Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[S:28][C:27]([Br:29])=[N:26][CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.O>CN(C=O)C>[Br:29][C:27]1[S:28][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:25][N:26]=1
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3cnc(Br)s3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3cnc(Br)s3)c[nH]c12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
14 mg (0.21 mmol) of potassium cyanide were added to 50 mg (0.11 mmol) of the compound from Example 69A in 1 ml of DMF. The mixture was stirred at 80° C. for 5 h, water was added to the reaction solution, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, the solid was filtered off, and the solvents were removed. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 38 mg (89% of theory) of the target compound were obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH3:34])[CH2:33][O:32][CH2:31]1>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:29][C:30]2([CH3:34])[CH2:33][O:32][CH2:31]2)=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19]
Reactant: CC1(CBr)COC1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1OCC1(C)COC1
Temperature: 80 °C
Yield: 38.6 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (115 mg, 0.843 mmol) and 3-(bromomethyl)-3-methyloxetane (139 mg, 0.843 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (40 mg, 38.5%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1.O[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[CH2:4][CH2:3]1
Reactant: CN1CCC(CCCCO)CC1
Reactant: N#Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(CCCCOc2cccc(C#N)c2)CC1
Yield: 70.6 %

Procedure:
To a 0° C. solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (0.74 g, 4.37 mmol), 3-hydroxy-benzonitrile (0.52 g, 4.37 mmol), and 3 mmol/g polymer supported PPh3 (2.30 g, 8.73 mmol) in THF (40 mL) was added diisopropyl azodicarboxylate (1.72 mL, 8.73 mmol) dropwise. After 6 h the mixture was filtered and concentrated. Purification by Method 1 afforded 840 mg (71%) of a yellow oil. MS (ESI): mass calcd for C17H24N2O, 272.19; m/z found, 273.4 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.38-7.33 (m, 1H), 7.24-7.20 (m, 1H), 7.14-7.09 (m, 2H), 3.96 (t, J=6.4, 2H), 2.88-2.80 (m, 2H), 2.26 (s, 3H), 1.94-1.84 (m, 2H), 1.82-1.73 (m, 2H), 1.72-1.64 (m, 2H), 1.52-1.42 (m, 2H), 1.34-1.17 (m, 5H).
Reaction SMILES: C([Li])(C)(C)C.[C:6]([Si:10]([O:13][C@H:14](/[CH:20]=[CH:21]/I)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[CH3:23][O:24][C:25](=[O:46])[CH2:26][S:27][CH2:28][CH2:29][CH2:30][S:31][C:32]1[C:36](=[O:37])[CH2:35][C@@H:34]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH:33]=1.[NH4+].[Cl-]>CCCCC.CCOCC.C1COCC1>[CH3:23][O:24][C:25](=[O:46])[CH2:26][S:27][CH2:28][CH2:29][CH2:30][S:31][C@H:32]1[C:36](=[O:37])[CH2:35][C@@H:34]([O:38][Si:39]([C:42]([CH3:43])([CH3:45])[CH3:44])([CH3:41])[CH3:40])[C@@H:33]1/[CH:21]=[CH:20]/[C@@H:14]([O:13][Si:10]([C:6]([CH3:7])([CH3:9])[CH3:8])([CH3:11])[CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)CSCCCSC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Reactant: CCCCC[C@@H](/C=C/I)O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC[C@@H](/C=C/[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1SCCCSCC(=O)OC)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
tert-Butyllithium (1.47 mL of a 1.7M solution in pentane, 2.5 mmol) was added dropwise to a solution of tert-butyl[(S)-1-((E)-2-iodovinyl) hexyloxy]dimethylsilane 6 (462.5 mg, 1.25 mmol) in Et2O (6.0 mL) at −78° C. After stirring for 30 min lithium 2-thienylcyanocuprate (6.0 mL of a 0.25M solution in THF, 1.5 mmol) was added and the reaction was stirred an additional 30 min at −78° C. A solution of enone 5 (430 mg, 1.1 mmol) in Et2O (1 mL) was added and stirring was continued for an additional 1 h. The reaction mixture was then quickly poured into saturated aqueous NH4Cl cooled to 0° C. The mixture was extracted with EtOAc and the organic portion was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was quickly purified by flash column chromatography (silica gel, 100% hexane followed by 8:1 hex/EtOAc) to afford 270 mg (39%) of the above titled compound.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([CH2:17][CH3:18])[C:6]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)C.C[O-].[Na+].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO.C1COCC1>[CH2:17]([C:7]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]([OH:4])[C:14]2[C:9]([CH:8]=1)=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH3:18]
Reactant: CCc1cc2cc(OC)ccc2c(OC(C)=O)c1-c1ccccc1
Agent: C[O-]
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of 3-ethyl-6-(methyloxy)-2-phenyl-1-naphthalenyl acetate (56) (0.61 g, 1.90 mmol) in MeOH (20 mL) and THF (20 mL) was added NaOMe (0.5M in MeOH, 10 mL). The mixture was stirred at room temperature for 3 h. Cooled to room temperature, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.74 g, 7.50 mmol) was added. Most of the solvent was removed and the residue was diluted with water (20 mL) and acidified with 5 N HCl. The mixture was extracted with CH2Cl2. The extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (10:1) to give 0.52 g (98%) of compound 57 as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.08 (t, J=7.5 Hz, 3H), 2.49 (q, J=7.5 Hz, 2H), 3.93 (s, 3H), 5.14 (s, 1H), 7.05-7.10 (m, 2H), 7.24 (s, 1H), 7.32-7.38 (m, 2H), 7.42-7.48 (m, 1H), 7.50-7.56 (m, 2H), 8.05-8.10 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])(=[O:5])=[O:4].N12CCCN=C1CCCCC2.C1CCN2C(=NCCC2)CC1.[C:39](=O)(OC1C=CC=CC=1)[O:40]C1C=CC=CC=1.CS(O)(=O)=O.[NH2:60][C:61]1[N:66]=[C:65]([CH2:67][Cl:68])[CH:64]=[C:63]([O:69][CH3:70])[N:62]=1>C(#N)C>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:39]([NH:60][C:61]1[N:66]=[C:65]([CH2:67][Cl:68])[CH:64]=[C:63]([O:69][CH3:70])[N:62]=1)=[O:40])(=[O:14])=[O:13])(=[O:5])=[O:4]
Reactant: COc1cc(CCl)nc(N)n1
Reactant: CN(C)S(=O)(=O)c1ccccc1S(N)(=O)=O
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(CCl)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
26.4 g of 2-(N,N-dimethylsulfamoyl)-benzenesulfonamide (0.1 mol) are suspended in 100 ml of acetonitrile; 15.7 g of 1,8-diazabicyclo(5,4,0)undec-7-ene DBU (0.1 mol) are added, and the mixture is stirred for 1 hour at room temperature. There are then added 21.4 g of diphenyl carbonate (0.1 mol) and stirring is continued for 1 hour. After a standing time of 15 hours, 9.7 g of methanesulfonic acid (0.1 mol) are added dropwise in the cold state. There are afterwards added 17.3 g of 2-amino-4-chloromethyl-6-methoxypyrimidine (0.1 mol), and the suspension is refluxed for 1 hour, in the course of which there is firstly formed a solution from which, after a short time, the product precipitates in crystalline form. The reaction mixture is cooled and the product is filtered off under suction to thus obtain 32 g of slightly yellowish product; m.p. 214°-216° C. (decomp.); yield 70% of theory.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:3]=1.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.ClC(Cl)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]2[C:3]=1[C:15]1([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=1.[CH3:1][C:2]1[CH:6]=[C:5]2[N:4]([CH:3]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:14][C:15]12[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1
Reactant: Cc1ccn(-c2ccccc2O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2n(c1)-c1ccccc1OC21CCN(C(=O)OC(C)(C)C)CC1
Product: Cc1ccn2c1C1(CCN(C(=O)OC(C)(C)C)CC1)Oc1ccccc1-2
Reaction time: 2 h

Procedure:
To 2-(3-methylpyrrol-1-yl)phenol (2.0 g, 12 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.5 g, 13 mmol) in dichloromethane (36 mL) under N2 was added, dropwise at 0° C., dichloroacetic acid (1.9 mL, 23 mmol) over 5 min. The mixture was stirred at that temperature for 2 h then held at 5° C. overnight. The mixture was washed with water (10 mL), 1M NaOH (20 mL) and brine (10 mL), dried over MgSO4 and purified by column chromatography (0-30% EtOAc/hexane) to give a mixture of product isomers (˜2.7 g, 68%, 2:1 ratio by NMR). The mixture was subjected to SFC separation using ChiralPak OD-H (30% MeOH w/0.1% DEA, 70% CO2) to give tert-butyl 3-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate as the first eluting fraction (1.0 g, 37%) and tert-butyl 2′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate as the second eluting fraction (0.40 g, 30%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[OH-].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH:8]=2)[CH:3]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCOc1ccc2cc(Br)ccc2c1

Procedure:
22.29 g (0.1 mol) of 2-bromo-6-naphthol, 11.22 g (0.2 mol) of potassium hydroxide, and 32.36 g (0.13 mol) of 1-bromododecane were dissolved in ethanol (300 ml), and the solution was refluxed for 8 hr. Thereafter, water was added thereto, the mixture was cooled, and the resultant precipitate was collected by filtration and washed with a sodium hydroxide solution and then with water. The crude product thus obtained was recrystallized from ethyl acetate to give 2-bromo-6-dodecyloxynaphthalene.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[C:25]([C:38](O)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:29]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:25]([C:38]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[CH:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:28][CH:29]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)n1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)nccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)nccc23)n1
Yield: 10.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-amine (Intermediate-6, 100 mg, 0.329 mmol), 3-chloro-6-(pivalamidomethyl)picolinic acid (Intermediate-3, 126 mg, 0.46 mmol), oxalyl chloride (87 mg, 0.69 mmol), DMF (1 drop) and DIPEA (129 mg, 1.00 mmol) in CH2Cl2 (5 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.89 (s, 1H), 8.34-8.30 (m, 2H), 8.17 (d, J=7.5 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.00 (d, J=6.3 Hz, 1H), 7.83-7.78 (t, J=7.8 Hz, 1H), 7.73-7.67 (m, 5H), 7.40 (d, J=8.7 Hz, 1H), 4.45 (d, J=6.0 Hz, 2H), 1.17 (s, 9H); MS [M+H]+: 557.18.
Reaction SMILES: [I:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[I-:1].[O:10]1[C:6]2([CH2:11][CH2:12][CH:3]([CH2:2][P+:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:4][CH2:5]2)[O:7][CH2:8][CH2:9]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ICC1CCC2(CC1)OCCO2
Solvent: CC#N
Product: [I-]
Product: c1ccc([P+](CC2CCC3(CC2)OCCO3)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.54 g of 8-iodomethyl-1,4-dioxa-spiro[4.5]decane and 5.15 g of triphenylphosphine are dissolved in 32 ml of acetonitrile and heated at the boil under reflux for 12 hours. The mixture is stirred at room temperature for two days and then concentrated under reduced pressure to a volume of about 15 ml, and 30 ml of diethyl ether are added. With vigorous stirring in an ice-bath, a precipitate begins to form. The precipitate is filtered off with suction and dried under reduced pressure. This gives 3.86 g of (1,4-dioxa-spiro[4.5]dec-8-ylmethyl)triphenylphosphoniumiodide.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]2[CH2:15][C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.CN(C)CCN(C)C.Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:28]=1[CH2:36]Br>C1COCC1>[Cl:6][C:7]1[C:8]2[C:15]3([CH2:36][C:28]4[C:27](=[CH:32][CH:31]=[C:30]([N+:33]([O-:35])=[O:34])[CH:29]=4)[CH2:26]3)[C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (0.29 ml, 0.74 mmol, 2.5 M) was added to a stirred solution of 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step B (50.0 mg, 0.295 mmol) at −78° C. in THF (30 mL). After complete addition of butyllithium, N,N,N′,N′-tetramethylethane-1,2-diamine (0.31 mL, 0.77 mmol) was added. After 1 h at −78° C., 1,2-bis(bromomethyl)-4-nitrobenzene (91.0 mg, 0.295 mmol, described in Intermediate 4) was added and the reaction warmed to ambient temperature. After 8 h, the reaction was quenched with H2O (2 mL) and the mixture was partitioned between EtOAc (50 mL) and H2O (50 mL). The aqueous solution was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=317 (M+1).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:7]([C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].Br[CH2:20][CH2:21][F:22].O>CN(C=O)C>[F:22][CH2:21][CH2:20][O:18][C:14]1[CH:13]=[C:12]([C:7]2[C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cccnc1-c1cccc(O)c1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1-c1cccc(OCCF)c1
Reaction time: 2 h
Yield: 45.3 %

Procedure:
Sodium hydride 60% (0.021 g, 0.925 mmol) was added to a solution containing 3-(3-nitropyridin-2-yl)phenol (0.2 g, 0.925 mmol) and 1-Bromo-2-fluoroethane (0.138 ml, 1.850 mmol) in DMF (Volume: 3.08 ml). The reaction was stirred for 2 hours. Diluted reaction with water and extracted with ethyl acetate. Combined organics, dried, filtered, and purified by ISCO column using 35% ethyl acetate in hexanes to afford 2-(3-(2-fluoroethoxy)phenyl)-3-nitropyridine (0.11 g, 0.419 mmol, 45.3% yield).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29](OCC)=[O:30])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46]>>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([NH:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH3:43])=[O:30])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reactant: CC(C)(C)CN
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc3c(C(=O)NCC(C)(C)C)noc3c2Cl)C[C@H](C)O1

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and 2,2-dimethylpropan-1-amine.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.[OH-].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:21])[CH:9]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)C=Cc2cc(Br)ccc2O)cc1
Reaction time: 8 h

Procedure:
5-Bromosalicylaldehyde (20.1 g) and p-methoxyacetophenone (15.0 g) were dissolved in ethanol (80 ml) and a solution of potassium hydroxide (26.5 g) in water (40 ml) was added, with cooling. The reaction mixture was allowed to stand overnight, and then was acidified by addition to excess hydrochloric acid. The precipitated 5-bromo-2-hydroxy.4'-methoxychalcone was filtered off, washed with water, and recrystallised from ethanol, 27.5 g, m.p. 177°-179°.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:9]=2[C:10]=1[NH:11][C:12](OCC)=[O:13])=O)C.O.[NH2:23][NH2:24]>C(O)C>[NH2:23][N:24]1[C:4](=[O:3])[C:6]2[O:7][C:8]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:9]=3[C:10]=2[NH:11][C:12]1=[O:13]
Reactant: CCOC(=O)Nc1c(C(=O)OCC)oc2ccc(Cl)cc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nn1c(=O)[nH]c2c(oc3ccc(Cl)cc32)c1=O

Procedure:
To a solution of 5-chloro-3-ethoxycarbonylamino-benzofuran-2-carboxylic acid ethyl ester (3.6 g, 11.6 mmol) in ethanol (50 mL) was added hydrazine hydrate (6.2 mL, 127 mmol). After heating at reflux for 4 h, the title compound was collected by filtration (2.9 g) and was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1)[CH3:2].[CH3:13][O:14]C(Cl)Cl.CCOCC>C(Cl)Cl>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=1[CH:13]=[O:14])[CH3:12]
Reactant: CCOc1ccc(OCC)cc1
Reactant: COC(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOc1ccc(OCC)c(C=O)c1
Reaction time: 0.08 h
Yield: 92 %

Procedure:
A mixture of 1,4-diethoxybenzene (24.9 g 0.150 mole) and 1,1-dichloromethyl methyl ether (18 g., 0.157 mole) in methylene chloride (80 ml.) was added with stirring during 20 minutes to a solution of stannic chloride (39 g., 0.150 mole) in methylene chloride (150 ml.) at approximately 0° C. The solution was then stirred at this temperature for 5 minutes and quenched by addition of aqueous hydrochloric acid (6 N., 100 ml.) which was added rapidly. The organic phase was separated washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and the solvent removed from the filtrate by evaporation under reduced pressure to yield a crystalline solid (29 g.) m.p. 57°-59° C. Recrystallation (from ether) gave 2,5-Diethoxybenzaldehyde (27.1 g., 0.138 mole, 93%) m.p. 60°-61° I.R.: 1738 cm-1 (aldehyde CO).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[CH:16](O)=[O:17]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:16]=[O:17])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1
Reactant: O=CO
Reactant: Nc1ccc(Br)cc1Oc1ccccc1
Product: O=CNc1ccc(Br)cc1Oc1ccccc1

Procedure:
Using the general procedure of J. Chem. Soc., Perkin I 1976, 1279-1285, 4-bromo-2-(phenoxy)aniline, prepared as described in J. Chem. Soc., 1930, 1202-1208, is heated with formic acid to afford the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[NH2:10][C:11]([C@@H:13]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[N:14]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:12].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[NH2:10][C:11]([C@@H:13]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[F:9])=[CH:20][CH:19]=2)[N:14]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:12]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@H]1C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3F)cc2)CC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
1-(Bromomethyl)-2-fluorobenzene (30 μl, 0.220 mmol) was added to a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate (D9, 45 mg, 0.146 mmol) and potassium carbonate (30 mg, 0.217 mmol) in acetonitrile (2 ml). The mixture was stirred overnight at room temperature. After the reaction was finished, as shown by TLC, ethyl acetate and water were added. The organic phase was then washed with brine, dried (Na2SO4), filtered and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (7:3 to 6:4) to afford the title compound (51 mg, 85%); Rt (HPLC): 5.56 min; Rf (cyclohexane:ethyl acetate=1:1): 0.28; 1H NMR (300 MHz, CDCl3) δ (ppm): 7.56-7.48 (m, 1H); 7.37-7.28 (m, 1H); 7.24-7.06 (m, 5H); 6.93 (d, 2H); 5.45-5.37 (br. s, 1H); 5.15 (s, 2H); 4.73-4.60 (m, 1H); 4.53-4.45 (m, 1H); 2.58-2.48 (m, 1H); 2.34-2.25 (m, 1H); 2.09-1.93 (m, 2H); 1.28-1.13 (br. s, 9H).