Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[NH3:27]>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH2:27])=[O:26])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: N
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Solvent: CO
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(N)=O)c2n1
Yield: 38 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K) and 7N NH3 in MeOH. The combined organic extracts were concentrated and the residue was purified by reverse phase HPLC (0-80% acetonitrile/water) to provide the title compound (15 mg, 38% yield). MS (apci) m/z=357.0 (M+H).
Reaction SMILES: C(Cl)(=O)C.[CH2:5]1[C:10]2([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][O:6]1>CO>[CH2:5]1[C:10]2([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH2:9][CH2:8][CH2:7][O:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCOC2)CC1
Solvent: CC(=O)Cl
Solvent: CO
Product: C1COCC2(C1)CCNCC2
Yield: 119.3 %

Procedure:
Acetyl chloride (1 mL) was added to stirred, cooled (0° C.) methanol (10 mL) and the mixture was stirred at 0° C. for 5 minutes. 1,1-Dimethylethyl 2-oxa-9-azaspiro[5.5]undecane-9-carboxylate (Description 138, 78 mg, 0.27 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, aqueous sodium carbonate (10%, 10 mL) was added and the mixture was extracted with dichloromethane (3×10 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (50 mg, 100%). m/z (ES+) 156 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:27][CH2:26]2)[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C@H:25]2[CH2:26][CH2:27][C@H:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:29][CH2:30]2)=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N[C@H]1CC[C@H](Nc2nc(Cl)ncc2Cl)CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CC[C@H](NS(C)(=O)=O)CC4)n3)cc2CC1

Procedure:
trans-N-(4-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and trans-N-[4-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white solid (96 mg, 53%). m.p.=189-192° C.; LCMS (m/e) 523 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.90 (s, 1H), 7.33 (d, 1H, J=7.5 Hz), 7.03 (d, 1H, J=8.0 Hz), 6.80 (s, 1H), 5.03 (d, 1H, J=7.2 Hz), 4.29 (d, 1H, J=7.5 Hz), 4.02-3.90 (m, 1H), 3.57 (t, 2H, J=5.5 Hz), 3.45-3.32 (m, 1H), 3.38 (s, 3H), 3.03 (s, 3H), 2.98-2.88 (m, 4H), 2.83-2.69 (m, 6H), 2.28-2.16 (m, 4H), 1.53-1.32 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([NH:18][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4])([CH3:17])([CH3:16])[CH3:15]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: CC(C)(C)N
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.04 g, 0.203 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen was added tert-butylamine (0.043 ml, 0.406 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was flash chromatographed with 3% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS (DCI) m/z 234 (M+H)+.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH3:14][C:15]([NH2:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].Cl>O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:22][C:15]([CH3:21])([CH3:14])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH:7][C:6]=2[CH:8]=1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Agent: Cl
Solvent: O
Product: CC(C)(C)CC(C)(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 30.4 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.5 g, 1.95 mm0l) in 1,1,3,3-tetramethylbutylamine (5 ml, 31 mmol) was stirred for 44 h at 120° C. in a sealed flask. Water (25 ml) was added to the cooled solution and pH was adjusted to <2 by the addition of 4M hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water, and then redissolved in 1N sodium hydroxide (15 ml) at 50-60° C. followed by treatment with decolorising charcoal. After filtration, the clear solution was acidified to pH 2 by the addition of 4M hydrochloric acid and the precipitate was filtered off and recrystallised from methanol to give 207 mg (31%) of the pure title compound; mp 369-371° C. dec; 1H-NMR (DMSO-d6): δ0.98 (s, 9H), 1.42 (s, 6H), 1,86 (s, 2H), 6.75 (br s, 1H), 7,12 (s, 1H), 10.55 (s, 1H); MS: m/e 349/351 (M+); (C13H20N3Cl1O2S2) calc. C, 44.63; H, 5.76; N, 12.01; found C, 44.74; H, 5.78; N, 11.84.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[CH2:11]([OH:13])[CH3:12]>>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:13][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#Cc1ccc(Cl)cc1
Agent: Cl
Product: CCOC(=N)c1ccc(Cl)cc1

Procedure:
Ethyl 4-chlorobenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, p-chlorobenzonitrile (25.6 g, 0.186 mol) was reacted with hydrogen chloride in ethanol (250 mL) to give 36.8 g (90%) of the target compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH:12](OC)(OC)OC.OS(O)(=O)=O>CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: COC(OC)OC
Reactant: O=C(O)c1ccc(F)c(O)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(F)c(O)c1
Temperature: 47.5 °C

Procedure:
4-Fluoro-3-hydroxybenzoic acid (20.0 g, 0.13 mol) was dissolved in anhydrous methanol (160 mL), mixed with trimethyl orthoformate (25 mL) followed by the addition of concentrated H2SO4 (3 mL) and the reaction was heated to 40-55° C. overnight. Half of the solvent was removed in vacuo, the remaining solution was poured into an ice/H2O mixture and the product was extracted twice with diethyl ether. The combined ether phases were washed twice with H2O, treated with a cold solution of saturated NaHCO3, treated with brine, dried with MgSO4, filtered, and the solvent was removed in vacuo to give 21.6 g (99% yield) of a white solid as the title compound (mp 93.5-94.5° C.). Mass spectrum (70 eV) m/z (relative intensity) 170 (44, M+), 139 (100), 111 (83), 83 (83), 82 (16), 81 (11), 63 (11), 57 (24).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.FC(F)(F)C(O)=O.[F:30][S:31]([F:50])([F:49])([F:48])([F:47])[C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([CH2:41][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[CH:40]=1)[C:35](O)=[O:36]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:35](=[O:36])[C:34]2[CH:38]=[C:39]([CH2:41][N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH:40]=[C:32]([S:31]([F:50])([F:49])([F:48])([F:30])[F:47])[CH:33]=2)=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: O=C(O)c1cc(CN2CCCC2)cc(S(F)(F)(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(CN3CCCC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
45 mg (0.16 mmol) of the compound of Example 6A and 70 mg (0.16 mmol) of the compound of Example 38A were reacted analogously to the procedure of Example 16, except that here the reaction was, after the reaction had ended, directly separated into its components by preparative HPLC (Method 15). The product-containing fractions were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed successively with saturated potassium carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Drying of the residue gave 48 mg (51% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]([OH:16])([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:3].N1C=CC=CC=1.[C:23]1([O:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:30](=[O:31])([O:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:16][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([CH3:1])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(O)c1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(OC(=O)Oc1ccccc1)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 2-(4-biphenyl)-2-propanol (53 g, 250 mmol) in dry CH2Cl2 (250.0 mL) was added pyridine (24.6 mL, 305 mmol) and phenylchloroformate (35.0 mL, 280 mmol) in CH2Cl2 (125.0 mL) at −5° C. After addition forms a thick precipitate, which, after the reaction mixture is allowed to stand overnight at 0° C. is mostly dissolved. The mixture is poured onto ice and diluted with CH2Cl2 (1000 mL). The organic phase is separated and washed three times with cold water. After drying over Na2SO4 the organic layer is evaporated at reduced pressure at a bath temp of <30° C. The crystalline residue is dissolved in diethyl ether (1000 mL) and the solution is then concentrated with a stream of nitrogen at atmospheric pressure at bath temperature of 60° C. to approximately 200 mL and then rapidly cooled to 0° C. to produce a pure crystalline product 55.0 g (66% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:19](=[O:22])(=[O:21])[NH2:20])[C:10]=1[NH:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[OH-].[Li+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:19](=[O:21])(=[O:22])[NH2:20])[C:10]=1[NH:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)n1
Reactant: BrCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(Nc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)n1

Procedure:
A suspension of 3-amino-4-(2-methyl-6-pyridylamino)-5-sulphamyl-benzoic acid (0.5 g) in water (25 ml) was adjusted to a pH of 8 by addition of 1N lithium hydroxide. To the resulting solution, benzyl bromide (0.2 g) was added while, under stirring, the pH was kept at 8 by automatic titration with 1N lithium hydroxide. After the base consumption had become negligible, the crude 3-benzylamino-4-(2-methyl-6-pyridylamino)-5-sulphamyl-benzoic acid was precipitated from the reaction mixture by adjusting the pH to 5 by means of 1N hydrochloric acid. The compound was collected by suction, recrystallized from aqueous ethanol, and dried. The melting point of the compound was 168°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[OH:34][CH2:35][CH2:36][NH2:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:37][CH2:36][CH2:35][OH:34])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-hydroxyethylamine by methods similar to those described in Example 6. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.38 (1H, br m), 8.60 (1H, s), 8.07 (1H, s), 7.24 (2H, m), 7.00 (2H, t, J=8.6 Hz), 4.36 (2H, t, J=7 Hz), 4.15 (2H, s), 3.87 (2H, t, J=5 Hz), 3.66 (2H, m), 3.51 (2H, t, J=8 Hz), 3.45 (2H, t, J=7 Hz), 2.37 (2H, t, J=8 Hz), 2.00 (2H, m).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:23]([O-])=[O:24].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.67 h

Procedure:
2.2 g of 1-(2-chloroethyl)-3-n-butyl-3-D-glucopyranosylurea are dissolved in 10 ml of formic acid, and one g of sodium nitrite is added gradually thereto at 0° to 5° C. for 40 minutes under stirring. The mixture is further stirred at the same temperature for 1.5 hours. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.0 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-glucopyranosylurea is thereby obtained as pale yellow caramel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:29])[CH2:20][CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:19]([CH3:18])[CH3:29])=[CH:28][CH:27]=1
Reactant: CN(C)CCc1ccc(N)cc1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C)CCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Yield: 73.9 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 4-(2-(dimethylamino)ethyl)aniline (247 mg, 1.5 mmol) to afford the desired product (324 mg, 73%) as a yellow solid: ESI MS m/z 438 [C23H24BrN3O+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCCCBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: BrCCCCCCOc1ccc(OCc2ccccc2)cc1
Reaction time: 96 h

Procedure:
4-Benzyloxyphenol and 1,6-dibromohexane were reacted using conditions reported in Example 15. The reaction time was 4 days and the extraction solvent used was toluene. The crude product was crystallized from hexane to give 1-benzyloxy-4-(6-bromohexyloxy)benzene, mp 72°-3°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:27]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:27])=[CH:4][CH:3]=1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)cc3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-chlorophenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][F:29])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:42]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][F:29])=[CH:22][N+:21]=1[O-:42])[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCF)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCF)c[n+]1[O-])C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 350 mg di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[5-(2-fluoroethoxy)pyridin-2-yl]methyl}-L-glutamate (0.68 mmol; see Example 17d) in dichloromethane (5 mL) was added 185 mg meta-chloro peroxybenzoic acid (70%), and the mixture was stirred for 1 h at room temperature. The mixture was extracted with aqueous sodium bicarbonate, followed by re-extraction of the aqueous layer with dichloromethane. The combined organic layers were concentrated in vacuo, and the residue was purified by preparative HPLC (Method D) to give 340 mg of the target compound (93% yield).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[OH:5][C@@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1>C1(C)C=CC=CC=1>[O:8]1[CH2:9][CH2:10][C@@H:6]([O:5][C:1]([Cl:4])=[O:2])[CH2:7]1
Reactant: O=C(Cl)Cl
Reactant: O[C@@H]1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)O[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.5 ml (24.15 mmol) of a 20% solution of phosgene in toluene are cooled in an ice-bath, a solution of 1.06 g (12.03 mmol) of (R)-(+)-3-hydroxytetrahydrofuran (JPS CHIMIE, Bevaix, Switzerland) in a small amount of toluene is then added dropwise and, after the mixture has been stirred at RT for 2 h, the excess phosgene is expelled with argon. After concentration by evaporation in a rotary evaporator under reduced pressure, the crude title compound is further processed without being further purified.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][C:43]([N:45]([CH3:53])[C:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=2)=[O:44])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][C:43]([N:45]([C:46]2[CH:51]=[CH:50][C:49]([NH:52]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:48][CH:47]=2)[CH3:53])=[O:44])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CCN2CCN(C(=O)OC(C)(C)C)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((2-(4-tert.butoxycarbonyl-piperazin-1-yl)-ethyl)-carbonyl)-N-methyl-p-phenylenediamine Rf value: 0.8 (silica gel, methylene chloride/methanol=5:1) C36H41N5O6
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:28]1([CH:27]=[C:26]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH2:20][C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[CH:18]=[C:13]3[CH:12]=2)[C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CN(C)C(=O)COc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)COc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 100 %

Procedure:
A solution of 2-{1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-N,N-dimethyl-acetamide (340 mg, 0.59 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 4 mL, 4 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), and washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-N,N-dimethyl-acetamide (276 mg, quant.) as a white solid: LC/MS m/e calcd for C25H29N3O4S [M+H]+ 468.59, observed 468.2.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][CH2:30][C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3.C(=O)([O-])[O-:32].[K+].[K+].OO.O>CS(C)=O>[F:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][CH2:30][C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([C:25]([NH2:26])=[O:32])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3
Reactant: O=C([O-])[O-]
Reactant: Cc1nn(-c2ncccc2C#N)cc1CN1CCC2(CC1)OCCc1cc(F)sc12
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nn(-c2ncccc2C(N)=O)cc1CN1CCC2(CC1)OCCc1cc(F)sc12
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 128.1 %

Procedure:
To a solution of 2-[4-[(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (0.71 mmol, 0.30 g) in dimethylsulfoxide (7.5 mL), potassium carbonate (0.049 g, 0.35 mmol) is added and the mixture is cooled to 0-5° C. before adding 33% hydrogen peroxide solution in water (0.39 mL, 3.78 mmol). The mixture is stirred at room temperature for 2 h. Then, water is added carefully and the reaction mixture is extracted with ethyl acetate. Organic layer is decanted, dried over magnesium sulfate and solvent is evaporated under reduced pressure. Crude is purified by normal phase Isco chromatography using as eluent dichloromethane/methanol mixtures to give 0.252 g that are further purified by reverse phase HPLC to yield 0.198 g of 2-[4-[(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carboxamide. MS (m/z): 442 (M+1).