Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](I)[CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=Cc1cc(O)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.2 %

Procedure:
A mixture of 2-benzyloxy-5-hydroxybenzaldehyde (8.93 g), ethyl iodide (7.31 g), anhydrous potassium carbonate (5.40 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-benzyloxy-5-ethoxybenzaldehyde as a colorless oil (9.25 g, 92%) from a fraction eluted with ethyl acetate-hexane (1:9, v/v).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][N:10]2[CH2:11][CH2:12][CH:7]([O:6][C:5]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:3]([Cl:2])[C:4]=3[CH3:17])[CH2:8][CH2:9]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1c(OC2CCNCC2)ccc(Cl)c1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1c(OC2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc(Cl)c1Cl
Temperature: 20 °C
Reaction time: 14 h
Yield: 79.9 %

Procedure:
Acetonitrile (144 mL) and water (336 mL) were added to a mixture of 4-(3,4-dichloro-2-methyl-phenoxy)-piperidine hydrochloride (60 g), 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (74.7 g) and potassium carbonate (57.3 g) and the mixture was heated to reflux for 7 h, then cooled over 30 min to 75° C. and held at 75° C. for 14 h, then heated over 30 min to reflux. Acetonitrile (192 mL) was added and then the mixture was cooled to 20° C. over 2 h to give a suspension. The suspension was filtered under vacuum, the filter cake was washed with water (180 mL) and then with acetonitrile (180 mL) and dried under vacuum at 40° C. to give 4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (73.9 g).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28][NH:27][C:26]1=[O:33])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([O:32][C:14]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:15])[CH2:28][NH:27][C:26]1=[O:33])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CNC1=O
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OC(=O)C2CCCCC2)CNC1=O
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Triethylamine (8.4 mL, 60 mmol) is added to a solution of cyclohexanecarbonyl chloride (6.3 g, 43.0 mmol), (3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one (7.0 g, 28.7mmol) and 100 mL of CH2Cl2 at 50° C. The reaction mixture is stirred at room temp. overnight. The reaction mixture is then partitioned with water, and the organic layer is dried (Na2SO4), and concentrated with rotary evaporation. The resulting residue is chromatographed (5% EtOAc—CH2Cl2) to give 10.1 g (99.5% of (3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one as a white solid: 1H NMR (CDCl3): δ 5.89 (d, J=5.27 Hz, 1H), 5.65 (t, J=4.90 Hz, 1H), 4.89 (s, 1H), 4.30 (q, J=4.14 Hz, 1H), 3.49 (m, 2H), 2.31 (tt, J=10.92 Hz and 3.39 Hz, 1H), 2.13 (d, J=14.32 Hz, 1H), 1.98 (d, J=13.56 Hz, 2H), 1.88 (d, J=14.31 Hz, 2H), 1.75 (d, J=11.30 Hz, 2H), 1.66 (s, 2H), 1.45 (s, 9H), 1.30 (m, 5H).
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.CCOCC.Cl>C1COCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([B:1]([OH:6])[OH:2])=[CH:17][CH:16]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of triisopropyl borate (4.6 mL, 20 mmol) in THF (1 mL) at -78° C. under nitrogen was added 4-fluorophenylmagnesium bromide (2M solution in diethylether, 10 mL) dropwise. The mixture was allowed to warm to room temperature. Ether (50 mL) was added, followed by 10% HCl (50 mL). The ether layer was then washed with H2O (25 mL) and brine (25 mL). The dried (MgSO4) ether layer was concentrated to dryness. The residue was triturated with hexanes to provide an off-white solid which was filtered and dried under vacuum to afford 1.38 g of 4-fluorophenyl boronic acid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH2:13][OH:14].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:14][CH2:13][C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:17]1[CH:16]=[C:15]([CH3:24])[CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=c1oc(CO)c(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cccc(-c2c(CO)oc(=O)c3ccccc23)c1
Yield: 40.2 %

Procedure:
The title compound was made in a similar way as that of the intermediate B2 using 4-bromo-3-(hydroxymethyl)-1H-isochromen-1-one (Intermediate A1, 0.5 g, 1.96 mmol), m-tolylboronic acid (0.400 g, 2.94 mmol), Pd(PPh3)4 (0.113 g, 0.098 mmol) and Cs2CO3 (0.64 g, 1.96 mmol) to afford the title compound (0.21 g, 40%).
Reaction SMILES: [C:1]1([CH2:11][C:12](Cl)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:12](=[O:13])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(Cl)Cc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNC(=O)Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 16.3 g of 1-naphthyl-acetic acid chloride in 80 ml of chloroform was added at +10° C. to a solution cooled to +10° C. of 15 g of N-(tert-butoxycarbonyl)-1,4-diamino butane, 100 ml of chloroform and 14 ml of triethylamine and after one hour of stirring at ambient temperature, the mixture was concentrated to dryness under reduced pressure. The residue was taken up in water, separated and dried under reduced pressure at 50° C. to obtain 27.8 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[CH3:16])[CH:6]=1>C(OCC)(=O)C.C(O)C>[CH3:16][C:8]1[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2C)cn1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc(N)cc2C)cn1
Yield: 99.4 %

Procedure:
A mixture of 4-methyl-1-(2-methyl-4-nitro-phenyl)-1H-imidazole (1.26 g, 5.8 mmol) and of stannous chloride dehydrate (6.81 g, 30.2 mmol) in ethyl acetate (40 mL) and ethanol (20 mL) was stirred for 1 hour at 70° C. The reaction mixture was quenched by addition of water, neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound (1.08 g, 99%) as a yellowish gum. MS ISP (m/e): 188.4 (100) [(M+H)+].
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C.O>[C:12]([CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:13]
Reactant: N#CCc1cccc2ccccc12
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCC(C#N)c1cccc2ccccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
In 125 ml of DMF was dissolved 12.54 g (75 mmol) of 1-naphthaleneacetonitrile. Then, 3.30 g (82.5 mmol) of 60% sodium hydride was added at room temperature and the mixture was heated to 60° C. and stirred for 30 minutes. After cooling to room temperature, 13.17 ml (82.5 mmol) of ethyl 5-bromovalerate was added. The reaction was further conducted at 60° C. for 30 minutes, after which the reaction mixture was cooled to <10° C. and diluted with 500 ml of pure water. The diluted mixture was extracted with 200 ml of ethyl acetate twice and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane-CH2Cl2 -ethyl acetate=4:2:1) to provide 17.16 g (yield 77.5%) of the title compound as light-yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)C(O)=O.CN(C)C=O.C(Cl)(=O)[C:38]([Cl:40])=[O:39]>ClCCl>[O:1]=[C:2]1[C:10]2([C:11]3=[CH:21][C:20]4[CH2:19][CH2:18][O:17][C:16]=4[CH:15]=[C:12]3[O:13][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:25][C:24]=1[C:38]([Cl:40])=[O:39]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (2.13 g, 5.1 mmol) and N,N-dimethylformamide (0.001 mL, catalytic amount) in anhydrous dichloromethane (30 mL) was treated with oxalyl chloride (4.50 mL, 5.1 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The crude product was concentrated in vacuo to afford 3-(((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride as a light yellow solid. A solution of 3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.27 g, 0.6 mmol), cyclohexanemethylamine (0.17 mL, 1.3 mmol), triethylamine (0.44 mL, 3.2 mmol), and 4-(dimethylamino)pyridine (0.005 g, catalytic amount) in anhydrous dichloromethane (5 mL), was stirred at ambient temperature for 20 h under nitrogen. The reaction mixture was diluted with dichloromethane (10 mL) and aqueous citric acid (10 mL) and the phases were separated. The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0% to 100% gradient) to afford N-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.33 g, 65%) as a colourless solid: 1H NMR (300 MHz, CDCl3) δ7.80 (s, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.48-7.37 (m, 2H), 7.23-7.15 (m, 2H), 7.08-7.00 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 6.19-6.09 (m, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H), 3.33-3.23 (m, 2H), 3.07-2.95 (m, 2H), 1.82-1.64 (m, 5H), 1.34-1.13 (m, 4H), 1.07-0.86 (m, 2H); MS (ES+) m/z 509.0 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:22]=[CH:21][C:6](/[CH:7]=[CH:8]/[C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:43]>C1COCC1>[Br:43][CH2:2][C:3]1[CH:22]=[CH:21][C:6](/[CH:7]=[CH:8]/[C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CBr)cc1

Procedure:
To a solution of the product of Example 149C (0.9 g, 2.97 mmol) dissolved in THF (50 mL) was added resin bound triphenylphosphine (5.93 mmol) and carbon tetrabromide (1.48 g, 4.45 mmol) and the resultant solution stirred at room temperature for 2 hours. The resin was then filtered off, washed with THF and the combined filtrate was then dried, filtered, and concentrated to afford the title compound. m/z 368 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([NH:11]/[C:12](/[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:13]\[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=[C:8]([C:29]([O:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[O:7][C@H:6]1[C@H:45]([OH:50])[C@H:46]([OH:49])[CH2:47][OH:48])(=[O:3])[CH3:2].[C:51](N1C=CN=C1)(N1C=CN=C1)=[O:52]>C(#N)C>[C:1]([NH:4][C@@H:5]1[C@@H:10]([NH:11][C:12]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=[C:8]([C:29]([O:31][CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:30])[O:7][C@H:6]1[C@H:45]([OH:50])[C@H:46]1[CH2:47][O:48][C:51](=[O:52])[O:49]1)(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@@H]1N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: CC#N
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H]2COC(=O)O2)OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@@H]1NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
Benzhydryl (2R,3R,4S)-3-(acetylamino)-4-({(E)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylate (see J. Med. Chem. 1998, 41, 787–797) (12.38 g; 17.7 mmoles) was dissolved in dry acetonitrile (130 ml) under nitrogen at room temperature. The solution was stirred and 1,1′-carbonyldiimidazole (2.87 g; 17.7 mmoles) was added. After 16 hours LC/MS showed the presence of starting triol so further 1,1′-carbonyldiimidazole (total of 0.493 g; 3 mmoles) was added. After a few hours LC/MS showed no triol present. The solvent was evaporated and the residue flash columned on silica, eluting with 1:1 ethyl acetate/40–60 petroleum ether. Fractions containing wanted product were evaporated then taken up in dichloromethane, dried with sodium sulphate, filtered and evaporated to give Intermediate 1 as an off white solid (11.05 g; 86%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:14]1[CH2:31][CH:30]([CH2:32]O)[O:29][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1)[C:11]#[C:12][CH3:13].CO.ClCCl>ClCCl>[CH2:10]([N:14]1[CH2:31][CH:30]([CH2:32][F:7])[O:29][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCN1CC(CO)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC#CCN1CC(CF)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
To a solution of diethylaminosulfur trifluoride (19.5 μL, 0.148 mmol) in dichloromethane (1.0 mL) at −78° C. was added dropwise a solution of tert-butyl 8-but-2-ynyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (50.0 mg, 0.148 mmol) in dichloromethane (1 mL). The reaction was stirred for 10 min at −78° C. then allowed to warm to room temperature and stirred for 16 h. Silica gel chromatography (4 g silica, 0-15% methanol/dichloromethane) provided tert-butyl 8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (23.0 mg, 46%). ESI-MS m/z calc. 340.2. found 341.3 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 4.52-4.40 (m, 1H), 4.39-4.28 (m, 1H), 4.06-3.91 (m, 1H), 3.71 (br s, 2H), 3.35-3.14 (m, 3H), 3.08 (t, J=11.4 Hz, 1H), 2.78 (d, J=10.3 Hz, 1H), 2.58 (d, J=11.1 Hz, 1H), 2.31 (d, J=13.5 Hz, 1H), 2.06 (t, J=12.5 Hz, 2H), 1.84 (t, J=2.3 Hz, 3H), 1.57-1.44 (m, 12H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([O:9][C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH3:8]>C(#N)C>[S:3]1[CH:4]=[N:5][N:6]=[C:2]1[NH:1][C:13]([NH:12][C:10](=[O:11])[O:9][CH2:7][CH3:8])=[S:14]
Reactant: Nc1nncs1
Reactant: CCOC(=O)N=C=S
Solvent: CC#N
Product: CCOC(=O)NC(=S)Nc1nncs1
Temperature: 24 °C
Yield: 79.4 %

Procedure:
To a stirred solution of 19.2 g (190 mM) of 2-amino-1,3,4-thiadiazole in 200 ml of acetonitrile were added in one portion 25 g (190 mM) of ethoxycarbonyl isothiocyanate. The reaction mixture was stirred at 24° C for sixteen hours. The precipitate was collected by filtration, washed three times with ethyl acetate and dried to provide 35 g (80% yield) of [(1,3,4-thiadiazol-2-ylamino)thioxomethyl]carbamic acid, ethyl ester.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[C:11]([C:20]2[C:21]([CH3:35])=[CH:22][C:23]3[C:28]([CH3:30])([CH3:29])[O:27][C:26](=[O:31])[N:25]([CH2:32][CH3:33])[C:24]=3[CH:34]=2)[CH:10]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:32]([N:25]1[C:24]2[CH:34]=[C:20]([C:11]3[CH:10]=[C:9]([CH:8]=[CH:7][C:6]([OH:36])=[O:5])[CH:14]=[CH:13][C:12]=3[O:15][C:16]([F:19])([F:17])[F:18])[C:21]([CH3:35])=[CH:22][C:23]=2[C:28]([CH3:30])([CH3:29])[O:27][C:26]1=[O:31])[CH3:33]
Reactant: CCN1C(=O)OC(C)(C)c2cc(C)c(-c3cc(C=CC(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1C(=O)OC(C)(C)c2cc(C)c(-c3cc(C=CC(=O)O)ccc3OC(F)(F)F)cc21

Procedure:
A solution of 0.068 g (0.15 mmol) of Compound 14F in 3 mL of dichloromethane and 2.5 mL of trifluoroacetic acid was stirred at room temperature overnight. The reaction mixture was then concentrated on the rotary evaporator to obtain 3-[3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-7-yl)-4-trifluoromethoxy-phenyl]-acrylic acid as a white solid (Compound 14, 0.06 g). MS (electrospray): mass calculated for C257H30F3NO5, 505.13; m/z found 506, [M+H]+.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@H:14]2[CH3:19])[N:10]=[C:9]([Cl:20])[N:8]=1)(=O)=O.[I-:21].[Li+]>O1CCOCC1>[Cl:20][C:9]1[N:10]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@H:14]2[CH3:19])[CH:12]=[C:7]([CH2:6][I:21])[N:8]=1
Reactant: C[C@@H]1COCCN1c1cc(COS(C)(=O)=O)nc(Cl)n1
Reactant: [I-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C[C@@H]1COCCN1c1cc(CI)nc(Cl)n1
Temperature: 107 °C
Yield: 85.3 %

Procedure:
(R)-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (80 g, 248.62 mmol) and lithium iodide (83 g, 621.54 mmol) were dissolved in dioxane (300 ml) and then heated at 107° C. for 1 hour. The reaction mixture was quenched with water (250 ml), extracted with EtOAc (3×250 ml), the organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and Et2O was added, the mixture was passed through silica (4 inches) and eluted with Et2O. Fractions containing product were evaporated and the residue was then triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to afford (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (75 g, 86%); m/z: (ESI+) MH+, 354.27.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([CH3:32])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:7]4[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:11][C:12]=3[CH3:32])=[O:17])[CH2:23][CH2:22]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3C)CC2)c(C)c1
Yield: 17.6 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (168 mg) and (4-bromo-2-methylphenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (516 mg) described in Preparation Example 118 and by the reaction and treatment in the same manner as in Example 1, the title compound (99 mg) was obtained.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:29]=[CH:28][C:14]2[C:15]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:20][CH2:19]3)=[N:16][O:17][C:13]=2[CH:12]=1.[ClH:30]>C1(C)C=CC=CC=1.CCOCC>[ClH:30].[F:10][C:11]1[CH:29]=[CH:28][C:14]2[C:15]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][O:27][C:8](=[O:9])[NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:20][CH2:19]3)=[N:16][O:17][C:13]=2[CH:12]=1
Reactant: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(Nc1ccccc1)OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
Phenylisocyanate (0.36 g, 3 mmol) and 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]propanol (0.3 g, 1.1 mmol) was refluxed in toluene (25 ml) for 6 h. The mixture was cooled to room temperature and hydrochloric acid in ether was added. The resulting precipitate was recrystallized from ethanol/ether and isopropanol/ether to give 180 mg of the title compound as white crystals. M.p. 204.5°-205.5° C. MS (70 eV): m/z 397 (39%, M+), 278 (4), 259 (26), 233 (50), 178 (28), 96 (100).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>C(O)C>[N:18]([CH2:2][C:3]1[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)=[N+:19]=[N-:20]
Reactant: CCOC(=O)c1c(CBr)cccc1S(N)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(CN=[N+]=[N-])cccc1S(N)(=O)=O
Temperature: 25 °C

Procedure:
A solution of 1.64 g of 3-bromomethyl-2-carboethoxybenzenesulfonamide and 0.43 g of sodium azide in ethanol was heated to reflux for 3 hours. The resulting reaction mixture was cooled to room temperature and the ethanol was removed on the rotovap. The residue was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated to give 1.32 g of a waxy solid.