Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[C:5]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH3:12][C:11]1([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:13]2[C:18](=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:2]([CH3:4])([CH3:3])[CH2:1]1
Reactant: C=C(C)C
Reactant: CC(c1ccccc1)c1ccc(O)cc1
Product: CC1(C)CC(C)(c2ccccc2)c2ccc(O)cc21
Reaction time: 5 h
Yield: 13.5 %

Procedure:
112 g of isobutylene were introduced with stirring into 198 g of 1-phenyl-1-(4-hydroxy-phenyl)-ethane and 30 g of an acid activated Fuller's earth at 150° C. and the reaction mixture was then stirred at this temperature for 5 hours. 34 g of 1,3,3-trimethyl-1-phenyl-5-hydroxy-indane could be obtained by distillation followed by recrystallisation.
Reaction SMILES: [CH:1]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)([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.[CH:24]([Mg]Br)=[CH2:25].[Cl-].[NH4+]>O1CCCC1>[CH:1]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:16]=1[NH:21][CH:25]=[CH:24]2)([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
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1ccccc1OC(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(C(Oc2cccc3cc[nH]c23)c2ccccc2)cc1
Reaction time: 0.83 h

Procedure:
11.95 mmol of the compound obtained in Step A above are dissolved, under an inert atmosphere, in 80 ml of anhydrous tetrahydrofuran. The temperature of the reaction mixture is then lowered to −40° C. and then 41.84 mmol of a 1M solution of vinylmagnesium bromide in tetrahydrofuran are added dropwise to the solution, which is then stirred for 2 hours 50 minutes from −40° C. to 0° C. The reaction mixture is then hydrolysed at 0° C. using 100 ml of a saturated aqueous ammonium chloride solution, and the aqueous phase is extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and evaporated. Purification by flash chromatography over silica gel (petroleum ether/ethyl acetate: 9/1) allows the expected product to be isolated.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:32][C:33]([CH3:36])=[N:34][N:35]=2)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[O:32][C:33]([CH3:36])=[N:34][N:35]=5)[CH:28]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reactant: Cc1nnc(-c2cccc(I)c2)o1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nnc(C)o4)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 73.1 %

Procedure:
To a solution of the compound from Example 3 (El) (0.125 g, 0.4 mmol) and 1-iodo-3-(5-methyl-[1,3,4]oxadiazol-2-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 2:1 ethyl acetate/hexanes, followed by recrystallization from ethyl acetate/hexanes, provided the title compound as a white solid (0.11 g, 61%), m.p. 117-119° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[C:12]1([CH2:18][C:19](Cl)=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>[OH-].[Na+]>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:19](=[S:20])[CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C(Cl)Cc1ccccc1
Reactant: Cc1cccc(C(=O)O)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C(=O)O)c1NC(=S)Cc1ccccc1
Yield: 93.4 %

Procedure:
Benzenethiol and butyl bromoacetate were reacted by a conventional method and then hydrolyzed to obtain α-phenylthioacetatic acid. α-phenylthioacetatic acid was reacted with thionyl chloride by a convention method to obtain α-phenylthioacetyl chloride. 3-Methylanthranilic acid 5g (33 mmol) was dissolved in 10% aqueous sodium hydroxide solution 27 ml and to this solution, α-phenylthioacetyl chloride 5.5 ml (33 mmol) was added dropwise at 0° C. The resulting solution was stirred at room temperature for 1 hour and neutralized with 10% hydrochloric acid solution. Deposited crystals were collected by filtration and recrystallized from ethanol and water to obtain 3-methyl-N-(phenylthioacetyl)anthranilic acid (melting point: 148° to 150° C.) 8.8 g (yield: 89%).
Reaction SMILES: [OH-].[K+].[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]([O:19]C)=[O:18])=[CH:9]1.Cl>CO.O>[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]([OH:19])=[O:18])=[CH:9]1
Reactant: COC(=O)c1cn(-c2nccs2)c2ncccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(-c2nccs2)c2ncccc12
Temperature: 100 °C

Procedure:
Potassium hydroxide (38.5 mg, 0.687 mmol) was added to a solution of methyl 1-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (35.6 mg, 0.137 mmol) in MeOH (343 μl) and water (343 μl) at RT. The mixture was heated at 100° C. for 2 h. After cooling to RT, the mixture was acidified with 2 N HCl and then concentrated under reduced pressure. The crude mixture was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C@@H:27]([CH3:30])[CH2:28][OH:29])=[N:24][CH:25]=1>>[OH:29][CH2:28][C@@H:27]([NH:26][C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1)[CH3:30]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: C[C@@H](CO)Nc1ccc(N)cn1
Product: C[C@@H](CO)Nc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-2-(5-amino-pyridin-2-ylamino)-propan-1-ol. LCMS calcd for C19H17F3N4O3 (m/e) 406, obsd 407 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:13]1[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14]1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O.[OH-].[Li+]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18]([CH:15]3[CH2:16][CH2:17][O:13][CH2:14]3)=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)C1CCOC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCOC1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), tetrahydrofuran-3-carboxylic acid (202 mg, 1.74 mmol) and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) at room temperature was treated with BOP—Cl (162 mg, 1.74 mmol). The mixture was stirred for 60 minutes, and the solvent was removed in vacuo. The resulting residue was dissolved in THF (10 mL) and treated with lithium hydroxide hydrate (109 mg, 2.61 mmol) in water (1 mL). After 30 minutes, the mixture was concentrated in vacuo, and water (5 mL) was added to the residue. The solid formed was filtered, washed with additional water and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-3-carboxamide (210 mg, 74% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.07 (br s, 1H), 9.65 (s, 1H), 8.35 (d, 1H), 7.59 (s, 1H), 3.95 (t, 1H), 3.81-3.68 (m, 3H), 3.26-3.18 (m, 1H), 2.11-2.05 (m, 2H); LCMS (APCI+) m/z 327.9, 329.9 (M+H)+, Retention time=2.44 min (Method 2).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:24][OH:25])[CH:12]=[N:13][C:14]=2[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])[CH2:3]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([CH:34]([CH:41]2[CH2:43][CH2:42]2)[CH2:35][C:36]([O:38]CC)=[O:37])[CH:29]=1.[H-].[Na+].Cl>C1COCC1>[CH:41]1([CH:34]([C:30]2[CH:29]=[C:28]([O:25][CH2:24][C:11]3[CH:12]=[N:13][C:14]([C:15]4[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=4[F:23])=[C:9]([O:8][CH2:7][CH:4]4[CH2:3][C:2]([CH3:26])([CH3:1])[O:6][CH2:5]4)[CH:10]=3)[N:33]=[CH:32][N:31]=2)[CH2:35][C:36]([OH:38])=[O:37])[CH2:43][CH2:42]1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2OCC2COC(C)(C)C2)c1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(COc3cc(C(CC(=O)O)C4CC4)ncn3)cc2OCC2COC(C)(C)C2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 14.6 %

Procedure:
To a solution of (5-((5,5-dimethyltetrahydrofuran-3-yl)methoxy)-6-(2-fluoro-5-methoxyphenyl)pyridin-3-yl)methanol (180 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (140 mg) in THF (5.0 mL) was slowly added 60% sodium hydride (60 mg) at 0° C. by small portions, and the mixture was stirred at 50° C. for 3 hr. The mixture was acidified with 1N hydrochloric acid at 0° C. and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (C18, mobile phase: water/acetonitrile (10 mM NH4HCO3-containing system)), and the obtained fraction was evaporated under reduced pressure to give the title compound (40 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O.[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C(OC(C)C)(C)C>>[O:19]([CH2:23][CH2:24][NH:25][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([N:2]([CH3:1])[CH3:14])[CH:4]=1)[N+:20]([O-:22])=[O:21]
Reactant: CN(C)c1cccc(OCC(=O)O)c1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CN(C)c1cccc(OCC(=O)NCCO[N+](=O)[O-])c1
Yield: 49.7 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.83 g of 3-dimethylaminophenoxyacetic acid and 0.60 g of nitroxyethylamine nitrate, 0.50 g of the title compound was obtained as pale yellow acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][O:14][CH2:13]2)[CH:3]=1.[OH-].[NH4+:17]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:17])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][O:14][CH2:13]2)[CH:3]=1
Reactant: [NH4+]
Reactant: Clc1ncnc2c1c(Br)cn2C1COC1
Agent: [OH-]
Product: Nc1ncnc2c1c(Br)cn2C1COC1
Temperature: 85 °C
Yield: 61.5 %

Procedure:
To 5-bromo-4-chloro-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidine (185 mg, 0.641 mmol) was added ammonium hydroxide (24.97 μl, 0.641 mmol) in a 25 ml sealable vial and heated at 85° C. over 24 hr. The solid was isolated by filtration and washed with water (5 mL) and dried to give 5-bromo-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (106 mg), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[O:4]C(OCC)=O.[N+:15]([O-])([OH:17])=[O:16].C(=O)(O)[O-].[Na+]>OS(O)(=O)=O>[F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:3]=1[OH:4]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Oc1ccc(F)cc1F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cc(O)c(F)cc1F
Temperature: 15 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of ethyl 2,4-difluorophenoxycarboxylate (3.27 g, 16.2 mmol) in concentrated H2SO4 (11 mL) at 0° C. was added fuming HNO3 (1.1 mL) dropwise, maintaining the internal temperature between 10 to 20° C. After stirring for 1 h, the mixture was poured over ice water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×40 mL), dried over MgSO4, and concentrated in vacuo. The residue was dissolved in MeOH (50 mL), and sodium bicarbonate (2.72 g, 32.3 mmol) was added. The resultant mixture was stirred at room temperature for 64 h and the solid was filtered. The filtrate was concentrated and the residue was taken up in H2O (100 mL). The pH was adjusted to 5 with the addition of conc. HCl, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×40 mL), dried over MgSO4, and evaporated under reduced pressure to give 2,4-difluoro-5-nitrophenol as a yellow solid (2.35 g, 13.4 mmol; 83% yield). 1H-NMR (DMSO-d6) δ 10.88 (s, 1H), 7.70 to 7.61 (m, 2H),
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([O:14]CC)=[O:13])[N:6]=1>C(O)C.O>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([OH:14])=[O:13])[N:6]=1
Reactant: CCOC(=O)c1nc(C)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C)nc(C(=O)O)n1
Reaction time: 12 h

Procedure:
A solution of 11.5 g of sodium hydroxide in 156 ml of ethanol and 78 ml of water is added to a stirred solution of 51.5 g of ethyl 4-methoxy-6methylpyrimidine-2-carboxylate in 280 ml of ethanol. Stirring is continued for 12 hours at room temperature, and the sodium salt of the carboxylic acid, which has precipitated, is filtered off with suction. The sodium salt is transferred to a solution of 17.3 g of acetyl chloride in 220 ml of methanol, and the sodium chloride, which has precipitated, is filtered off with suction. The methanolic solution is evaporated on a rotary evaporator. This gives 30.9 g of 4-methoxy-6-methylpyrimidine-2-carboxylic acid of melting point 140°-141° C. as the residue.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14]([C@H:16]([CH2:25][CH:26]=[CH2:27])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])C1C=CC=CC=1.[Li+].[OH-].OO.[Li+].[OH-].OO.C([O-])(O)=[O:37].[Na+].[O-]S([O-])=O.[Na+].[Na+]>O.C1COCC1>[C:21]([O:20][C:18](=[O:19])[CH2:17][C@@H:16]([CH2:25][CH:26]=[CH2:27])[C:14]([OH:15])=[O:37])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C([O-])O
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a 250 mL round-bottomed flask, (R)-tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)hex-5-enoate, Intermediate S8B (3.2 g, 8.57 mmol) was added to THF (30 mL) to give a colorless solution. The mixture was cooled on ice/water bath. In a 100 mL flask, LiOH (0.616 g, 25.7 mmol) was added to water (22 mL) to give a colorless solution. The LiOH mixture was cooled in an ice/water bath. Next, 30% H2O2 in water (2.183 mL, 21.38 mmol) was added to the LiOH mixture. The mixture was stirred at ice/water bath for another 10 min. The LiOH/H2O2 solution was added to the THF solution of starting material. The resulting reaction mixture was stirred in ice/water bath. The reaction was monitored by HPLC and was found to be complete after 30 min. The mixture was stirred for another 1.5 h. Next, 15 mL sat NaHCO3 was added, followed by the addition of ice and the slow addition of 20 mL saturated aqueous Na2SO3 to the mixture. The mixture was maintained at a temperature of less than 15° C. by the addition of ice. The mixture was stirred in the ice/water bath and periodically tested with a peroxide test strip until negative for peroxide. Water was added and the mixture was extracted with CH2Cl2 (3×). The aqueous layer was cooled with ice and acidified slowly with concentrated HCl to pH 4. EtOAc was added and solid NaCl was added very slowly with extensive bubbling. The organic layer was separated and the aqueous layer was twice extracted with EtOAc. The combined organic layers were washed twice with brine and then dried over MgSO4. The layer was filtered and concentrated to afford (R)-2-(2-(tert-butoxy)-2-oxoethyl)pent-4-enoic acid, Intermediate S8C (0.44 g, 2.054 mmol, 86% yield) as a clear colorless oil. 1H NMR (400 MHz, chloroform-d) δ 5.84-5.63 (m, 1H), 5.16-5.03 (m, 2H), 2.98-2.84 (m, 1H), 2.66-2.54 (m, 1H), 2.52-2.39 (m, 2H), 2.36-2.24 (m, 1H), 1.44 (s, 9H).
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:2]1.[F:10][C:11]([F:33])([F:32])[O:12][C:13]([F:31])([O:18][C:19]([F:30])([O:24][C:25]([F:29])([F:28])[CH2:26][OH:27])[C:20]([F:23])([F:22])[F:21])[C:14]([F:17])([F:16])[F:15].ClC[C@H](O)CCCCC=C.[OH-].[K+]>O.COCCOC>[F:10][C:11]([F:32])([F:33])[O:12][C:13]([F:31])([O:18][C:19]([F:30])([O:24][C:25]([F:29])([F:28])[CH2:26][O:27][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([OH:1])[CH3:2])=[CH2:9])[C:20]([F:22])([F:21])[F:23])[C:14]([F:17])([F:16])[F:15]
Reactant: C=CCCCC[C@@H]1CO1
Reactant: OCC(F)(F)OC(F)(OC(F)(OC(F)(F)F)C(F)(F)F)C(F)(F)F
Agent: C=CCCCC[C@@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: C=C(CCCCC(C)O)OCC(F)(F)OC(F)(OC(F)(OC(F)(F)F)C(F)(F)F)C(F)(F)F
Temperature: 45 °C
Reaction time: 1 h

Procedure:
This chlorohydrin was converted in situ to (R)-1,2-epoxy-7-octene and reacted with 2-(2-(2-(trifluoromethoxy(tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol using the following procedure: (R)-8-chloro-7-hydroxy-oct-1-ene (100 g, 0.61 mol), aqueous potassium hydroxide (45 mL of 45 wt. %), 2-(2-(2-(trifluoromethoxy(tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol (291 g, 0.733 mol), Adogen™ 464 (60 g), and 1,2-dimethoxyethane (60 mL) were added to a one liter flask fitted with a mechanical stirrer, an addition funnel, a reflux condenser, and a thermometer. The resulting solution was stirred for one hour at 45° C. and then warmed to 60° C., at which time aqueous potassium hydroxide (70 mL of 45 wt %) was added dropwise. This solution was heated for 2 hours at 60° C. and then at 70° C. for 8 hours. Water (300 mL) was added, and the resulting organic phase was separated and washed with 7 weight % HCl (300 mL). The organic phase was again separated and was concentrated under reduced pressure (25 torr). The resulting crude product was then purified by silica gel chromatography using toluene as eluent to give 268 g of (R)-8-(2-(2-(2-(trifluoromethoxy(tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-7-hydroxyoct-1-ene.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Br:23])[CH:17]=1)[CH3:14].Cl>C1COCC1.[Li+].[OH-]>[Br:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[C:15]([N:13]([CH3:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])=[O:24]
Reactant: COC(=O)CCCc1ccccc1N(C)C(=O)c1ccc(Cl)c(Br)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1CCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
To a solution of 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid methyl ester (1.11 g, 2.6 mmol, Step 13D) in THF (8 mL), 2N LiOH (6.5 mL) was added and the mixture was stirred for 2 hours at rt. 1N HCl was added to the reaction mixture to yield a pH˜2 followed by extraction with EtOAc (2×). The combined organic layers were washed with water and brine, dried (Na2SO4) and concentrated in vacuo to afford 1.1 g of 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid as a white solid. MS [M+H]+: 411.7; tR=2.57 min, (method 1)
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([C:13]3[C:14]([F:33])=[C:15]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH3:32])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C)C.[CH:38]1([NH2:41])[CH2:40][CH2:39]1.O>[Cl-].[Na+].O>[CH:38]1([NH:41][C:2]2[C:3]3[C:10]([C:11]([C:13]4[C:14]([F:33])=[C:15]([NH:20][S:21]([C:24]5[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][CH3:32])=[CH:28][CH:29]=5)(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=4[F:19])=[O:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:40][CH2:39]1
Reactant: NC1CC1
Reactant: CCCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(Cl)c34)c2F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(NC5CC5)c34)c2F)cc1
Temperature: 80 °C
Yield: 101.7 %

Procedure:
To N-[3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-4-propyl-benzenesulfonamide (P-1034, 50 mg, 0.10 mmol), 0.702 mL of isopropyl alcohol is added, followed by cyclopropylamine (79, 0.0357 mL, 70% aqueous solution, 0.509 mmol). The reaction is heated at 80° C. in an oil bath for 17 hours, then poured into water and brine and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (P-1040, 52 mg). MS (ESI) [M+H+]+=512.0.
Reaction SMILES: [CH3:1][O:2][C:3]([O:8][CH3:9])([CH3:7])[C:4](=O)[CH3:5].C([O-])(=O)C.[NH4+].C([BH3-])#[N:16].[Na+].Cl>CO>[CH3:5][CH:4]([NH2:16])[C:3]([O:8][CH3:9])([O:2][CH3:1])[CH3:7]
Reactant: COC(C)(OC)C(C)=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: COC(C)(OC)C(C)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 126.6 %

Procedure:
To a stirred mixture of 3,3-dimethoxybutan-2-one (J.Chem.Soc. 1953, 3135; 1.32 g., 10 m moles) and ammonium acetate (7.7 g., 0.1 mole) in methanol (30 ml.) at 25° C. was added sodium cyanoborohydride (380 mg., 6 m moles) and the pH of the mixture was reduced to 6.0 by addition of a solution of HCl in methanol. The mixture was stirred for 2 hours at 25° C. then the solvent was evaporated under reduced pressure. The residue was taken up in water and the pH adjusted to 5 with 2N aqueous HCl. The solution was washed with ether (3×20 ml.) and the pH of the aqueous phase raised to above 10 by addition of sodium carbonate. The product was extracted with ether (5×20 ml.) and the combined extracts were dried (MgSO4) and evaporated to dryness to give 1-methyl-2,2-dimethoxypropylamine (1.02 g., 77%) as a pale yellow oil having the following n.m.r. spectrum in CDCl3 : 1.05 (d, 3H); 1.2 (s, 3H); 1.6 (m, 2H); 3.25 (s, 6H); 3.0-3.6 (m, 1H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([O:10][C:11]([NH:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]([C:30]2[N:31]=[CH:32][N:33]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=3)[CH:34]=2)([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>CN(C=O)C>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]([N:33]2[CH:34]=[C:30]([C:21]([CH2:20][C:17]3[CH:18]=[N:19][C:14]([NH:13][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])=[CH:15][CH:16]=3)([C:22]([O:24][CH3:25])=[O:23])[C:26]([O:28][CH3:29])=[O:27])[N:31]=[CH:32]2)=[CH:40][CH:39]=1
Reactant: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1cn(-c2ccc(N)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
824 mg (3.66 mmol) of tin(II) chloride dihydrate were added to a solution of 384 mg (0.73 mmol) of the compound from example 12e in 10 ml of DMF and stirred at RT overnight. The solvent was then evaporated off, and the residue was partitioned between EA and sat. aqueous NaHCO3 solution. The aqueous phase was extracted twice with EA. The combined organic phases were dried over Na2SO4, filtered and concentrated. 103 mg of the desired compound were obtained.