]4[C@H:28]([CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][C:34]6[C:43]([O:44]5)=[CH:42][C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=6)[CH2:27][CH2:26][CH2:25]4)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[CH:13][C@@H:12]2[CH2:11]3)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[BH4-].[Na+]>CCO>[CH:1]1([S:4]([NH:7][C:8]([C@:10]23[NH:50][C:49](=[O:51])[C@@H:48]4[CH2:52][C@@H:45]5[CH2:46][N:47]4[C:53](=[O:54])[C@@H:20]([NH:21][C:22](=[O:55])[O:23][C@H:24]4[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]6[C:43]([O:44]5)=[CH:42][C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=6)[CH2:27][CH2:26][CH2:25]4)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[CH:13][C@@H:12]2[CH2:11]3)=[O:9])(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C1N[C@H]2CCCCCC=C[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3CC3)NC(=O)[C@@H]3C[C@H](CN3C2=O)Oc2cc3ccccc3nc2C=CCCC[C@@H]2CCC[C@H]2O1
Agent: O=C1N[C@H]2CCCCC/C=C\[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3CC3)NC(=O)[C@@H]3C[C@H](CN3C2=O)Oc2cc3ccccc3nc2/C=C/CCC[C@@H]2CCC[C@H]2O1
Agent: O=C1N[C@H]2CCCCC/C=C\[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3CC3)NC(=O)[C@@H]3C[C@H](CN3C2=O)Oc2cc3ccccc3nc2CCCCC[C@@H]2CCC[C@H]2O1
Agent: [BH4-]
Solvent: CCO
Product: O=C1N[C@H]2CCCCCC=C[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3CC3)NC(=O)[C@@H]3C[C@H](CN3C2=O)Oc2cc3ccccc3nc2CCCCC[C@@H]2CCC[C@H]2O1
Temperature: 40 °C

Procedure:
To a 0° C. solution of the compound from Step 6 (26 mg, 0.034 mmol) in EtOH (20 mL) was added BiCl3 (154 mg, 0.487 mmol) and then NaBH4 (363 mg, 9.61 mmol). The mixture was then warmed to 40° C. for 15 minutes. The black solids were then filtered off and washed with EtOH. 1N HCl was then added to quench the mixture at 0° C.; the EtOH was then removed in vacuo; and the pH was adjusted to ˜4. The mixture was then extracted with EtOAc (2×), dried over MgSO4, and the solvent was removed in vacuo to yield crude material which was purified by reverse phase chromatography using a 0-100% CH3CN/0.15% aqueous trifluoracetic acid gradient to yield the title compound. 1H NMR (500 MHz) (CD3OD) δ 8.99 (s, 1H), 8.56 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.92 (app. t, J=7.2 Hz, 1H), 7.83 (app. t, J=7.6 Hz, 1H), 5.68 (q, J=10.0 Hz, 1H), 5.61 (app. t, J=3.2 Hz, 1H), 5.05 (app. t, J=8.8 Hz, 1H), 4.95-4.47 (m, 2H), 4.51 (dd, J=10.2 Hz, 6.8 Hz, 1H), 4.30 (d, J=10.4 Hz, 1H), 4.14 (dd, J=11.8 Hz, 3.6 Hz, 1H), 3.17 (m, 2H), 2.85 (m, 1H), 2.65 (m, 2H), 2.53 (m, 1H), 2.45 (q, J=8.4 Hz, 1H), 2.0-1.8 (m, 5H), 1.8-1.2 (m, 21H), 1.2-0.9 (m, 4H). LRMS ESI+ (M+H) 776.1, calcd for C41H54N5O8S: 776.3.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:5]=1[CH3:15])([O-])=O.[Cl-].[Cl-].[Ca+2]>C(O)C.O.[Zn]>[CH3:15][C:5]1[CH:6]=[C:7]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:8]=[C:9]([CH3:10])[C:4]=1[NH2:1]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(C)(C)C)cc(C)c1N
Temperature: 65 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Water, 20 mL, was added to a mixture of 12.0 g (58.0 mmol) of 1-nitro-4-tert-butyl-2,6-dimethylbenzene dissolved in 160 mL of ethanol. To the stirring solution of 1-nitro-4-tert-butyl-2,6-dimethylbenzene was added CaCl2, 4.8 g (43.2 mmol), dissolved in 20 mL of water, followed by the addition of zinc powder, 50.0 g (76.5 mmol). The reaction was stirred overnight at 65° C., then cooled to ambient temperature and filtered. The filtrate was extracted three times with ether, and the organic layer was dried over MgSO4. Removal of the solvent gave 9.58 g (93%) of a brown oil. 1H NMR (300 MHz, CDCl3): δ=6.90, s, 2H; 3.40, broad singlet, 2H; 2.11, s, 6H, 1.21, s, 9H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=S)[N:10]=2)=[CH:5][CH:4]=1.[OH-:24].[Na+].OO>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:24])[N:10]=2)=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(-c2n[nH]c(=S)nc2-c2ccc(OC)cc2)cc1
Agent: OO
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2n[nH]c(=O)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A slurry of 9.6 g of 5,6-bis-(4-methoxyphenyl)-1,2,4-triazin-3-thione (29.5 mmol) in 100 mL of water was treated with 2.64 g of 50% aqueous sodium hydroxide (33 mmol). Most of the solids dissolved. The reaction mixture was cooled in an ice bath and 3.8 g of 30% hydrogen peroxide (33 mmol) was added slowly. An additional 4 mL of hydrogen peroxide solution was added, and the reaction mixture was stirred overnight at room temperature. The solids were filtered, washed with water, and dried under vacuum to give 8.6 g of product, mp 238–242° C.