Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11]COC)=[CH:7][C:4]=1[CH:5]=[O:6].Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[OH:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: COCOc1ccc(OC)c(C=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(O)cc1C=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)benzaldehyde (33.5 g, 0.17 mol, 1 eq.) in THF (150 mL) was added HCl (3 N, 250 mL, 4.4 eq.). The reaction was stirred at 50° C. for 1 h, cooled to rt, and diluted with water (500 mL). The mixture was neutralized to pH 7-8 with solid K2CO3. The pale yellow solid was collected, washed with water, and dried to give 5-hydroxy-2-methoxybenzaldehyde (17.9 g, 74.6%) as a pale yellow solid. 1H NMR (400 MHz; DMSO) δ=10.31 (s, 1H), 8.03 (s, 1H), 6.89 (s, 1H), 3.80 (s, 3H). LRMS (M+H+) m/z 154.0.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:16]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:17][CH2:18][C:19]([CH3:21])=O.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[CH2:1]1[O:4][C:19]([CH3:21])([CH2:18][CH2:17][C:16]([O:23][CH2:24][CH3:25])=[O:22])[O:3][CH2:2]1
Reactant: CCOC(=O)CCC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CCC1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of about 110.86 g of ethylene glycol, about 2 g of p-toluenesulfonic acid and about 800 ml of toluene was refluxed using a Dean-Stark trap until no more water came off. An about 250 g portion of ethyl levulinate was added and refluxing was continued until no more water came off. The mixture was then cooled to room temperature, poured into saturated sodium bicarbonate, the organic layer dried and the solvent removed. The residue was distilled (about 67°-70° C., 0.35 mm) and the distillate stirred for about 20 minutes with about 6 g of sodium borohydride in ethanol. The solvent was removed, the residue dissolved in ether, washed with saturated sodium bicarbonate, dried and then distilled (about 41°-45° C., 0.3 mm), giving about 83 g of the desired title compound.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:11])[C:8]=1[CH:9]=[O:10].C(O)C>O>[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:11])[C:8]=1[CH2:9][OH:10]
Reactant: Cc1csc(C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1csc(C)c1CO
Reaction time: 0.25 h

Procedure:
0.68 G. (18 mmol) of sodium borohydride was added in three portions to a solution of 10.08 g. (72 mmol) of 2,4-dimethylthiophene-3-carboxaldehyde in 120 ml. of ethanol. After 15 min., the reaction mixture was poured into water, extracted with ether, dried and the solvent evaporated. The resulting residue was recrystallized from hexane to yield 2,4-dimethyl-3-hydroxymethylthiophene, m.p. 80°-81° C.
Reaction SMILES: [C:1]1(/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:1]1(/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:8]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([O:19][CH3:18])=[O:28])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)/C(=C/c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCNC(=O)/C(=C/c1ccccc1)c1ccccc1
Yield: 84.2 %

Procedure:
To a solution of (2E)-2,3-diphenylacrylic acid (0.32 g, 1.4 mmol) (prepared according to procedure given in example 1) in DMF (5 mL) was added Methyl-7-aminoheptanoate (0.25 g, 1.3 mmol), EDCI (0.55 g, 2.8 mmol) and HOBt (0.19 g, 1.4 mmol). TEA (0.6 mL, 4.3 mmol) was added dropwise with constant stirring to the above reaction mixture and it was stirred for 2 hours at room temperature. Reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×100 mL). The organic layer was washed successively with water (3×50 mL), and brine solution (1×50 mL). The organic layer was dried over Na2SO4 and concentrated to afford the title compound (0.4 g, 61% yield).
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:35])[CH2:21][CH2:22][C:23]([F:34])([F:33])[C:24]([O:27]C(OCC)C)([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43]C2CCCCO2)[CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:33][C:23]([F:34])([CH2:22][CH2:21][C@H:20]([C@@H:19]1[C@:36]2([CH3:42])[C@H:16]([C@H:15]3[C@H:39]([CH2:38][CH2:37]2)[C@:40]2([CH3:41])[C:12]([CH2:11][C@@H:10]([OH:43])[CH2:9][C@@H:8]2[OH:7])=[CH:13][CH2:14]3)[CH2:17][CH2:18]1)[CH3:35])[C:24]([OH:27])([CH3:25])[CH3:26]
Reactant: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C[C@H](CCC(F)(F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1.87 g (0.0027 mol) of [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-ene, 70 mL of methanol and 0.30 g of p-toluenesulfonic acid monohydrate was stirred at 25° C. for 4 hr. The mixture was quenched by adding 1.0 g of sodium bicarbonate and stirring for 0.5 hr. The mixture was then evaporated to dryness. The residue was triturated with ethyl acetate, filtered, and evaporated to dryness. The crude solid was recrystallized from ethyl acetate to yield [1α,3β]-24,24-difluorocholest-5-en-1,3,25-triol, mp 177°-179°, [α]D21 -15° (c 0.6, MeOH).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26]2[S:39][CH:38]=[CH:37][C:27]=2[N:28](C(OC(C)(C)C)=O)[N:29]=1)=O)(C)(C)C.[CH3:40][Mg]Br.O>O1CCCC1>[C:18]1([C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][C:9]([C:25]2[C:26]4[S:39][CH:38]=[CH:37][C:27]=4[NH:28][N:29]=2)=[CH:10]3)([OH:24])[CH3:40])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C(=O)c4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 5-benzoyl-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [Intermediate (13)] in anhydrous tetrahydrofuran (5 mL) is added methylmagnesium bromide (1M in tetrahydrofuran, 0.8 mL) at −78° C. Stirred under nitrogen for 30 minutes. Added another 0.88 mL of methylmagnesium bromide and let the reaction warm to room temperature slowly. After overnight water/saturated ammonium chloride (2 mL) is added at 0° C. and extracted twice with ethyl acetate (25 mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate. The residue is chromatographed on 10 g silica gel, eluting with 30 to 50% ethyl acetate gradient in heptane to afford 1-phenyl-1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-ethanol (56 mg, 71%, Example 26) as a beige solid; LC/MS: 360 (M+H); 1H NMR [(CD3)2SO)]: δ 13.20 (1H, s), 11.45 (1H, s), 7.73 (1H, d), 7.62 (1H, s), 7.43 (2H, m), 7.25 (6H, m), 6.59 (1H, s), 5.53 (1H, s), 1.86 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3I)[CH:13]=2)=[CH:4][CH:3]=1.[S:18]1[CH:22]=[N:21][N:20]=[C:19]1[NH:23][C:24]1[CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:28][CH:29]=1>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:26]3[CH:25]=[C:24]([NH:23][C:19]4[S:18][CH:22]=[N:21][N:20]=4)[CH:29]=[CH:28][CH:27]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ccc3c(I)cnn3c2)cc1
Reactant: CC1(C)OB(c2cccc(Nc3nncs3)c2)OC1(C)C
Solvent: COCCOC
Product: Fc1ccc(-c2ccc3c(-c4cccc(Nc5nncs5)c4)cnn3c2)cc1
Temperature: 150 °C
Yield: 8.8 %

Procedure:
A mixture of 6-(4-fluoro-phenyl)-3-iodo-pyrazolo[1,5-a]pyridine (150 mg, 0.44 mmol), 3-([1,3,4]thiadiazol-2-ylamino)-phenyl boronic acid pinacol ester (190 mg, 0.62 mmol) and PdCl2ddpf (32 mg, 0.04 mmol) in DME (1.5 ml) and 2N Na2CO3 (aq, 1.5 ml) in a microwave vial was deoxygenated by bubbling N2 through for 30 seconds. The vial was sealed and then stirred and heated at 150° C. in the microwave for 30 minutes. After cooling to RT the mixture was partitioned between CH2Cl2/H2O. The organic layer was evaporated and the residue was purified by preparative HPLC to give the title compound (15 mg, solid).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH3:17])[CH:7]=[C:6]([C:18]([O:20]CC)=[O:19])[C:5]2=[O:23].C(O)C.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:23]
Reactant: CCOC(=O)c1cn(C)c2cc(-n3cccc3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2cc(F)c(-n3cccc3)cc21
Yield: 68.6 %

Procedure:
A mixture of 1.2 g of ethyl 6-fluoro-7-(pyrrol-1-yl)-1-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, 10 ml of ethanol, 15 ml of 10% sodium hydroxide solution and 10 ml of water is heated under reflux for 2 hours. 30 ml of 8M hydrochloric acid are added, the mixture is left to cool and the product is filtered off, washed with water and recrystallized from acetic acid to give 0.75 g of a solid melting at 284°-285° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:25](S(C2C=CC(C)=CC=2)(=O)=O)[C:16]2=[N:17][CH:18]=[C:19]3[CH:23]=[N:22][N:21]([CH3:24])[C:20]3=[C:15]2[CH:14]=1.[H-].[Na+].[Na+].[I-].[P:40]([O:52][CH2:53]Cl)([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CN(C=O)C>[P:40]([O:52][CH2:53][N:25]1[C:16]2=[N:17][CH:18]=[C:19]3[CH:23]=[N:22][N:21]([CH3:24])[C:20]3=[C:15]2[CH:14]=[C:13]1[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH3:12])[CH:7]=1)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:41]
Reactant: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2C
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1COP(=O)(OC(C)(C)C)OC(C)(C)C)cnn4C)cn2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.1 %

Procedure:
7-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (1.00 g, 3.02 mmol [WO2009/152133, Example #42]) and NaH (60 wt % in mineral oil, 0.200 g, 5.00 mmol) were added to DMF (40 mL) then the mixture was stirred at rt for about 10 min. Then NaI (0.068 g, 0.453 mmol) and di-tert-butyl chloromethyl phosphate (1.60 g, 6.19 mmol, [Journal of Medicinal Chemistry (2008), 51(5), 1111-1114]) were added then the mixture was warmed to about 60° C. for about 45 min. The mixture was cooled to rt then concentrated under reduced pressure. The material was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was isolated and the aqueous layer was extracted with EtOAc (2×50 mL) then DCM (2×30 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified using an 80 g silica column and eluting with EtOAc to give di-tert-butyl (7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methylpyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)methyl phosphate (0.486 g, 29%): LC/MS (Table 2, Method a) Rt=2.68 min; MS m/z 554 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=3)=[CH:20][NH:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CN(C)C=O.C(OCC)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][O:4][C:5]4[CH:13]=[CH:12][CH:11]=[C:10]5[C:6]=4[CH:7]=[CH:8][NH:9]5)[CH2:28][CH:29]=3)=[CH:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: ClCCOc1cccc2[nH]ccc12
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Clc1ccc2c(C3=CCN(CCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-2-(1H-indole-4-oxy)ethane (0.359 g, 1.85 mmol) and 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.500 g, 2.13 mmol) in the presence of 2.0 equivalents of potassium carbonate (0.51 g, 3.7 mmol) in dimethylformamide at 90° C. Yield 0.101 g (14%) of a tan foam. The oxalate salt was prepared by treating the free base with 1.0 equivalent of oxalic acid in diethyl ether and evaporating. mp 120°-124° C. (browns) FDMS m/e=391 (M+ of free base).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]([CH3:18])[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[O:19]([C:21]#N)[K]>CCCCCC>[CH3:18][N:4]1[C:3]2[NH:2][C:21](=[O:19])[C:17]3[C:12]([C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: N#CO[K]
Reactant: Cn1c(N)c(-c2ccccc2)c2ccccc21
Agent: Cl
Solvent: CCCCCC
Product: Cn1c2ccccc2c2c3ccccc3c(=O)[nH]c21
Yield: 20.1 %

Procedure:
The same product as in the foregoing example is prepared by heating to 270°-280° C. for 15 minutes 2.59 g (0.01 mole) of 2-amino-1-methyl-3-phenylindole hydrochloride and 3.24 g (0.04 mole) of KOCN in 25 ml of vaseline oil. The reaction mass is taken up with hexane and the insoluble parts, collected by filtration under vacuum, are washed with water in order to remove inorganic salts and crystallized from dimethylformamide, yielding 0.5 g of the pure desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[NH2:21][C@H:22]([CH2:24][OH:25])[CH3:23]>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:21][C@@H:22]([CH3:23])[CH2:24][OH:25])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: C[C@H](N)CO
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(N[C@@H](C)CO)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
A solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (5.0 g, 22.6 mmol) in 50 mL of dry DMF was cooled to 0° C. under an atmosphere of N2. Triethylamine (6.3 mL, 45.2 mmol) and L-alaninol (2.1 mL, 27.1 mmol) were added sequentially. After approximately 15 minutes, the reaction was allowed to warm to ambient temperature, and then heated to 35° C. for 3 days. The reaction mixture was concentrated under reduced pressure to give an orange-brown solid. The resulting solid was partitioned between 50 mL of ethyl acetate and 50 mL of H2O. The layers were separated and the organic portion was washed sequentially with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Chromatography (SiO2, 40-60% ethyl acetate/hexanes) afforded (2S)-2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol (3.62 g) as an orange solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COCCOCCOCCOCCC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOCCOCCOCCC(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To tert-butyl 2,5,8,11-tetraoxatetradecan-14-oate (65 g, 222.6 mmol) (example-1), was added p-toluenesulfonic acid (21.16 g, 111 mmol) and water (31.7 mL). The contents were heated to 80° C. and stirred at that temperature for 2 h. The completion of the reaction was monitor by TLC. The reaction mixture was cooled to 0° C. and basified to pH 10 to 11 using sodium hydroxide solution (17.7 g dissolved in 65 mL water). The contents were stirred at 25-30° C. for 10 minutes. Added Ethyl acetate (65 mL×2), stirred and separated the layer. The aqueous layer was cooled to 0 to 5° C. and the pH was adjusted to 3.5 to 4 using 11 N HCl solution and the product was extracted to methylene chloride (120 ml×2). The combined organic layer was washed with water, brine solution and dried over sodium sulphate. The solvent was removed under vacuum to afford 2,5,8,11-tetraoxatetradecan-14-oic acid (40.5 g, 77.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=O)[CH2:18][CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:34])[NH:32][NH2:33])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[N:33][NH:32][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:34])[CH2:18][CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CCC(=O)C1CCCN(C(=O)OCc2ccccc2)C1)OC
Reactant: CC(C)(C)OC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COC(CCC(=NNC(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)OC
Reaction time: 4 h
Yield: 94.2 %

Procedure:
The product from step 1 (16.32 g, 46.70 mmol) was dissolved in 100 mL of CH2Cl2 and treated with tert-butylcarbazate (6.48 g, 49.04 mmol) followed by para-toluensulfonic acid monohydrate (0.44 g, 2.33 mmol) and the mixture was stirred 4 h. The mixture was poured into a separatory funnel and extracted with 50 mL 2M aq. Na2CO3. The aqueous phase was extracted with 50 mL of CH2Cl2 and the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified using an ISCO® instrument (Red-Sep 330, 30%-100% EtOAc hexanes) to give 20.40 g of a clear oil. 1H NMR (300 MHz, DMSO-d6) δ 9.48 (bs, 1H), 7.40-7.28 (m, 5H), 5.04 (s, 2H), 4.32 (m, 1H), 4.05 (bd, 1H), 3.96 (bd, 1H), 3.20 (m, 6H), 2.88-2.63 (m, 2H), 2.31-2.11 (m, 1H), 1.87 (m, 1H), 1.66, (m, 1H), 1.59 (m, 1H), 1.42 (s, 9H), 1.40-1.24 (m, 5H). ES-MS m/z 463.9 [M+Na]+, HPLC RT (min) 3.67
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][C@@H:11]2[C@@H:15](OS(C)(=O)=O)[CH2:14][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12]2)=[CH:5][CH:4]=1.[N-:42]=[N+:43]=[N-:44].[Na+].O>CS(C)=O>[N:42]([C@H:15]1[C@@H:11]([O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:12][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2OS(C)(=O)=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2N=[N+]=[N-])(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 100 °C
Yield: 92.7 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3-(bis(4-methoxyphenyl)(phenyl)methoxy)-4-(methylsulfonyloxy)pyrrolidine-1-carboxylate (4.0 g, 6.85 mmol) in anhydrous DMSO (70 mL) was added sodium azide (1.78 g, 27.4 mmol). The resulting mixture was heated at 100° C. for 18 hours. The solution was cooled to ambient temperature, poured into water (150 mL) and the solid which separated was collected by filtration and washed with water and dried to afford (3R,4S)-tert-butyl 3-azido-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylate (3.37 g, 93%).
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].[F:6][C:7]([F:14])([F:13])[C:8](OCC)=[O:9]>O1CCOCC1>[F:6][C:7]([F:14])([F:13])[C:8](=[O:9])[CH2:4][C:3]#[N:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#CCC(=O)C(F)(F)F
Temperature: 10 °C
Yield: 98.5 %

Procedure:
To a stirred suspension of 60% NaH (33.80 g, 1.408 mol, 2 eq.) in dioxane (700 mL) was added acetonitrile (44.3 mL, 0.845 mol, 1.2 eq.) at 0° C. over a period of 30 min followed by ethyl trifluoroacetate (83.70 mL, 0.704 mol, 1.0 eq.). The reaction mixture was slowly and carefully heated to 10° C. for 3 h. The dioxane was evaporated under reduced pressure and the pH was adjusted to ˜6 with 1N HCl and the mixture extracted with ether (200 mL×4), dried (MgSO4) and the solvent evaporated under vacuum to get 4,4,4-trifluoro-3-oxobutanenitrile (95 g, crude, brown oil).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]=[CH:14][C:15]1[C:16]([NH:23][CH2:24][CH3:25])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[NH:13][CH2:14][C:15]1[C:16]([NH:23][CH2:24][CH3:25])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1
Reactant: CCNc1nc(SC)ncc1C=Nc1c(F)c(OC)cc(OC)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1nc(SC)ncc1CNc1c(F)c(OC)cc(OC)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A solution of 7.19 g (assume 15.86 mmol) of (5-[(2,6-difluoro-3,5-dimethoxy-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-ethyl-amine in 130 mL of anhydrous tetrahydrofuran was cooled to 0° C. using an ice/acetone bath. The cooled mixture was treated dropwise via syringe with 23.79 mL (23.79 mol) of 1 M solution of lithium aluminum hydride in tetrahydrofuran which resulted initially with vigorous bubbling. The resulting mixture continued to stir at 0° C. for 1 hour under nitrogen atmosphere. The ice bath was removed and the reaction mixture was allowed to warm up to room temperature and continued stirring at room temperature overnight. The reaction mixture was cooled to 0° C. using an ice/acetone bath and quenched by the slow addition of 23.79 mL of water, 23.79 mL of 15% sodium hydroxide and 47.58 mL of water. The salts were filtered over a bed of Celite and removed the tetrahydrofuran in vacuo. The residue was redissolved in dichloromethane and filtered again. The layers were separated and dried the organic layer over sodium sulfate, filtered and evaporated. The crude product was purified using medium-pressure chromatography eluting with 2:1 hexanes/ethyl acetate to give 4.45 g (76%) of the title compound: mp 95° C.–99° C. MS (APCI) (m+1)/z 371.1.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CI.[CH3:25]COC(C)=O>C1COCC1>[C:1]([N:8]([C@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:25])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCOC(C)=O
Reactant: C#C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C#C[C@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(R)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne was synthesized according to Method Y above by the treatment of (R)-N-Boc-2-amino-1-(-tert-butyldimethylsilyloxy)-but-3-yne (200 mg, 0.67 mmol) (Example 104B) with NaH (21 mg, 0.87 mmol) and MeI (189 mg, 1.34 mmol) in THF (12 mL). The product was obtained after silica gel column chromatography with a 0-10% EtOAc in hexanes gradient. (Yield 200 mg, 95%).