Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[NH:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1.[H-].[Na+].[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl>O1CCCC1>[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31][N:12]1[C:11]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:10]=2[N:9]=[C:8]1[NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:23]
Reactant: CCOC(=O)Cc1ccc2nc(Nc3ccccc3C)[nH]c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2cc(CC(=O)O)ccc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.7 %

Procedure:
A solution of ethyl (2-o-tolylamino-3H-benzimidazol-5-yl)acetate (5 g, Reference Example 8) in tetrahydrofuran (200 mL) was treated with sodium hydride (0.71 g, 60% dispersion in mineral oil) under nitrogen with stirring at room temperature. On completion of the addition the mixture was stirred at room temperature for a further 30 minutes and then treated with (2-trimethylsilylethoxy)methyl chloride (2.95 g). After stirring at room temperature for a further 1 hour the mixture was evaporated to low bulk and the residue was partitioned between ethyl acetate (500 mL) and water (500 mL). The organic phase was separated then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of pentane and ether (3:2, v/v). The material (5.2 g) from chromatography was dissolved in methanol (100 mL) and the solution was treated with aqueous sodium hydroxide solution (30 mL, 1M). After standing at room temperature for 4 hours the mixture was evaporated to low bulk and then diluted with water (50 mL). The mixture was acidified by addition of acetic acid to give a white gum which was decanted from which the aqueous mother liquors. The gum was washed once by decantation with a little water and then triturated with the minimum of ethanol to give the title compound (910 mg) as a white solid. Evaporation of the ethanol solution gave a further quantity of the title compound (3.0 g) as an orange foam.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:22][C:23](O)=[O:24])[C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:27]>>[CH2:26]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[C:23](=[O:24])[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH3:27]
Reactant: CCNCc1cccc(C)n1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cn1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3-yl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[C:10]([OH:17])[N:11]=[CH:12]3)[CH:4]=[N:3]1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[S:19]([O:17][C:10]1[N:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[N:16]=[CH:15][CH:14]=2)(=[O:20])=[O:18]
Reactant: Cn1cc(-c2nccc3cnc(O)cc23)cn1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2nccc3cnc(OS(=O)(=O)C(F)(F)F)cc23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridin-3-ol (Preparation 89, 15 mg, 0.066 mmol) in DCM (0.5 mL) was added Tf2O (0.013 mL, 0.080 mmol) and triethylamine (9.3 uL, 0.066 mmol). The reaction mixture was stirred at room temperature under 1 hour. The reaction mixture was concentrated in vacuo. The residue was passed through a SCX-2 cartridge eluting with 100% MeOH—1M NH3 in MeOH to give the title compound (14 mg, 59%).
Reaction SMILES: [C:1]([N:3]1[C:7](=[O:8])[C:6]([CH:10]([CH3:12])[CH3:11])([CH3:9])[N:5]=[C:4]1[C:13]1[N:27]=[CH:26][CH:25]=[CH:24][C:14]=1[C:15]([O:17]CC[Si](C)(C)C)=[O:16])#[N:2].[F-].[CH2:29]([N+:33]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32]>O1CCCC1>[C:1]([N:3]1[C:7](=[O:8])[C:6]([CH:10]([CH3:12])[CH3:11])([CH3:9])[N:5]=[C:4]1[C:13]1[N:27]=[CH:26][CH:25]=[CH:24][C:14]=1[C:15]([O-:17])=[O:16])#[N:2].[CH2:42]([N+:33]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:43][CH2:44][CH3:45]
Reactant: CC(C)C1(C)N=C(c2ncccc2C(=O)OCC[Si](C)(C)C)N(C#N)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C1(C)N=C(c2ncccc2C(=O)[O-])N(C#N)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.4 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl 2-(1-cyano-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate (7.74 g, 0.02 mol) and tetrahydrofuran is added tetrabutylammonium fluoride (0.020 mol, 1.0M, 20.0 mL). The reaction mixture is stirred at room temperature for 72 hours, concentrated in vacuo to an oil and the oil is dissolved into methylene chloride. The methylene chloride solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound as a dark yellow syrup (8.7 g, 82%), identified by IR and NMR spectral analyses.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:10]1[C:31]([CH3:32])=[CH:30][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][N:26]=[C:25](Cl)[CH:24]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)(=O)C(C)(C)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[C:41]([O:40][C@@H:9]([C:10]1[C:31]([CH3:32])=[CH:30][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:49]5[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]5)[CH:24]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[CH2:8][OH:7])([CH3:43])([CH3:44])[CH3:42]
Reactant: Cc1cc2nc(-c3cccc(-c4ccnc(Cl)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: CN1CCNCC1
Product: Cc1cc2nc(-c3cccc(-c4ccnc(N5CCN(C)CC5)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 120 °C

Procedure:
The reaction mixture of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(3-(2-chloropyridin-4-yl)phenyl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (16 mg, 0.025 mmol), 1-methylpiperazine (1 mL) was heated at 120° C. overnight. Then the reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated. To the residue was added THF, MeOH, 2N NaOH, the mixture was heated at 45° C. After the reaction finished, the reaction was washed by sat NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C36H39ClN4O2S: 627.2 (M+H+); Found: 627.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18]>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18]
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Reactant: CCN(CC)CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])c(Cl)c1

Procedure:
Prepared analogously to Example 4.1.a. from 3-chloro-4-nitrophenol and (2-chloroethyl)diethylamine hydrochloride. Yield: 1.25 g (79.5% of theory); C12H17ClN2O3 (M=272.73); calc.: molecular ion peak (M+H)+: 273/275; found: molecular ion peak (M+H)+: 273/275; Rf value: 0.44 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[C:41]=1[OH:55].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[Cl:39][C:40]1[C:41]([OH:55])=[C:42]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[CH:44][CH:45]=1
Reactant: CC1(C)OB(c2cccc(Cl)c2O)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc(Cl)c3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 55 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.30 mmol), sodium carbonate (32 mg, 0.30 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 0.01 mmol) in 1,2-dimethoxyethane (900 μl) and water (225 μl) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 35%, hexane-ethyl acetate) to give 58 mg (55% yield, 77% purity) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:16](Br)([F:18])[F:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(N(C)C)=O.[Zn]>[C:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[C:16]([F:18])[F:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCCCOCc1ccccc1
Reactant: FC(F)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: FC(F)=CCCCCOCc1ccccc1

Procedure:
Another multi-step synthesis of ethers started with the reaction of a commercially available alkylene diol, e.g., 1,6-pentanediol, with an alkyl or aralkyl halide, e.g., phenylmethyl bromide, in the presence of potassium hydroxide in xylene solvent, yielding 7-phenyl-6-oxaheptan-1-ol (XVI). Oxidation of (XVI) with pyridinium chlorochromate produced the corresponding aldehyde, 7-phenyl-6-oxaheptanal (XVII). Reaction of (XVII) with dibromodifluoromethane, triphenylphosphine, and powdered zinc in dimethylacetamide provided 6,6-difluoro-5-hexenyl phenylmethyl ether (XVIII). This synthesis is detailed in Example 11.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19](OC)OC)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:24]([C@@H:28]([C@H:30]([C:32]([O:34][CH3:35])=[O:33])[OH:31])[OH:29])([O:26][CH3:27])=[O:25]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]3[O:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[CH:28]([C:24]([O:26][CH3:27])=[O:25])[O:29]3)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Reactant: COC(OC)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1OC(c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc2Cl)OC1C(=O)OC
Yield: 76.2 %

Procedure:
3.0 g of 3-chloro-2-(4-chloro-3-dimethoxymethylphenyl)-5-trifluoromethyl-pyridine, 5.4 g of dimethyl L(+)-tartrate and 100 mg of p-toluenesulfonic acid in 180 ml of anhydrous toluene were refluxed for 10 hours. The solution was cooled and then washed with 50 ml of 10% by weight sodium bicarbonate solution and three times with 50 ml of water each time, dried over sodium sulfate and concentrated. Chromatography on silica gel resulted in 3.0 g (77%) of colorless crystals; melting point: 48°-53° C.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4([C:28](O)=[O:29])[CH2:27][CH2:26]4)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:39][NH2:40]>>[CH3:39][NH:40][C:28]([C:25]1([C:21]2[CH:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:37])[CH3:38])([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)[CH:24]=[CH:23][N:22]=2)[CH2:27][CH2:26]1)=[O:29]
Reactant: C[C@@H](c1ccc(-c2ccnc(C3(C(=O)O)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN
Product: CNC(=O)C1(c2cc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)ccn2)CC1
Yield: 59 %

Procedure:
The title compound was prepared from 1-[4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-pyridin-2-yl]-cyclopropanecarboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 59% of theory; LC (method 3): tR=2.57 min; Mass spectrum (ESI+): m/z=528 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:56][CH:57]4[CH2:62][CH2:61][O:60][CH2:59][CH2:58]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (60 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and 4-aminotetrahydropyran (17.3 μL, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (38 mg, 85%) which was obtained as a white solid. MS: m/e=412.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:25])[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[C@@H:15]([NH:19][CH:20]=O)[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:24])[CH3:23])=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([OH:25])[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[C@@H:15]([N+:19]#[C-:20])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:23])[CH3:24])=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC=O)C(=O)C1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+][C@H](C(=O)C1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)C(C)C
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a mixture of N-((2S)-1-((4R)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylcyclohexyl)-3-methyl-1-oxobutan-2-yl)formamide (109 mg, 0.298 mmol) and TEA (0.208 mL, 1.490 mmol) in CH2Cl2 (5 mL) was added POCl3 (0.027 mL, 0.298 mmol) at 0° under N2. The mixture was stirred at 0-5° C. for 3 h. The mixture was quenched with NaHCO3 (aq), extracted into CH2Cl2, and dried over Na2SO4. After concentrating, the crude residue was purified via column chromatography (CH2Cl2) to give (2S)-1-((4R)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylcyclohexyl)-2-isocyano-3-methylbutan-1-one (85 mg, 0.244 mmol, 82% yield) as a light yellow oil.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=O)=O.C(N=[C:22]=[O:23])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O>ClC1C=CC=CC=1>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][N:10]=[C:22]=[O:23]
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C=NSc1ccccc1-c1ccccc1
Reaction time: 2 h

Procedure:
23.3 g of 2-biphenylylsulfonamide, 10.9. g of n-butyl isocyanate, a catalytic amount of 1,4-diazabicyclo[2,2,2]-octane and 180 ml of chlorobenzene were refluxed with stirring for 2 hours. Then, phosgene in a slight excess of the theroretical amount was blown through the reaction mixture over 2 hours while maintaining the internal temperature at 115°-120° C. At this time, any unreacted phosgene escaping from the reaction system was trapped in a dry ice trap and returned to the reactor. After addition of the phosgene, the reaction mixture was further stirred at the reflux temperature for a short time to complete the reaction. The mixture was cooled, and if necessary, it was filtered under reduced pressure to remove the insoluble matter. It was then concentrated under reduced pressure, to obtain 20.0 g of 2-biphenylylsulfanylisocyanate, B.p 135°-137° C./0.7-0.8 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Cl.[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19]Cl)([CH3:16])[CH3:15].[H-].[Na+]>CN(C)C=O>[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5](=[O:12])[C:6]1=[O:11])([CH3:16])[CH3:15]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(CCN1C(=O)C(=O)c2cc(F)ccc21)C(C)C
Temperature: 80 °C
Yield: 85.1 %

Procedure:
To a suspension of 3.30 g of 5-fluoroisatin and 4.00 g of 2-diisopropylaminoethyl chloride hydrochloride in 75 ml of dry N,N-dimethylformamide was added 1.60 g of sodium hydride (60% dispersion in mineral oil) with stirring under ice-cooling. The mixture was stirred for 30 minutes at room temperature and then heated at 80° C. for 17 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with benzene, and the benzene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-petroleum benzine (boiling point range of 50°-80° C., and containing 60-70% hexane; distributed by Wako Pure Chemical Industries, LTD) to obtain 4.97 g of 1-(2-diisopropylaminoethyl)-5-fluoroisatin having a melting point of 100°-102° C.
Reaction SMILES: C([O:5][C:6](=[O:43])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:14]2)=[CH:9][CH:8]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:36])([F:34])[F:35])=[C:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([O:18][C@H:15]4[CH2:16][CH2:17][N:13]([C:10]5[CH:11]=[CH:12][C:7]([C:6]([OH:43])=[O:5])=[CH:8][CH:9]=5)[CH2:14]4)=[CH:24][CH:23]=3)=[O:27])[N:29]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](Oc3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N2CC[C@H](Oc3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
The above 4-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-benzoic acid tert-butyl ester (150 mg) was dissolved in a mixture of methylene chloride (2 mL) and trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 1 hr and solvents were evaporated. The residue was extracted with ethyl acetate and water. The organic layer was dried and solvents were evaporated. The residue was triturated with ethyl acetate and hexanes to give a tan solid as 4-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-benzoic acid (75 mg). LC-MS for C28H22F3N3O5 (m/e) calcd 537, obsd 538 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:33]([NH:40][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([N:11]2[C:10](=[S:28])[N:9]([C:6]3[CH:7]=[N:8][C:3]([C:1]#[N:2])=[C:4]([C:29]([F:31])([F:30])[F:32])[CH:5]=3)[C:16](=[O:17])[C:12]32[CH2:15][CH2:14][CH2:13]3)=[CH:19][C:20]=1[F:27])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)O)c(F)c3)C2=S)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)NCc4ccccc4)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
A mixture of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid (Compound 224, 68 mg, 0.14 mmol), benzylamine (22 mg, 0.21 mmol), HATU (70 mg, 0.18 mmol), and DIEA (40 μL, 0.21 mmol) in DMF (3 mL) was stirred at room temperature for 3 h. The crude reaction mixture was purified by reverse phase HPLC (acetonitrile/water:TFA) to afford 51 mg of N-benzyl-4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.22 (d, 1H), 9.12 (t, 1H), 8.75 (d, 1H), 7.87 (t, 1H), 7.49 (dd, 1H), 7.40 (dd, 1H), 7.37-7.31 (m, 4H), 7.29-7.24 (m, 1H), 4.51 (d, 1H), 2.69-2.63 (m, 2H), 2.55-2.44 (m, 2H), 2.03-1.94 (m, 1H), 1.62-1.56 (m, 1H). LCMS [M+1]+ 554.5.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[C:23](=[O:24])[CH2:22][N:14]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: OCCCCNCc1ccccc1
Product: Cc1ccc(N(CC(=O)N(CCCCO)Cc2ccccc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 4-benzylamino-butan-1-ol
Reaction SMILES: [N+](C1C(N[C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=C(C=CC=1)C(O)=O)([O-])=O.[BH4-].[Na+].[CH3:26][C:27]([OH:29])=[O:28]>[OH-].[Na+].O>[N:15]1[C:20]2=[C:21]3[C:16](=[CH:17][CH:18]=[C:19]2[N:22]=[CH:23][CH:14]=1)[N:15]=[C:14]1[C:23]([C:26]([C:27]([OH:29])=[O:28])=[CH:17][CH:16]=[CH:21]1)=[N:22]3
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Nc1cnc2ccccc2n1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc2nc3ccc4nccnc4c3nc12
Yield: 73 %

Procedure:
A solution of 3-nitro-(quinoxalinylamino)benzoic acid (0.8 g, 2.58 mmol) in 5M NaOH (40 mL) was treated with NaBH4 (0.9 g, 12.9 mmol), and the mixture was heated under reflux for 2 h. The cooled mixture was diluted with water (40 mL), then neutralized with glacial AcOH to give pyrazino[2,3-α]phenazine-11-carboxylic acid (0.52 g, 73%): mp (MeOH/Et3N/AcOH)>350° C. 1H NMR [CF3CO2D] δ 8.62 (dd, J=8.8, 7.3 Hz, 1 H, H-9), 8.91 (d, J=9.8 Hz, 1 H, H-5 or H-6), 8.97 (d, J=9.8 Hz, H-5 or H-6), 9.18 (dd, J=8.8, 1.0 Hz, 1 H, H-8), 9.47 (dd, J=7.3, 1.0 Hz, 1 H, H-10), 9.57 (d, J=2.2 Hz, 1 H, H-2 or H-3), 9.65 (d, J=2.2 Hz, 1 H, H-2 or H-3),