Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][NH:12][CH2:13][C@@H:14]([NH:19][C:20](=[O:36])[CH2:21][C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)[CH:25]=[N:24][CH:23]=2)[C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:45]([O:47][CH3:48])=[O:46]>ClCl>[CH3:48][O:47][C:45]([N:12]([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)[CH2:13][C@@H:14]([NH:19][C:20](=[O:36])[CH2:21][C:22]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)[CH:25]=[N:24][CH:23]=1)[C@@H:15]([CH3:18])[CH2:16][CH3:17])=[O:46]
Reactant: COC(=O)Cl
Reactant: CC[C@H](C)[C@@H](CNCc1cccc2ccccc12)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Agent: ClCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CN(Cc1cccc2ccccc12)C(=O)OC)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Example 2 (40 mg, 0.083 mmol) in CH2 Cl2 (1 ml) and triethylamine (24 μl, 0.17 mmol) at 0° C. was added methyl chloroformate (39 μl of a 2.1M solution in CH2 Cl2, 0.082 mmol). The reaction was stirred at room temperature for 3 hr, the solvent evaporated in vacuo and the residue purified by preparative HPLC (C-18; 95:5 to 5:95 water:CH3CN containing 0.1% trifluoroacetic acid; gradient elution). Lyophilisation of the collected fractions afforded the title compound as a white solid.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Br.[N+:16]([C:19]1[C:24]2[NH:25]CCNC(=O)C=2C=CC=1)([O-])=O>>[F:10][C:8]1[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]2[NH:16][CH2:19][CH2:24][NH:25][C:3](=[O:15])[C:4]=2[CH:9]=1
Reactant: O=C1NCCNc2c1cccc2[N+](=O)[O-]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1Br
Product: O=C1NCCNc2c1cc(F)cc2[N+](=O)[O-]

Procedure:
This compound was prepared from 2-bromo-5-fluoro-3-nitro-benzoic acid methyl ester according to the procedure described in Example 2 for the intermediate f. Obtained 2.20 g (68%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=3)=[O:15])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=3)([OH:15])[C:25]([F:27])([F:26])[F:24])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(/C=C/c1ccc(-n2cncn2)cc1)c1cc(Cl)cc(Cl)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(/C=C/c1ccc(-n2cncn2)cc1)(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
To a solution of (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one (1 g, 3 mmol) in THF (150 mL) was added trifluoromethyltrimethylsilane (0.517 g, 3.644 mmol) and tetra-n-butylammonium fluoride (TBAF) (1.0 M, 1 mL) at 0° C. The reaction was slowly warmed to ambient temperature and allowed to stir for 2 h. The reaction was then cooled to 0° C. and 5 M HCl solution was added and the reaction was stirred for an additional 4 h at ambient temperature. The reaction was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 25% EtOAc/hexanes) to afford the title compound as an off-white solid (0.3 g, 25%).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25].CCN(C(C)C)C(C)C.[CH3:36][N:37]([CH3:43])[C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:40]4[CH2:41][CH2:42][C@H:38]([N:37]([CH3:43])[CH3:36])[CH2:39]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)CCC1(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](N(C)C)C4)ccc23)CCC1(F)F

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.66 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.26 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.56 (m, 1H), 1.27-1.32 (m, 1H), 1.00 (d, 3H). m/z: 481 [M+H]
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[CH:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[C:18]1[CH2:27][CH2:26][CH2:25][CH2:24][N:19]12.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:17]2[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][CH:15]=3)[N:19]3[CH2:24][CH2:25][CH2:26][CH2:27][C:18]=23)=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Reactant: c1ccc2c(c1)cc1n2CCCC1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2c3n(c4ccccc24)CCCC3)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-methyl-1-naphthoyl chloride (37 mg, 0.18 mmol) and 6,7,8,9-tetrahydropyrido[1,2-a]indole (30 mg, 0.18 mmol) in 1 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (0.22 mL, 0.40 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature and stirred for 3 d then cooled to −70° C. and 4-methyl-1-naphthoyl chloride (4 mg, 0.020 mmol) and ethyl aluminum dichloride (20 μL, 0.036 mmol) added and allowed to warm to room temperature and stirred 6 h. The reaction mixture was again cooled to −70° C. and 4-methyl-1-naphthoyl chloride (4 mg, 0.020 mmol) and ethyl aluminum dichloride (20 μL, 0.036 mmol) added and allowed to warm to room temperature overnight. It was again cooled to −70° C. and 4-methyl-1-naphthoyl chloride (8 mg, 0.040 mmol), ethyl aluminum dichloride (40 μL, 0.072 mmol), and 1 mL CH2Cl2 added and allowed to warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 25% ethyl acetate in hexanes to give CBX005 (22 mg, 0.065 mmol). 1H NMR (500 MHz, CDCl3, δ): 1.80-1.95 (m, 2H), 2.05-2.33 (m, 2H), 2.82 (s, 3H), 2.97 (t, J=6.3 Hz, 2H), 4.13 (t, J=6.2 Hz, 2H), 7.09 (t, J=7.6 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.30-7.37 (m, 2H), 7.40 (d, J=7.1 Hz, 1H), 7.43-7.52 (m, 2H), 7.58 (t, J=7.6 Hz, 1H), 8.08-8.19 (m, 2H). 13C NMR (500 MHz, CDCl3, δ): 19.87, 20.03, 22.31, 25.20, 42.65, 108.94, 113.75, 121.25, 122.03, 122.44, 124.31, 124.99, 125.93, 126.05, 126.24, 126.41, 126.97, 130.34, 132.89, 136.27, 139.26, 147.09, 193.08. MS m/z 340.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[Cl:28][C:29]1[C:30]([CH2:35][NH2:36])=[N:31][CH:32]=[CH:33][N:34]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:28][C:29]1[C:30]([CH2:35][NH:36][C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])=[N:31][CH:32]=[CH:33][N:34]=1
Reactant: NCc1nccnc1Cl
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A THF (370 mL) solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (15.14 g, 81.30 mmol) and CDI (13.18 g, 81.30 mmol) was placed under a nitrogen atmosphere and stirred at 60° C. for 4 h. The reaction mixture was cooled to r.t., then, (3-chloropyrazin-2-yl)methylamine bis-hydrochloride salt (16.00 g, 73.91 mmol) and DIPEA (31.52 g, 244.00 mmol, 42.5 mL) was added. After stirring at 60° C. for 20 h, the reaction was concentrated in vacuo. The crude reaction mixture was purified by a silica gel glass column chromatography (eluted with 3:2 DCM/EtOAc) to obtain the pure desired product as a slightly yellowish creamy white powder; 1H NMR (CDCl3, 400 MHz) δ 1.43-1.65 (m, 4H), 2.01-2.14 (m, 4H), 2.25 (tt, J=12.0, 3.6 Hz, 1H), 2.34 (tt, J=11.6, 3.2 Hz, 1H), 3.68 (s, 3H), 4.70 (d, J=4.4 Hz, 2H), 6.81 (s, br, -NH), 8.32-8.36 (m, 1H), 8.46 (d, J=2.4 Hz, 1H); MS (ES+): m/z 312.17/314.12 (84/32) [MH+]; HPLC: tR=2.44 min (OpenLynx, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1cccc(F)c1
Product: COc1ccc(NC(=O)Nc2cccc(F)c2)cc1-c1c(Cl)cnn1C
Yield: 1 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-Fluorophenyl isocyanate in a similar manner to as described in Example 1.53, providing 0.5 mg (1%) of Compound 36: LCMS m/z (%)=377 (M+H37Cl, 40), 375 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.23 (s, 1H), 7.45 (dt, J1=12, J2=4, J3=2 Hz, 1H), 7.37 (s, 1H), 7.32 (s, 1H), 7.17 (d, J=24 Hz, 1H), 7.15 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.03 (dd, J1=8 Hz, J2=4 Hz, 1H), 6.77 (d, J=2 Hz, 1H), 6.63 (td, J1=8 Hz, J2=4 Hz, 1H), 3.68 (s, 3H), 3.52 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:13])[N:4]=1)[CH3:2].[F:14][C:15]1[CH:16]=[CH:17][C:18]([O:33][CH3:34])=[C:19]([C:21]([CH3:32])([CH3:31])[CH2:22][C:23]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH:24]=O)[CH:20]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:13]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])([OH:30])[CH2:22][C:21]([C:19]2[CH:20]=[C:15]([F:14])[CH:16]=[CH:17][C:18]=2[O:33][CH3:34])([CH3:31])[CH3:32])[N:4]=1)[CH3:2]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: CCc1ccc2c(N)cccc2n1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCc1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Yield: 80.1 %

Procedure:
Analogously to Example 37, 334 mg (1.94 mmol) of 2-ethylquinolin-5-ylamine is reacted with 500 mg (1.62 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanal in 2.20 ml of concentrated acetic acid and 15 ml of toluene. After purification on silica gel with hexane-ethyl acetate (0-100%), 600 mg (80% of theory) of the corresponding imine is obtained.
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][N:6]=1)([CH3:4])[CH3:3].[F:21][C:22]1[C:29]([F:30])=C(C)[C:27]([F:32])=[C:26]([F:33])[C:23]=1[CH2:24]O>[Ti].C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[N:6]=[CH:7][C:8]([CH:11]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:12]([O:14][CH2:15][C:16]2[C:29]([F:30])=[C:22]([F:21])[C:23]([CH3:24])=[C:26]([F:33])[C:27]=2[F:32])=[O:13])=[CH:9][N:10]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)C(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Reactant: Cc1c(F)c(F)c(CO)c(F)c1F
Agent: [Ti]
Solvent: Cc1ccccc1
Product: Cc1c(F)c(F)c(COC(=O)C(c2cnc(C(C)(C)C)nc2)C(C)(C)C)c(F)c1F
Yield: 46.6 %

Procedure:
A mixture of ethyl (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (0.07 g), 2,3,5,6-tetrafluoro-4-methylbenzyl alcohol (0.1 g), titanium VI ethoxide (catalytic amount) and dry toluene (2 cm3) was heated at the reflux temperature for 10 hours. After cooling, the solvent was evaporated under reduced pressure to leave a brown gum, which was purified by preparative thin layer chromatography on 20 cm×20 cm×0.2 cm silica gel plates, eluting with dichloromethane containing 2% by volume ethyl acetate, to give the title compound (0.05 g) as an oil which solidified on standing.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>C(#N)C.CCOC(C)=O.[Cu]I>[CH3:16][N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: CN1CCN(C(=O)c2cccc(I)c2)CC1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)c2cccc(C#C[Si](C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
(3-Iodophenyl)(4-methylpiperazin-1-yl)methanone (1.15 g, 3.5 mmol) and ethynyl-trimethyl-silane (0.58 mL, 4.2 mmol) in dry acetonitrile (30 mL) were purged with nitrogen and treated with TEA (0.97 mL, 7.0 mmol, 2 eq.), CuI (0.033 g, 0.17 mmol) and Pd (Ph3P)2Cl2 (0.120 g, 0.17 mmol). The reaction was stirred at room temperature for 2 h, then was diluted with EtOAc (30 mL), washed with water (2×20 mL), brine, dried over sodium sulphate, and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 95/5) to afford the title compound (0.95 g, 91%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c11) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=2[F:16])[CH2:6][O:5][CH2:4][CH:3]1[CH2:7][OH:8].C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[C:32]([N:40]=[C:41]=[S:42])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1.C(OCC)(=O)C>[Br:15][C:13]1[CH:12]=[CH:11][C:10]([F:16])=[C:9]([C:2]2([NH:1][C:41]([NH:40][C:32](=[O:39])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[S:42])[CH:3]([CH2:7][OH:8])[CH2:4][O:5][CH2:6]2)[CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC1(c2cc(Br)ccc2F)COCC1CO
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NC(=S)NC1(c2cc(Br)ccc2F)COCC1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of racemic ((3RS,4SR)-4-amino-4-(5-bromo-2-fluorophenyl)tetrahydrofuran-3-yl)methanol (75 g, 259 mmol) in tetrahydrofuran (1.3 L) at 25° C. under a nitrogen atmosphere is added dropwise bis(trimethylsilyl)trifluoroacetamide (76.3 mL, 259 mmol) keeping the internal temperature below 30° C. The reaction is stirred at 25° C. for 30 minutes. Benzoyl isothiocyanate (38.4 mL, 284 mmol) is added over 10 minutes keeping internal temperature below 35° C. and the reaction is stirred at 25° C. for 30 min. The reaction mixture is diluted with ethyl acetate (500 mL) and is washed three times with 1 N HCl (3×500 mL), followed by water and brine. The solution is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using a linear gradient of 25% to 50% ethyl acetate in hexanes to give the title compound (110 g, 94%). ES/MS m/e (79Br/81Br) 453, 455 (M+1).
Reaction SMILES: CS(O[CH2:6][C@:7]1([CH3:19])[CH2:11][C:10]2[C:12]([CH3:18])=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:9]=2[O:8]1)(=O)=O.[C:20]1([CH:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[CH3:19][C@@:7]1([CH2:6][N:31]2[CH2:32][CH2:33][CH:28]([NH:27][CH:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:29][CH2:30]2)[CH2:11][C:10]2[C:12]([CH3:18])=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:9]=2[O:8]1
Reactant: Cc1cc(C)c2c(c1C)O[C@](C)(COS(C)(=O)=O)C2
Reactant: c1ccc(C(NC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c2c(c1C)O[C@](C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)C2
Temperature: 177 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
A suspension of (S)-(2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl methanesulfonate (0.34 g), N-(diphenylmethyl)-4-piperidinamine (0.73 g), and potassium carbonate (0.38 g) in N,N-dimethylacetamide (2 mL) was stirred under argon gas at 177° C. for 6 hours. This reaction mixture was diluted with water and extracted with diisopropyl ether. The organic layer was washed with water and extracted with 1N-hydrochloric acid. The aqueous layer was made basic with 2N-sodium hydroxide/water and extracted with diisopropyl ether. The extract was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to provide the title compound (0.49 g). Yield 79%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[CH3:23][O-:24].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:24][CH3:23])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Temperature: 80 °C
Yield: 61.7 %

Procedure:
A vial was charged with (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (Intermediate 1B, 1.0 g, 2.63 mmol) and DMSO (13.14 mL). Sodium methoxide (0.710 g, 13.14 mmol) was added and the reaction mixture was heated to 80° C. for 2.5 hours. The reaction mixture was cooled to RT and quenched with aqueous, saturated ammonium chloride solution. Water and EtOAc were added, and the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography (0-100% EtOAc/hexanes) to afford (S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (Example 21A; 0.611 g, 1.624 mmol, 61.8% yield) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12].FC1C=CC([B:23]([OH:25])[OH:24])=C(O[C@H](CC=C)C)C=1>>[F:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[C:2]([B:23]([OH:25])[OH:24])[CH:7]=1
Reactant: C=CC[C@H](C)Oc1cc(C)c(F)cc1Br
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1B(O)O
Product: C=CC[C@H](C)Oc1cc(C)c(F)cc1B(O)O
Yield: 100 %

Procedure:
Prepared in 100% yield from (S)-1-bromo-5-fluoro-4-methyl-2-(pent-4-en-2-yloxy)benzene following the procedure for (S)-(4-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid. NMR is complex and suggests an oligomeric mixture. The material, however, was used as is and was fully compentent for undergoing a Suzuki coupling.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CN(C=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][N:10]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C1CNC(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccc([N+](=O)[O-])cc2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.3 %

Procedure:
A solution of 3-benzylimidazolidin-2,4-dione (5.7 g, JACS 1965, 3414) in DMF (10 ml) was added under N2 to a stirred suspension of anhy. K2CO3 (4.1 g) in DMF (10 ml), followed by the addition of a solution of p-nitrobenzyl bromide (6.45 g, Aldrich) in DMF (10 ml). After additions were complete, the mixture was stirred at room temperature for 72 hours, then poured into ice-water and extracted with ethyl acetate (×3). The combined extracts were washed with water (×2) and brine, dried over MgSO4 and evaporated to give a yellow oil which was flash chromatographed through a silica column using chloroform to give the desired product as a pale yellow solid (7.9 g).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[CH:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[CH3:13][O:14][CH2:15][C:16]1[C:23]([F:24])=[C:22]([F:25])[C:19]([CH2:20][OH:21])=[C:18]([F:26])[C:17]=1[F:27].N1C=CC=CC=1>O1CCCC1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[CH:6]([C:7]([O:21][CH2:20][C:19]2[C:18]([F:26])=[C:17]([F:27])[C:16]([CH2:15][O:14][CH3:13])=[C:23]([F:24])[C:22]=2[F:25])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: COCc1c(F)c(F)c(CO)c(F)c1F
Reactant: CC(C)=CC1C(C(=O)Cl)C1(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCc1c(F)c(F)c(COC(=O)C2C(C=C(C)C)C2(C)C)c(F)c1F
Temperature: 25 °C

Procedure:
3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride {containing the stereoisomers in a ratio of (1R)-trans form: (1R)-cis form: (1S)-trans form: (1S)-cis form=76:19:4:1} is added to a mixture of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol, pyridine and tetrahydrofuran under ice-cooling. The resulting mixture is heated to room temperature and stirred at room temperature. The reaction mixture is poured into ice water and extracted with ethyl acetate. The combined ethyl acetate layer is washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant residue is subjected to silica gel column chromatography to obtain 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropane-carboxylate (hereinafter referred to as the present compound 7).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH3:12][O-:13].[Na+]>CO>[F:11][C:4]1[C:3]([CH2:2][O:13][CH3:12])=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: C[O-]
Reactant: N#Cc1cccc(CBr)c1F
Agent: [Na+]
Solvent: CO
Product: COCc1cccc(C#N)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
3-(Bromomethyl)-2-fluorobenzonitrile (Intermediate 84, 1.39 g, 6.49 mmol) was dissolved in MeOH (10 mL) and sodium methoxide (1.238 mL, 6.49 mmol) was added. The mixture was stirred at r.t. for 2 h. This mixture was concentrated and then partitioned between water and EtOAc. The organic layer was separated and then concentrated in vacuo. The resulting residue was purified by flash chromatography using EtOAc/heptanes as eluent to give the title compound (0.900 g, 84% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 3.32 (s, 3 H) 4.52 (br. s, 2 H) 7.42 (t, 1 H) 7.77-7.84 (m, 1 H) 7.86-7.92 (m, 1 H); MS (EI) m/z 166 M+.