Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[CH2:4][C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9]([F:15])=[N:10][C:11]=2[NH2:14])[N:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:34][CH2:35][CH2:36][C:37]#[CH:38])(=O)=O>CN(C=O)C>[F:15][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:5]([CH2:4][C:3]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:2]=3[Br:1])[N:6]2[CH2:38][CH2:37][CH2:36][C:35]#[CH:34])=[C:11]([NH2:14])[N:10]=1
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc(Br)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc(OC)c(OC)cc2Br)nc2c(N)nc(F)nc21

Procedure:
A solution of 8-(2-bromo-4,5-dimethoxy-benzyl)-2-fluoroadenine (13 mg, 0.034 mmol), Cs2CO3 (11 mg, 0.034 mmol), pent-4-ynyl tosylate (10 mg, 9 L, 0.044 mmol) in anhydrous DMF (80 L) was stirred at 60° C. for 30 min. Following solvent removal, the product (8.2 mg, 53.6%) was collected through silica gel column purification (CHCl3:EtOAc:hexanes:i-PrOH at 20:10:20:1). 1H NMR (400 MHz, CDCl3) 7.06 (s, 1H), 6.67 (s, 1H), 5.92 (bs, 2H), 4.31 (s, 2H), 4.14 (t, J=7.4 Hz, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 2.25-2.20 (m, 2H), 1.99 (t, J=2.6 Hz, 1H), 1.96-1.89 (m, 2H); 13C NMR (100 MHz, CDCl3) 160.0, 158.3, 156.7, 153.4, 151.3, 149.4, 127.2, 117.3, 115.9, 114.5, 113.2, 82.7, 70.2, 56.62, 56.56, 42.7, 34.3, 30.1, 28.5, 16.3; MS ink 447.9 (M+H)+. HPLC: (a) 99.0% (60% water-40% acetonitrile); (b) 98.8% (35% to 55% acetonitrile).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[S:6][C:7]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(COCc2ccccc2)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(COCc3ccccc3)s2)c1Br
Yield: 31.2 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamide was prepared as described in Example 2 from 2-chlorosulfonyl-5-(benzyloxymethyl)thiophene (520 mg, 1.72 mmol) and 5-amino-4-bromo-3-methyl isoxazole (319 mg, 1.8 mmol). Purification by column chromatography using 10% MeOH/CHCl3) gave 238 mg of pure N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamide as brown semisolid (31% yield, m.p. 92° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[I:10]I>C(O)C.C(Cl)Cl.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:1][C:2]1[CH:8]=[C:7]([I:10])[C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: Nc1c(F)cc(Cl)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of 4-chloro-2-fluoroaniline (1.15 g, 7.9 mmol) in 125 mL of ethanol added silver sulphate (1.7 g, 8.3 mmol), then followed by addition of I2 (2.1 g, 8.3 mmol) in portions. After the addition was completed, the mixture was stirred at RT for 2 hours. The mixture was filtered through celite and the filtration was evaporated to give dark oil which was dissolved in 125 mL of DCM. The solution was washed with 2 M sodium hydroxide (40 mL×2), saturated Na2S2O3 (40 mL×2) and water (40 mL×2). The resulting solution was dried over MgSO4 and then evaporated to give the crude 4-chloro-2-fluoro-6-iodoaniline as dark oil (2.1 g, yield: 98%).
Reaction SMILES: [CH2:1]([CH:8]1[C:14](=[O:15])[C:13](=[N:16]O)[CH:12]2[CH2:18][CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:19].[H][H]>[Pd].C(O)C>[ClH:19].[NH2:16][CH:13]1[CH:12]2[CH2:18][CH:9]([CH2:10][CH2:11]2)[CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:14]1=[O:15]
Reactant: O=C1C(=NO)C2CCC(C2)C1Cc1ccccn1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NC1C(=O)C(Cc2ccccn2)C2CCC1C2
Reaction time: 3 h
Yield: 86 %

Procedure:
A solution of 2-aza-2-benzyl-4-oximino-3-oxobicyclo[3.2.1]octane in 10 mL/mmole of ethanol and 5.8 mL/mmole of 3N HCl containing 0.5 g/mmole of 10% Pd/C was saturated with hydrogen gas to 45 psi. The mixture was shaken for 3 hours and then filtered through a layer of Celite. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as a solid (86% yield). This procedure is further described in E. Reimann, Arch. Pharm. 310, 102–109 (1977).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH3:5][CH:6]1[CH2:10][O:9][C:8](=[O:11])[O:7]1>>[CH3:5][CH:6]1[CH2:10][O:9][C:8]2([O:4][CH2:1][CH:2]([CH3:3])[O:11]2)[O:7]1
Reactant: CC1CO1
Reactant: CC1COC(=O)O1
Product: CC1COC2(OCC(C)O2)O1
Yield: 70 %

Procedure:
4-methyl-1,3-dioxolan-2-one and propylene oxide were reacted in a similar manner to the procedure of Example 2, whereby 2,7-dimethyl-1,4,6,9-tetraoxaspiro[4.4]nonane was obtained in yield of about 70%.
Reaction SMILES: [CH3:1][C:2]([C:4]([C:9]([CH3:11])=[O:10])=[CH:5]OCC)=[O:3].[NH2:12][C:13]1[C:14]([Cl:24])=[C:15]([C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=1)[C:16]([OH:18])=[O:17]>C1(C)C=CC=CC=1>[CH3:11][C:9]([C:4]([C:2]([CH3:1])=[O:3])=[CH:5][NH:12][C:13]1[C:14]([Cl:24])=[C:15]([C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=1)[C:16]([OH:18])=[O:17])=[O:10]
Reactant: CCOC=C(C(C)=O)C(C)=O
Reactant: Nc1cc(Cl)c(Cl)c(C(=O)O)c1Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=CNc1cc(Cl)c(Cl)c(C(=O)O)c1Cl)C(C)=O
Temperature: 10 °C
Yield: 741.6 %

Procedure:
46.8 g (0.3 mole) of methyl 1-methylcarbonyl-2-ethoxyvinyl ketone were added dropwise to a suspension of 48.1 g (0.02 mole) of 3-amino-2,5,6-trichlorobenzoic acid in 100 ml of toluene. The mixture was heated for 2 hours to 80° C and was then cooled to 10° C, and the precipitate was filtered off. After digesting with acetonitrile, 52 g (74% of theory) of 3-[2,2-bis-(methylcarbonyl)-vinylamino]-2,5,6-trichlorobenzoic acid were obtained in the form of colourless crystals of melting point 242°-244° C.
Reaction SMILES: [CH2:1]([S:3]SCC)[CH3:2].[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([S:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[Na+].II>>[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([S:13](=[O:15])([S:3][CH2:1][CH3:2])=[O:14])=[CH:9][CH:8]=1
Reactant: CCSSCC
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: II
Agent: [Na+]
Product: CCSS(=O)(=O)c1ccc(C)cc1
Yield: 100 %

Procedure:
The reaction was carried out using 0.60 mL (4.87 mmoL) of diethyl disulfide, 2.78 g (15.6 mmoL) of sodium p-toluenesulfinate, 2.47 g (9.74 mmoL) of iodine in accordance with the method of Reference Example 3, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain 2.11 g of the heading compound as a colorless oily substance (yield 100%).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[N:10]=[CH:11][S:12][CH:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:29]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[N:10]=[CH:11][S:12][CH:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH:30]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:29]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2cscn2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)CCC1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CCC(=O)O)C2)NC(c2cscn2)=NC1c1ccc(Cl)cc1Cl
Yield: 44.9 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-4-yl)-1,4-dihydropyrimidine-5-carboxylate (0.73 g, 1.53 mmol) was reacted with 3-(morpholin-2-yl)propanoic acid hydrochloride (0.3 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.38 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[N:6][CH:7]=1.[CH3:16][Mg]Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH3:16])=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(F)cn1
Solvent: ClCCl
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[(1E)-(5-fluoropyridin-2-yl)methylene]-2-methylpropane-2-sulfinamide (52.12 g, 228 mmol) in dichloromethane (1000 mL) at −78° C. was added methylmagnesium bromide (3.0 M in tetrahydrofuran; 198 mL, 594 mmol). The mixture was allowed to warm to ambient temperature. After 30 min, the mixture was cooled down to −78° C. and was quenched with saturated aqueous ammonium chloride (100 mL). The mixture was allowed to warm to ambient temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% ethyl acetate) gave the title compound. MS 245 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:27]3[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)s1

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (360 mg, 1 mmol) and commercially available 5-bromothiophene-2-sulfonamide (221 mg, 1 mmol) according to general procedure II. Obtained as an off-white solid (300 mg, 57%). MS (ISP) 516.2 [(M+H)+]; mp 248–250° C.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].[CH:21]1(C(OCC)=O)CCC1>>[CH2:16]([C:2]1([CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:10])([CH3:11])[CH3:12])=[O:6])[CH2:20][CH2:21][CH2:1]1)[CH2:17][CH:18]=[CH2:19]
Reactant: CCOC(=O)C1CCC1
Reactant: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Product: C=CCCC1(COC(=O)N[C@H](C(=O)O)C(C)(C)C)CCC1

Procedure:
N-{[(1-But-3-en-1-ylcyclobutyl)methoxy]carbonyl}-3-methyl-L-valine was prepared according to the procedure for N-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine by using ethyl cyclobutanecarboxylate instead of ethyl isobutyrate in Step 1. LRMS (ESI) m/z 298.3 [(M+H)+; calcd for C16H28NO4: 298.2].
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[CH2:28](Cl)/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH2:28][CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]1=[O:21]
Reactant: ClC/C=C/c1ccccc1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Product: O=c1c2oc3ccccc3c2n(CC=Cc2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with trans-cinnamyl chloride and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.09 (s, 1H); 5.11 (s, 1H); 6.49-6.58 (m, 2H); 7.18-7.30 (m, 3H); 7.37-7.47 (m, 3H); 7.64 (dd, J=8 Hz, 1H); 7.82 (d, J=8 Hz, 1H); 8.07 (d, J=8 Hz, 1H), 10.73 (br s, 1H); Ret. time=2.66 min, m/z=333.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N+:3]=1[O-].COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>>[CH3:1][C:2]1[N:3]=[C:4]([C:24]#[N:25])[CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: [C-]#N
Reactant: Cc1cc(C=Cc2ccccc2)cc[n+]1[O-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: Cc1cc(/C=C/c2ccccc2)cc(C#N)n1

Procedure:
Following the general method described in example 2b, 2-methyl-4-styryl-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and chromatography (SiO2 with CH2Cl2) the title compound was obtained as a yellow crystalline material. MS: m/e=220 (M+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[F:20][CH2:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:25][CH2:24][NH:23][CH:22]([CH2:21][F:20])[CH2:27]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: FCC1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(CF)C3)c(F)cc2c1=O
Temperature: 115 °C
Yield: 36.1 %

Procedure:
A suspension of 530.4 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 590.7 mg of 2-(fluoromethyl)piperazine and 2 ml of pyridine was heated at 115° C. for 30 minutes, then filtered and the filtrate refrigerated overnight. The resulting crystals were collected, washed with water, ether and dried, giving 262 mg of the desired compound as light yellow crystals, mp 202°-203° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C@@H:10]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]2[OH:12])=[N:4][NH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:19](OC(=O)C)(=[O:21])[CH3:20]>CO>[OH:1][C:2]1[C:3]([C@@H:10]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]2[OH:12])=[N:4][N:5]([C:19](=[O:21])[CH3:20])[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1[nH]nc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)n1nc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(O)c1C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 g. of 4-hydroxy-3-β-D-ribofuranosylpyrazole-5-carboxamide in 20 cc. of anhydrous methyl alcohol was stirred and cooled to 0°C. To the cold stirred solution was added 5 cc. of acetic anhydride dropwise over about 10 minutes. The reaction mixture was stirred for about 1 hour while the temperature was allowed to increase to about 25°C. The solvent was removed under reduced pressure to provide an oily residue which was dissolved in 25 cc. of 50 percent methanol-toluene. Again the solvent was removed under reduced pressure. This procedure was repeated three times to insure complete removal of any excess acylating agent. After the final solvents were totally removed, 4-hydroxy-3β-D-ribofuranosyl-N1 -acetylpyrazole-5-carboxamide remained as a white solid.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[NH4+:14].[OH-]>C(O)(C)C>[NH2:14][CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1ccc(OC[C@H]2CO2)cc1
Agent: [OH-]
Solvent: CC(C)O
Product: N#Cc1ccc(OC[C@H](O)CN)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
4-[(2R)-Oxiranylmethoxy]benzonitrile (see step (i) above; 14.65 g, 83.6 mmol) was mixed with NH4OH (conc., 64 mL) and 87 mL of isopropanol. The mixture was stirred at rt for 18 h. The reaction mixture was then filtered and evaporated to give 14.6 g (91%) of the sub-title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].CCN(C(C)C)C(C)C>C1COCC1>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(F)ccc2[N+](=O)[O-])c(OC)c1
Temperature: 25 °C

Procedure:
A solution of 2,4-difluoro-1-nitrobenzene (1.1 mL), 2,4-dimethoxy benzylamine (1.5 mL) and DIEA (5.2 mL), in THF (40 mL) was heated at 60° C. for 60 min, allowed to cool to RT, partitioned between EtOAc and H2O, separated, dried (MgSO4), filtered and evaporated to yield the titled product as a yellow solid (3.14 g). 1H-NMR (300 MHz, CDCl3) δ 8.5 (br s, 1H), 7.2 (dd, 1H), 7.2 (d, 1H), 6.6-6.4 (m, 3H), 6.3 (m, 1H), 4.3 (d, 2H), 3.9 (s, 3H), 3.8 (s, 3H).
Reaction SMILES: Br[CH:2]([CH3:18])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4].C(=O)(O)[O-].[Na+].[CH3:24][NH2:25]>C(#N)C>[CH3:24][NH:25][CH:2]([CH3:18])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4]
Reactant: CCCCCCCCCCCCOC(=O)C(C)Br
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCOC(=O)C(C)NC
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a stirred solution of 59 (10 g, 31.2 mmol) in acetonitrile (20 mL) was added sodium bicarbonate (2.62 g, 31.2 mmol) and followed by mono methyl amine (40% in water) (30 mL, 3 vol) at 25-30° C. The reaction mixture was stirred for 3 hour at 25-30° C.; the reaction was monitored by TLC. The solid obtained in the reaction mixture was filtered under vacuum. The solvent was concentrated, diluted with ethyl acetate/water and stirred for 15 minutes at 25-30° C. The aqueous and organic layers were separated, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine solution, dried over Na2SO4 and concentrated under vacuum to afford crude 60 (7 g, yield: 82.3%) as a liquid
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.1 mmol) in THF (24 mL) and methanol (6 mL) at 0° C. was added a solution of (trimethylsilyl)diazomethane in hexanes (2.0 M, 5.46 mL, 10.9 mmol). The yellow solution was allowed to gradually warm to room temperature over 1 h. The volatile materials were removed and the residue was treated with aqueous hydrochloric acid (1 M). The aqueous mixture was extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, filtered, and concentrated to provide crude methyl 4-bromo-2-fluorobenzoate (2.7 g, quantitative yield). This material was used in the subsequent step without further purification. 1H NMR (400 MHz, CDCl3): 7.85-7.81 (m, 1H), 7.38-7.33 (m, 2H), 3.93 (s, 3H); MS (EI) for C8H6BrFO2: 232, 234 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:37]=[CH:36][C:23]([CH2:24][N:25]4[CH2:28][CH:27]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:26]4)=[CH:22][CH:21]=3)[N:16]=2)=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:2][CH3:3].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH2:1]([C:4]1[C:5]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:37]=[CH:36][C:23]([CH2:24][N:25]4[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]4)=[CH:22][CH:21]=3)[N:16]=2)=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:2][CH3:3]
Reactant: CCCc1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)cc3)no2)noc1-c1ccccn1

Procedure:
A solution of tert-butyl 1-(4-(5-(4-propyl-5-(pyridin-2-yl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to yield 1-(4-(5-(4-propyl-5-(pyridin-2-yl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid trifluoroacetic acid salt (17.4 mg). The compound had an HPLC retention time=7.75 min.—Column: Xbridge Ph 3.5 u 4.6×150 mm; Gradient time: 12 min, hold for 3 minutes; Flow rate=2 ml/min; Solvent A=5% MeCN—95% Water—0.05% TFA; Solvent B=95% MeCN—5% water—0.05% TFA; Start % B=10; Final % B=100. LC-MS: M+1=446+. 1H NMR (500 MHz, MeOD) δ ppm 1.04 (t, 3H), 1.73-1.83 (m, 2H), 3.34-3.40 (m, 2H), 3.73 (t, J=8.25 Hz, 1H), 4.39 (d, J=7.42 Hz, 4H), 4.54 (s, 2H), 7.51 (ddd, J=6.74, 4.67, 2.06 Hz, 1H), 7.70 (d, J=8.25 Hz, 2H), 7.98-8.06 (m, 2H), 8.30 (d, J=8.25 Hz, 2H), and 8.78 (d, J=4.40 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32]Cl>C(Cl)Cl>[CH3:15][C:14]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[O:13][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[CH:8]=[O:9])([CH3:17])[CH3:16]
Reactant: COCCOCCl
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Yield: 75.7 %

Procedure:
A mixture of 11.7 g (0.05 mole) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 19.4 g (0.15 mole) of diisopropylethylamine in 150 mL of CH2Cl2 is treated with 18.7 g (0.15 mole) of 2-methoxyethoxymethyl chloride (MEM Cl) and the resulting solution is heated under reflux for 48 hours and evaporated to dryness. The residue is taken up in CH2Cl2, washed with 1N HCl and brine, and dried with MgSO4. The solution is evaporated and the residue is filtered through flash grade silica gel, washing with 1:1 CH2Cl2 /n-hexane. Evaporation gives a tan oil, 12.2 g of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzaldehyde (76%) which is used without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6][CH2:5]1.I[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:38]3[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6][CH2:5]1
Reactant: Cn1ccc(I)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-7-(2-hydroxy-2-methylpropyl)-7-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazepan-2-one and 4-iodo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 18 Step 2. LC-MS Method 4 tR=1.11 min, m/z=497, 475, 457, 417.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[NH2:11].N1C=CC=CC=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:10][N:8]([CH3:9])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N:11]=[C:19]=[O:21])[CH:4]=1
Reactant: CN(C)c1ccc(F)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)c1ccc(F)c(N=C=O)c1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
1.09 g (7.1 mmol) of 4-fluoro-N1,N1-dimethylbenzene-1,3-diamine followed by 4.6 cm3 of pyridine are added, at a temperature in the region of 5° C., under an argon atmosphere, to 2.82 g (9.5 mmol) of triphosgene in solution in 150 cm3 of dichloromethane. After stirring for 18 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), to give a residue which is triturated in 40 cm3 of tetrahydrofuran. After filtration, a solution of 5-dimethylamino-2-fluorophenyl isocyanate in approximately 0.14 N tetrahydrofuran is obtained, which solution is used directly in the subsequent step.