Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O-:30])=O)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[C:28]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:28](=[O:30])[C:27]4[CH:26]=[CH:25][C:24]([N:21]5[CH2:20][CH2:19][O:18][CH2:23][CH2:22]5)=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1)(=[O:30])[CH:27]=[CH2:26]
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: C=CC(=O)Nc1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc32)cc1

Procedure:
Compound 390 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-morpholinobenzoate. 1H NMR (500 MHz, Acetone-d6) δ 9.59 (s, 1H), 9.47 (s, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 7.98 (dd, J=2, 9 Hz, 4H), 7.81 (m, 2H), 7.77 (d, J=9 Hz, 1H), 7.05 (d, J=9 Hz, 2H), 6.52-6.38 (m, 2H), 5.75 (dd, J=2, 10 Hz, 1H), 3.80 (m, 4H), 3.29 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:19](=[O:21])[CH3:20])[C:12]([OH:18])=[CH:13][CH:14]=2)[CH:9]=1.Br[C:24]([Br:27])([CH3:26])C.[C:28](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:19](=[O:21])[CH3:20])[C:12]([O:18][CH2:28][CH2:26][CH2:24][Br:27])=[CH:13][CH:14]=2)[CH:9]=1
Reactant: COC(=O)CCCOc1ccc2ccc(O)c(C(C)=O)c2c1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Br)Br
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCOc1ccc2ccc(OCCCBr)c(C(C)=O)c2c1
Yield: 75 %

Procedure:
A mixture of 2.7 g of 4[(8-acetyl-7-hydroxy-2-naphthalenyl)oxy]butanoic acid methyl ester, 9.6 ml of dibromopropane and 1.95 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone was stirred at reflux for 17 hours. The mixture was filtered and the filtrate was concentrated in vacuo to an oil which was purified by open column chromatography (eluting with 2.5%-10% of ethylacetate/toluene) to yield 2.98 g (75%) of 4-[[8-Acetyl-7-(3-bromopropoxy)-2-naphthalenyl]oxy]butanoic acid methyl ester as an oil.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Ga+3:4].[CH2:5]([Mg]Cl)[C:6]([CH3:9])([CH3:8])[CH3:7]>C(OCC)C>[CH2:5]([Ga:4]([CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: [Ga+3]
Reactant: CC(C)(C)C[Mg]Cl
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C)(C)C[Ga](CC(C)(C)C)CC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A flask charged with 9.578 g. (54.41 mmol) of freshly sublimed gallium trichloride dissolved in 250 ml. of dry diethyl ether (from sodium/benzophenone), was fitted with a condenser, mechanical stirrer and a pressure equalizing addition funnel. Under a cover of argon, 100 ml., 2.27M neopentyl magnesium chloride in diethyl ether solution (previously prepared from purified neopentyl chloride and magnesium turnings) was transferred to the addition funnel. The Grignard reagent was then added to the gallium trichloride solution over a period of 20 min. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The stirrer, condenser and addition funnel were replaced by stoppers and S Teflon valve adapter. The diethyl ether was then removed by vacuum distillation at room temperature. The crude product, a trisneopentylgallium etherate mixture, was isolated by vacuum distillation at 125° C. into a sidearm flask (cooled to -196° C.) attached to the reaction flask by means of an 85° elbow. This distillation must be continued for approximately 5 hours. The diethyl ether was then removed from stirred, crude trisneopentyl gallium by simple vacuum distillation at room temperature for 1 hour. The product was finally purified by vacuum distillation in a short path still at 59.5° C. (0.01 mm, static vacuum). The yield of purified trisneopentyl gallium was 14.04 g (49.58 mmol, 91.1% based on gallium trichloride).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=1>C(Cl)Cl>[ClH:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][N:23]([C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[CH2:24][CH2:25]2)=[CH:14][CH:13]=1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Product: Cl
Product: O=C(c1ccccc1F)N1CCN(CCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.7 g of 2-fluorobenzoyl chloride in 20 ml of methylene chloride is added dropwise, over a period of 10 minutes, to a solution, stirred at room temperature, of 6.6 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine in 70 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, diluted with approximately 250 ml of methylene chloride, washed with sodium hydroxide solution and with water, dried over sodium sulphate and concentrated to dryness by evaporation. The residue is purified and characterised via the hydrochloride which has a melting point of 233°-235°. 1-[2-(4-chlorophenyl)-ethyl]-4-(2-fluorobenzoyl)-piperazine hydrochloride is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[C:9]([NH:21][CH3:22])[CH:8]=2)=[C:4]([F:25])[CH:3]=1.COC1C=C2C(=CC=1OC)N=C(SC)C=C2OC1C=CC(N[C:50]([C:52]2([C:55]([NH:57][C:58]3[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=3)=[O:56])[CH2:54][CH2:53]2)=[O:51])=CC=1F>>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:50]([C:52]2([C:55]([NH:57][C:58]3[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=3)=[O:56])[CH2:54][CH2:53]2)=[O:51])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[C:9]([NH:21][CH3:22])[CH:8]=1
Reactant: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Reactant: CNc1cc(Oc2ccc(N)cc2F)c2cc(OC)c(OC)cc2n1
Product: CNc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)c2cc(OC)c(OC)cc2n1

Procedure:
′N-(3-fluoro-4-{[2-(methylamino)-6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide was synthesized from [4-(4-amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-yl]-methyl-amine in a similar manner as N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluoro-phenyl)cyclopropane-1,1-dicarboxamide. It was purified by preparatory HPLC using ammonium acetate and isolated as a white solid (6.0 mg, 4.0% yield). 1H NMR (DMSO-d6) δ 10.42 (s, 1H), 9.91 (s, 1H), 7.88 (dd, 1H), 7.56 (m, 2H), 7.44 (m, 4H), 7.09 (t, 2H), 5.90 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.39 (br s, 1H), 2.92 (s, 3H), 1.41 (dt, 4H). LCMS: m/z 535 (M+H)+.
Reaction SMILES: C([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])C1C=CC=CC=1.C(OCC)(=[O:17])C.I([O-])(=O)(=O)=O.[Na+].[OH2:27]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[OH:27][C@H:10]1[C@@H:11]([OH:17])[C:12](=[O:13])[NH:8][C:9]1=[O:14]
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: O
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Product: O=C1NC(=O)[C@H](O)[C@@H]1O
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
A solution of N-benzylmaleimide (50.0 kg), in 125 L of acetonitrile and 859 L of ethyl acetate was combined with an aqueous mixture of 0.499 kg of ruthenium (III) chloride hydrate in 352 L of water, and the resulting reaction mixture was cooled to about 5° C. Sodium periodate (74.4 kg) was added with stirring to the reaction solution in small portions, while maintaining the reaction temperature between 3° C. and 5° C. Once the addition was complete, the reaction was quenched with an aqueous solution of sodium thiosulfate (45 kg) in 38 L of water, and the resulting slurry was granulated for about 20 minutes. The inorganic salts were removed by suction filtration, and the filter cake was washed with ethyl acetate. The combined filtrates were washed with water and allowed to settle. The aqueous layer was extracted with ethyl acetate and the product-rich organic layers were combined and washed with a solution of 8 kg of sodium chloride in 72 L of water. The organic extracts were concentrated by atmospheric distillation at a temperature of about 75° C., cooled to room temperature, and allowed to granulate for 2 to 4 hours. Hexanes (360 L) was added to the cooled (5° C. to 15° C.) slurry and granulation was continued for about 1 hour. The precipitated solids were collected by suction filtration, washed well with ethyl acetate followed by hexanes, and then dried in vacuo at a temperature of about 40° C. to about 45° C. to provide the title compound (42.0 kg, 71% yield) as a white solid.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:5]=1.[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CCOC(C)=O.CCCCCC>C(#N)C>[F:20][CH:9]1[C:4](=[O:3])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
Tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate, 2.2 (300 g, 1.102 mol) was dissolved in dry Acetonitrile (300 mL) and cooled to 0° C. and Selectfluor (430 g, 1.21 mol) was added in portion wise over a period of 45 min. under N2 atmosphere. After addition completed, the reaction mixture was allowed to room temperature and stirred for 2 h. The reaction was monitored by TLC (50% EtOAc/hexane). After completion of reaction by TLC the reaction mixture poured into ice cold saturated brine solution (300 mL) and extracted with EtOAc (2×200 mL). The combined EtOAc layers were washed with brine solution, water, dried over Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography on silica gel (10-40% EtOAc-Hexane) to afford tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate 2.3 (170 g; 70.7%). 1HNMR (CDCl3, 400 MHz): δ 4.88 (dd, 0.5H), 4.77 (dd, 0.5H), 4.47 (brs, 1H), 4.17 (ddd, 1H), 3.25 (brs, 1H), 3.23 (ddd, 1H), 2.58 (m, 1H), 2.51 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:32])[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[C:18]([N+:29]([O-])=O)[CH:17]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1.O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH2:29][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][C:23]1=[O:28])[C:15]([NH:14][C@H:9]([C:7]1[NH:6][C:5]2[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1)[CH2:10][CH2:11][S:12][CH3:13])=[O:32]
Reactant: CSCC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1)c1nc2cc(Cl)ccc2[nH]1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CSCC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(N)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
65 mg (0.13 mmol) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide dissolved in 2 ml of ethyl acetate are combined with 143 mg (0.63 mmol) tin(II)chloride-dihydrate and 130 mg (1.55 mmol) sodium hydrogen carbonate and refluxed for 2 hours. The reaction solution is combined with ice water, stirred for 10 minutes and then the precipitate formed is filtered off. After drying for 3 days the residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol 100:0->91:9).
Reaction SMILES: [Br:1][CH2:2][C:3]1([CH3:25])[CH:7]([C:8]([OH:10])=[O:9])[N:6]2[C:11](=[O:24])[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:5]2[S:4]1.[OH:26]O>C(O)(=O)C.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Br:1][CH2:2][C:3]1([CH3:25])[CH:7]([C:8]([OH:10])=[O:9])[N:6]2[C:11](=[O:24])[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:5]2[S:4]1=[O:26]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(CBr)C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S1=O
Temperature: 0 °C

Procedure:
Sodium tungstate (0.02 g) was added to a solution of 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylic acid (3.1 g) in acetic acid (8 ml) at 7°-10° C. under stirring and then to the mixture was added 30% aqueous hydrogen peroxide (1.2 ml). The mixture was stirred at 7°-10° C. for 1 hour. After the reaction, ice-water (50 ml) was added to the reaction mixture and then extracted with ethyl acetate. The extract was washed with water and back-extracted with 5% sodium bicarbonate aqueous solution. The aqueous layer was washed with ethyl acetate twice, acidified with 5% hydrochloric acid to pH2 and then extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give powder of 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylic acid-1-oxide (2 g).
Reaction SMILES: [OH-:1].[Na+].O[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=1.Cl>C(O)C>[OH:1][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:5](=[O:6])[CH2:4][CH:19]([C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1)[OH:20]
Reactant: O=Cc1ccncc1
Reactant: [OH-]
Reactant: O=C(CO)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(CC(O)c1ccncc1)c1ccccc1O
Temperature: 25 °C

Procedure:
According to the method of Corvaisier (Bull. Soc. Chim. Fr. 1962, 528) 15 ml of an 11 N aqueous sodium hydroxide solution are added to a solution of 24 g of 2-hydroxyacetophenone and 21 g of pyridine-4-carbaldehyde in 130 ml of absolute ethanol maintained an ambient temperature. An abundant yellow precipitate forms at first which then gradually dissolves. After two hours at ambient temperature the mixture is adjusted to pH 1 by means of hydrochloric acid. The yellow precipitate obtained is filtered, washed with water and dried. 27 g of 1-(2-hydroxyphenyl) 3-(4-pyridyl) 3-hydroxy 1-propanone melting at 150° C. are obtained.
Reaction SMILES: [C:1]([O:12][CH:13]1[CH2:17][CH2:16][C:15]2([CH2:22][C:21](=[O:23])[N:20]([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:19](=[O:29])[CH2:18]2)[CH2:14]1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:30]1[CH:31]=[CH:32][C:33]2[S:38][N:37]=[C:36]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:34]=2[CH:35]=1.C([O-])([O-])=O.[K+].[K+].CO.C(Cl)Cl>CC#N>[C:1]([O:12][CH:13]1[CH2:17][CH2:16][C:15]2([CH2:22][C:21](=[O:23])[N:20]([CH2:24][CH2:25][CH2:26][CH2:27][N:42]3[CH2:43][CH2:44][N:39]([C:36]4[C:34]5[CH:35]=[CH:30][CH:31]=[CH:32][C:33]=5[S:38][N:37]=4)[CH2:40][CH2:41]3)[C:19](=[O:29])[CH2:18]2)[CH2:14]1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CCCCCCCCCC(=O)OC1CCC2(CC(=O)N(CCCCBr)C(=O)C2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCC(=O)OC1CCC2(CC(=O)N(CCCCN3CCN(c4nsc5ccccc45)CC3)C(=O)C2)C1
Yield: 51.6 %

Procedure:
8-(4-Bromobutyl)-7,9-dioxo-8-azaspiro[4.5]decan-2-yl decanoate (3.03 g, 1.00 equiv), BITP 14 (2.38 g, 1.69 equiv) and K2CO3 (3.37 g, 3.80 equiv) were reacted in 125 mL of CH3CN according to the general procedure. Flash chromatography with a 3% to 5% MeOH/CH2Cl2 gradient yielded 12 (2.02 g, 52%) as a yellow oil. Conversion to the oxalate salt and recrystallization from CH3CN/EtOH afforded the analytically pure test compound, m.p. 117-9° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([Cl:28])=[C:7]([NH:13][C:14]3[N:19]=[C:18]([NH:20][CH2:21][CH3:22])[C:17]4=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:16]4[N:15]=3)[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=2)[CH2:2]1.[CH2:29]1[O:32][C@H:30]1[CH3:31]>CN1C(=O)CCC1.CO>[Cl:28][C:6]1[C:5]([CH:3]2[CH2:2][N:1]([CH2:29][C@@H:30]([OH:32])[CH3:31])[CH2:4]2)=[CH:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH2:21][CH3:22])[C:17]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:16]2[N:15]=1
Reactant: CCNc1nc(Nc2cc(C#N)cc(C3CNC3)c2Cl)nn2c(C#N)cnc12
Reactant: C[C@H]1CO1
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCNc1nc(Nc2cc(C#N)cc(C3CN(C[C@H](C)O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 32.9 %

Procedure:
A suspension of 2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 367)(16 mg, 0.041 mmol) and (S)-(−)-propylene oxide (0.085 mL, 1.22 mmol) in a mixture of NMP (0.8 mL) and MeOH (0.2 mL) was stirred at 50° C. for 4.5 hr. The solvent was removed and the product was purified by preparative HPLC (Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 15-55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) to give the title compound (6.1 mg). This was converted to the mono HCl salt.
Reaction SMILES: [F:1][C:2]([F:39])([C:8]1([O:29][C@H:28]([CH2:30][O:31][CH2:32][C:33]2C=CC=CC=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:10]1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].B(F)(F)F.[CH3:44][CH2:45][O:46]CC.C(=O)(O)[O-:50].[Na+]>C(OC(=O)C)(=O)C.CCOCC>[C:45]([O:9][C:8]1([O:29][C@H:28]([CH2:30][O:31][C:32](=[O:50])[CH3:33])[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:10]1[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:2]([F:39])([F:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:46])[CH3:44]
Reactant: CCOC(=O)C(F)(F)C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CCOCC
Reactant: O=C([O-])O
Agent: FB(F)F
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(F)(F)C1(OC(C)=O)O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 2 h

Procedure:
To a stirred solution of 2.40 g of 2-deoxy-2,2-difluoro-4,5,7-tris-O-(phenylmethyl)-D-arabino-3-heptulofuranosonic acid, ethyl ester in 8.8 ml of acetic anhydride at 0° C. was added 1.08 ml of boron trifluoride etherate. After 2 hours at 0° C., the solution was diluted with ether and stirred with aqueous sodium bicarbonate solution. The organic layer was washed with water and brine, dried, and concentrated. The residue was subjected to column chromatography on silica gel to give an oil, CMR δ 20.7 and 215 (singlets, CH3CO).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH2:14][CH2:13][S:12][CH2:11][CH:10]=2)=[C:4]([F:15])[CH:3]=1.N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH2:14][CH2:13][S:12][CH2:11][CH:10]=2)=[C:4]([F:15])[CH:3]=1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cc(F)c(C2=CCSCC2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(F)c(C2=CCSCC2)c(F)c1)OCc1ccccc1
Reaction time: 18 h
Yield: 94.3 %

Procedure:
4-(4-Amino-2,6-difluorophenyl)-5,6-dihydro-2H-thiopyran (15.0 g, 66 mM) was dissolved in dry dichloromethane (250 ml), pyridine (9.45 g, 113 mM) added, and the whole stirred under nitrogen at −20°. Benzyl chloroformate (17.1 g, 100 mM) in dry dichloromethane (25 ml) was added dropwise, and the mixture allowed to warm to ambient over 18 hours. The mixture was washed with hydrochloric acid (1M, 2×200 ml), then brine (200 ml) and dried (magnesium sulfate). Evaporation to a small volume and dilution with isohexane gave the desired product as a white solid (22.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[F:12][C:13]([F:23])([F:22])[C:14]([C:18]([F:21])([F:20])[F:19])([OH:17])[CH2:15]O.Cl.C1(C)C=CC=CC=1>N1C=CC=CC=1>[F:12][C:13]([F:22])([F:23])[C:14]([C:18]([F:19])([F:21])[F:20])([OH:17])[CH2:15][O:9][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(O)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
Under ice cooling, a solution of 54 g of p-toluene sulfonate in 140 g of pyridine was added dropwise to a mixture of 93 g of the 61 wt % IPE solution of 3,3,3-trifluoro-2-trifluoromethyl-1,2-propane diol prepared in Reference Synthesis Example and 140 g of pyridine. Stirring was continued for 48 hours at room temperature. The reaction solution was ice cooled and poured into a mixture of 678 g of 20 wt % hydrochloric acid aqueous solution and 100 g of ice to quench the reaction. Toluene, 500 g, was added to the reaction solution, which was separated into layers. The organic layer was washed with water, concentrated, and recrystallized from heptane, obtaining 74 g of 3,3,3-trifluoro-1-(p-toluene-sulfonyloxy)-2-trifluoromethylpropan-2-ol (yield 74%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:10])([CH3:9])[C:3]=1[CH2:11][CH2:12][C:13](=O)[CH3:14].[C:16](O)(=O)C.[CH:20]([NH2:22])=[NH:21]>C(O)CCC>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:10])([CH3:9])[C:3]=1[CH2:11][CH2:12][C:13]1[CH:14]=[CH:16][N:22]=[CH:20][N:21]=1
Reactant: N=CN
Reactant: CC(=O)O
Reactant: CC(=O)CCC1=C(C)CCC(C)C1(C)C
Solvent: CCCCO
Product: CC1=C(CCc2ccncn2)C(C)(C)C(C)CC1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A 100 mL reaction flask is charged with 4-(2,5,6,6-tetramethyl-cyclohex-1-enyl)-butan-2-one (10 g, 0.05 mol, commercially available at IFF), formamidine acetate (26 g, 0.3 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 4-[2-(2,5,6,6-tetramethyl-cyclohex-1-enyl)-ethyl]-pyrimidine (˜10 g) is obtained.