Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[C:18]([O:21][C@H:22]1[CH2:39][CH2:38][C@@:37]2([CH3:40])[C@@H:24]([CH2:25][CH2:26][C@:27]3([CH3:51])[C@@H:36]2[CH2:35][CH2:34][C@H:33]2[C@@:28]3([CH3:50])[CH2:29][CH2:30][C@@:31]3([CH:48]=O)[CH2:43][C:42](=[O:44])[C:41]([CH:45]([CH3:47])[CH3:46])=[C:32]32)[C:23]1([CH3:53])[CH3:52])(=[O:20])[CH3:19]>CN(C=O)C>[C:18]([O:21][C@H:22]1[CH2:39][CH2:38][C@@:37]2([CH3:40])[C@@H:24]([CH2:25][CH2:26][C@:27]3([CH3:51])[C@@H:36]2[CH2:35][CH2:34][C@H:33]2[C@@:28]3([CH3:50])[CH2:29][CH2:30][C@@:31]3(/[CH:48]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:43][C:42](=[O:44])[C:41]([CH:45]([CH3:46])[CH3:47])=[C:32]32)[C:23]1([CH3:52])[CH3:53])(=[O:20])[CH3:19]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C=O)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
To a suspension of ethyl 2-(diethoxyphosphoryl)propanoate (3.12 g, 13.09 mmol) in DMF (35 mL) stirred under nitrogen at 0° C. was added NaH (0.60 g, 80 wt %, 20 mmol) during 5 min and stirred for 10 mins. The solution was warmed to rt and stirred for 30 mins before (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (5.0 g, 10 mmol) was added to above mixture. After overnight, the reaction was quenched with water and washed with saturated NaHCO3 and water. The solid was solved into EtOAc, dried over Na2SO4, filtered and concentrated to remove the majority of solvent. The residue was recrystallized from petroleum ether/EtOAc (8:1), filtered and the filtrate was concentrated to give the residue, which was purified by silica gel eluting with petroleum ether/EtOAc (15:1-10:1) to obtain the product (E)-ethyl 3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-acetoxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylate (1.0 g, 1.291 mmol, 12.82%) as a yellow solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Li]CCCC.C(NC(C)C)(C)C.[CH3:21][C:22]1[O:26][N:25]=[CH:24][CH:23]=1.CS[C:29]1[S:30][CH2:31][CH2:32][N:33]=1>C1COCC1>[NH2:25][C:24]1[N:33]2[CH2:32][CH2:31][S:30][C:29]2=[CH:21][C:22](=[O:26])[CH:23]=1
Reactant: CSC1=NCCS1
Reactant: Cc1ccno1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Nc1cc(=O)cc2n1CCS2
Reaction time: 20 h
Yield: 50.8 %

Procedure:
To a solution of lithium diisopropylamide (LDA), prepared from n-BuLi (106.6 ml, 0.16M) and diisopropylamine (16.7 g, 23.1 ml, 0.16M), in dry THF (100 ml) was added under N2 at -10° C., 5-methylisoxazole (6.8 g, 0.08M). The resultant yellow suspension was mechanically stirred at -10° C. for 30 min before the 4,5-dihydro-2-methylthiothiazole (11 g, 0.08M) was added dropwise. After the addition was complete, an orange oil separated, and the mixture was allowed to warm to ambient over a period of 20 hr. A mixture of MeOH (60 ml) and glacial acetic acid (4.5 ml, 0.08M) was slowly added and the resultant reddish solution was stirred at ambient overnight. The solvents were evaporated in vacuo, and the residual oil was flash column chromatographed on silica gel (EM-60) with 30% MeOH in CH2Cl2 as the eluent to give the desired amine (7 g), which was further recrystallized from MeOH/Et2O to give the title compound (5.4 g, 40%), mp>241° C. TLC (30% MeOH in CH2Cl2); Rf=0.33. IR (KBr) cm1, 3350-3000 (broad), 1675, 1625.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.[Br:23][C:24]1[CH:32]=[CH:31][C:27]2[CH2:28][CH2:29][O:30][C:26]=2[CH:25]=1.[O-:33][P:34]([O-:37])([O-:36])=[O:35].[K+:38].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Br:23][C:24]1[CH:32]=[CH:31][C:27]2[CH2:28][CH2:29][O:30][C:26]=2[CH:25]=1.[O-:35][P:34]([O-:37])([O-:36])=[O:33].[K+:38].[K+:38].[K+:38].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:32]=[CH:31][C:27]2[CH2:28][CH2:29][O:30][C:26]=2[CH:25]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Brc1ccc2c(c1)OCC2
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc4c(c3)OCC4)cc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A 0.25 M solution of 6-bromo-2,3-dihydrobenzofuran was prepared in dioxane. A 0.30 M solution of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate was also prepared in dioxane. Lastly, a 1.00 M solution of K3PO4 was prepared in water. In a vial was added 400 uL of the 0.30 M dioxane solution of 6-bromo-2,3-dihydrobenzofuran (100 umol, 1.00 eq). 400 uL of the 0.25 M dioxane solution of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (120 umol, 1.20 eq) was then added followed by the addition of 200 uL of the 1.00 M aqueous solution of K3PO4 (200 umol, 2.00 eq). Under nitrogen atmosphere was added (1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (3.9 mg, 6.0 umol, 0.06 eq). The vial was caped and shook for 2 hours at 120° C. The reaction was filtered and concentrated by Speedvac. The residue was washed with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (1 mL, 3×). The organic layer was collected and dried over anhydrous sodium sulfate, filtered, and concentrated to give crude methyl 6-chloro-5-(2,3-dihydrobenzofuran-6-yl)-1H-indole-3-carboxylate. To the crude intermediate was added anhydrous tetrahydrofuran (1.5 mL) followed by Me3SiOK (128 mg, 1000 umol, 10.0 eq). The vial was capped and shaken at 80° C. for 16 hours. The reaction was concentrated by Speedvac and the residue was purified by preparative HPLC to provide the title compound. MS (ES+) 314 (M+H)+. Retention time: 2.56 min. Column: Agella Venusil ASB dC18 150×21.2 mm, 5 μm. Modifier: TFA 0.225%. Gradient: 66% H2O/34% MeCN linear to 36% H2O/64% MeCN over 10.0 min., HOLD at 100% MeCN to 1.0 min. Flow: 30.0 mL/min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.[CH:22](OCC)=[O:23].[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][CH:11]([CH:22]=[O:23])[C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC1(c2cccc(OC)c2)CCCCC1=O
Reactant: CCOC=O
Agent: [Na]
Product: CCOC(=O)CC1(c2cccc(OC)c2)CCCC(C=O)C1=O

Procedure:
Following the procedure set forth in Example 1, 2-(3-methoxyphenyl)-2-ethoxycarbonylmethylcyclohexanone was reacted with ethyl formate in the presence of metallic sodium to provide 2-(3-methoxyphenyl)-2-ethoxycarbonylmethyl-6-formylcyclohexanone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@@:8]2([CH3:21])[NH:17][C:16](=S)[C:11]3([CH2:15][CH:14]=[CH:13][CH2:12]3)[S:10](=[O:20])(=[O:19])[CH2:9]2)[CH:7]=1.[NH3:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@@:8]2([CH3:21])[N:17]=[C:16]([NH2:23])[C:11]3([CH2:15][CH:14]=[CH:13][CH2:12]3)[S:10](=[O:20])(=[O:19])[CH2:9]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CC=CC2)C(=S)N1
Reactant: N
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CC=CC2)C(N)=N1
Temperature: 60 °C
Reaction time: 48 h
Yield: 86.7 %

Procedure:
A mixture of (R)-8-(5-bromo-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-2-en-10-thione (300 mg, 742 μmol, Eq: 1.00) and ammonia (7 N in MeOH) (7.87 g, 10 ml, 70.0 mmol, Eq: 94.3) was stirred in a sealed tube for 48 hours at 60° C. Extracted with ethyl acetate and sat. NaHCO3-sol., dried the organic layer over Na2SO4, filtered and evaporated. The residue was chromatographed with ethyl acetate to give (R)-8-(5-bromo-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]deca-2,9-dien-10-ylamine (249 mg, 643 μmol, 86.7% yield) as a white foam. MS (ISP): m/z=387.3 [M+H]+ and 389.3 [M+2+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=2)[O:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:24]2[CH:25]=[CH:26][C:21]([B:16]3[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]3)=[CH:22][CH:23]=2)[CH:9]=1)=[O:4]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COC(=O)c1cc(CO)c(C)o1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (0.5 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.9 g) and triphenylphosphine (2.3 g) in dry tetrahydrofuran (20 mL) under a nitrogen atmosphere was cooled to 0° C. Diisopropylazodicarboxylate (1.8 mL) was added drop-wise and the mixture was stirred at room temperature for 72 hours. After concentrating in vacuo, the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was extracted with pentane and the pentane phase was decanted and concentrated to give compound 51 as an oil. This was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:4]=1[C:5]([OH:7])=[O:6].C(OCC)(OCC)O[CH2:19][CH3:20]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:4]=1[C:5]([O:7][CH2:19][CH3:20])=[O:6]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1OC
Reactant: CCOC(OCC)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c([N+](=O)[O-])ccc(OC)c1OC

Procedure:
2,3-Dimethoxy-6-nitrobenzoic acid (l, 180.0 g, 0.792 mole) was dissolved in triethyl orthoformate (466.2 g, 3.14 mole) optionally containing dimethylformamide (4 mL) and the mixture was heated to reflux for one hour. The solvent was removed in vacuo, the residue was extracted with chloroform (2 L) and the organic layer was dried over magnesium sulfate. Removal of the solvent in vacuo gave the product as a pale brown oil which crystallized upon standing at room temperature, 202 g (100%, m.p. 70°-72° C.). This material could be recrystallized from isopropanol but was generally reacted in the next step without additional purification.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](OC)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[SH:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:12]=[C:11]([C:13]3[S:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C:15](=[O:23])[N:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(-c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(-c3ccccc3)n2)sc2ccccc12
Yield: 57.7 %

Procedure:
6-Phenyl-2-pyridinecarbonitrile (0.72 g, 4.0 mmol) and methyl thiosalicylate (1.20 g, 7.1 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. After cooling, the precipitates were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.73 g, 57%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](Cl)=[N:10][OH:11].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([OH:29])[C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:14]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C.CCOCC>[Cl:28][C:24]1[CH:23]=[C:22]([C:21]2[O:11][N:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:20]=2[CH:19]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[OH:29])[CH:27]=[CH:26][CH:25]=1
Reactant: OC(C#Cc1cccc(Cl)c1)c1cccnc1
Reactant: ON=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Product: OC(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1cccc(Cl)c1
Temperature: 55 °C
Reaction time: 20 h
Yield: 16.7 %

Procedure:
A mixture of 53 mg (0.24 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 50 mg (0.21 mmol) of 1-(3-pyridyl)-3-(3-chlorophenyl)-2-propyn-1-ol, and 26 mg (0.31 mmol) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. on a rotary table shaker equipped with a heated sand bath. After 20 hrs, an additional 20 mg of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride and 10 mg of sodium bicarbonate was added, and the reaction mixture was stirred and heated for another 16 hrs. The mixture was then diluted with ether, and the solution was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 15 mg (0.035 mmol) of 5-(3-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. 1H NMR (CDCl3): δ 5.92 (br s, 1), 7.04 (d of d, 1), 7.12 (d, 1), 7.72 (m, 1), 8.86 (br s, 1), and 8.29 ppm (br s, 2). MS m/z: 430.9 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:33]#[C:34][CH2:35][OH:36])=[C:26]([C:28]([O:30][CH2:31]C)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(I)=C(C(OC)=O)N=1)CC2)=O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:33]#[C:34][CH2:35][OH:36])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCO
Agent: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1I
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCO

Procedure:
Compound 47E was prepared in a similar manner to the synthesis of compound 36B by substituting compound 34C with compound 47D in step 2 of Example 34: LCMS (APCI): m/z 635 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.[N:21]1[C:30]2[CH2:29][CH2:28][NH:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[N:21]1[C:30]2[CH2:29][CH2:28][N:27]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: c1cnc2c(c1)CNCC2
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4ncccc4C3)n2)c1

Procedure:
B38 was prepared following the general procedure reported for B10 using A1 and 5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride. The title compound (B38) was purified by reverse phase RP-HPLC (column: C18), using H2O (0.1% TFA) and MeOH (0.1% TFA) as eluents; yield: 67.6 mg (17%), colorless amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.98 (bs, 2H), 4.12 (t, J=6.0 Hz, 2H), 4.26 (bs, 2H), 4.95 (s, 2H), 6.86 (bs, 2H), 7.02 (d, J=7.9 Hz, 1H), 7.25 (dd, J=7.8 Hz, J=4.7 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.47-7.80 (bm, 2H), 7.83-8.10 (bm, 1H), 8.39 (dd, J=4.8 Hz, J=1.6 Hz, 1H), 8.30 (s, 1H), 9.77 (s, 1H). MS (ES) C18H19N7O2S requires: 397. found: 398 (M+H)+.
Reaction SMILES: [CH2:1]([O:13][P:14](=[O:17])([OH:16])[OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)C.[OH-].[Na+:22].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Zn+2:35]>O>[CH2:1]([O:13][P:14]([O-:17])([O-:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Zn+2:35].[Na+:22]
Reactant: CCCCCCCCCCCCOP(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCOP(=O)([O-])[O-]
Reaction time: 0.5 h

Procedure:
50 g of monolaurylphosphoric acid and 100 g of ethanol were put into a 500 ml reaction vessel. Further, a solution of 7.83 g of 96% sodium hydroxide (purity was taken into consideration by calculating it from the degree of neutralization determined by titration) dissolved in 200 g of ion-exchanged water was added thereto. After the temperature was elevated to 80° C., it was confirmed that they were dissolved. Further, the solution was continuously stirred for 30 minutes. A solution of 28.1 g of zinc sulfate heptahydrate dissolved in 100 g of ion-exchanged water was added dropwise thereto to carry out a salt exchange reaction. After the completion of the addition, the mixture was stirred for 30 minutes. 11.75 g cf an aqueous solution of 33.33% sodium hydroxide was added dropwise thereto to adjust the pH of the reaction mixture to 5. Further, the mixture was stirred for one hour. After the completion of the reaction, the reaction mixture was cooled and the product was recovered, washed with water and dried, to obtain 49.6 g of the particles of sodium zinc monolaurylphosphate.
Reaction SMILES: CN(S(F)(F)[F:5])C.O[CH:9]([C:17]1[CH:26]=[N:25][C:24]2[N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22](=[O:36])[N:21]3[N:37]=[CH:38][N:39]=[C:20]3[C:19]=2[CH:18]=1)[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(#N)C.C(=O)(O)[O-].[Na+]>[F:5][CH:9]([C:17]1[CH:26]=[N:25][C:24]2[N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22](=[O:36])[N:21]3[N:37]=[CH:38][N:39]=[C:20]3[C:19]=2[CH:18]=1)[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CN(C)S(F)(F)F
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(O)CN4CCOCC4)cnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(F)CN4CCOCC4)cnc32)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.8 %

Procedure:
(Dimethylamino)sulfur trifluoride (0.010 ml, 0.18 mmol) was added to a stirred solution of 9-(1-hydroxy-2-morpholinoethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (49 mg, 0.090 mmol) in acetonitrile (1 ml). After 4 hours, additional (dimethylamino)sulfur trifluoride (0.035 ml, 0.36 mmol) was added and the mixture was stirred at 60° C. for 20 hours, cooled to room temperature, diluted with aqueous sodium bicarbonate (3 mL) and extracted with DCM (2×3 mL). The combined extracts were concentrated under a stream of nitrogen and the residue was taken up in methanol, filtered and purified by preparative HPLC. The resulting material retained some impurities so it was diluted with aqueous sodium bicarbonate (3 mL) and extracted with DCM (2×3 mL). The combined extracts were concentrated under a stream of nitrogen and the residue was purified by flash chromatography (elution with 0-40% IPA in ethyl acetate) to afford 9 mg (21%) of 269 as a white powder.
Reaction SMILES: C([C@@H]1CO[C:10](=O)[N:9]1[C:14](=[O:33])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[C:22]([F:31])[C:21]=1[F:32])[CH2:16]C=O)C1C=CC=CC=1.[N:34]1[NH:35][CH:36]=[C:37]2[C:42]=1[CH2:41][CH2:40][CH:39](N)[CH2:38]2.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[Cl:26][C:25]1[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:10][N:9]([CH:39]3[CH2:40][CH2:41][C:42]4[C:37](=[CH:36][NH:35][N:34]=4)[CH2:38]3)[C:14]2=[O:33])=[C:21]([F:32])[C:22]([F:31])=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:24]=1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(C(F)(F)F)c(F)c1F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: NC1CCc2n[nH]cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C1[C@H](Cc2c(Cl)cc(C(F)(F)F)c(F)c2F)CCN1C1CCc2n[nH]cc2C1
Yield: 46.1 %

Procedure:
Combine a solution of (R)-4-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(6-chloro-2,3-difluoro-4-trifluoromethyl-benzyl)-4-oxo-butyraldehyde (Preparation 46) (0.30 g, 0.6 mmol) and 4,5,6,7-Tetrahydro-2H-indazol-5-ylamine (Preparation 40) (88 mg, 0.64 mmol) in CH2Cl2 (15 mL) and MeOH (1 mL) and treat the solution with HOAc (0.03 mL, 0.6 mmol). Stir the reaction for 30 min at room temperature, treat the reaction with sodium triacetoxyborohydride (0.39 g, 1.8 mmol), and stir overnight at room temperature. Quench the reaction with water and extract with EtOAc. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by SCX resin exchange column using 2M ammonia in MeOH to elute the pure product. Remove the solvent to afford 0.12 g (46%) of the title compound. MS (m/e): 434 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3([O:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]4[CH:30]=[CH:31][CH:32]=[C:21]34)[CH2:17][CH2:16]2)=[O:14])=[CH:7][C:4]=1[CH:5]=[O:6].CO>>[OH:6][CH2:5][C:4]1[C:3]([O:2][CH3:1])=[CH:10][C:9]([O:11][CH3:12])=[C:8]([C:13]([N:15]2[CH2:16][CH2:17][C:18]3([O:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]4[CH:30]=[CH:31][CH:32]=[C:21]34)[CH2:19][CH2:20]2)=[O:14])[CH:7]=1
Reactant: COc1cc(OC)c(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1C=O
Solvent: CO
Product: COc1cc(OC)c(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1CO
Reaction time: 0.25 h

Procedure:
2,4-Dimethoxy-5-(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)benzaldehyde (65 mg, 0.15 mmol) was suspended in MeOH (1 mL) NaBH4 (60 mg, 1.6 mmol) was added and the reaction mixture was allowed to stir for 15 minutes. The reaction mixture was filtered and was then purified by reverse phase preparative liquid chromatography utilizing a gradient of 20-99% methanol in water containing no modifier to give (5-(hydroxymethyl)-2,4-dimethoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 434.2, found 435.5 (M+1)+; Retention time: 1.63 minutes (3 min run).
Reaction SMILES: F[C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([O:20]CC)=[O:19])=[C:15]([CH3:23])[CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.C(N1C(=O)N(C2SC(C(OCC)=O)=C(C)C=2)C=N1)C1C=CC=CC=1>>[CH2:6]([N:7]1[C:11](=[O:12])[N:10]([C:13]2[S:17][C:16]([C:18]([OH:20])=[O:19])=[C:15]([CH3:23])[CH:14]=2)[CH:9]=[N:8]1)[C:5]1[CH:24]=[CH:25][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)cc1C
Agent: CCOC(=O)c1sc(-n2cnn(Cc3ccccc3)c2=O)cc1C
Product: Cc1cc(-n2cnn(Cc3ccccc3)c2=O)sc1C(=O)O
Yield: 86 %

Procedure:
Following the procedure as described in Example 30, making variations as required to replace ethyl 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylate with ethyl 5-(1-benzyl-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylate, the title compound was obtained as a colorless solid in 86% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.99 (br s, 1H), 8.75 (s, 1H), 7.40-7.24 (m, 6H), 4.97 (s, 2H), 2.46 (s, 3H); MS (ES−) m/z 314.2 (M−1).