Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][CH3:12])[CH:5]=1.C([O-])(=O)C.[Na+].[Br:18]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH3:12][O:11][CH2:10][C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=[CH:8][C:7]=1[Br:18]
Reactant: COCc1cccc(COC)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCc1ccc(Br)c(COC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
To a solution of m-xylylene dichloride (25.0 g) in methanol (125 ml) was added a 28% methanol solution (82.6 g) containing sodium methoxide at room temperature, and the mixture was stirred with heating at 60° C. for 3 hr. The solvent was evaporated and water (150 ml) was added to the residue. The mixture was extracted twice with heptane (80 ml) and heptane was evaporated under reduced pressure to give m-xylylene glycol dimethyl ether (25.3 g). m-Xylylene glycol dimethyl ether (25.3 g) was dissolved in acetic acid (125 ml) and sodium acetate (68 g) was added, which was followed by dropwise addition of bromine (68 g) at room temperature. The mixture was stirred at room temperature for 3 hr and poured into 10% aqueous sodium sulfite solution (750 ml), which mixture was extracted twice with heptane (350 ml). The heptane layer was extracted twice with 10% aqueous sodium hydroxide solution (150 ml) and once with water (150 ml). The solvent was evaporated and the residue was purified by silica gel column chromatography using heptane-ethyl acetate (15:1) as an eluent to give the title compound (10.4 g, yield:29.7%) as a colorless transparent oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10](=[O:42])[C@@H:11]([NH2:41])[CH2:12][NH:13][C:14]([C:16]1[CH:40]=[C:19]2[C:20](=[O:39])[N:21]([CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:22][CH2:23][N:18]2[N:17]=1)=[O:15]>C1COCC1>[CH3:8][O:9][C:10](=[O:42])[C@@H:11]([NH:41][C:1](=[O:3])[CH3:2])[CH2:12][NH:13][C:14]([C:16]1[CH:40]=[C:19]2[C:20](=[O:39])[N:21]([CH2:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)[CH2:22][CH2:23][N:18]2[N:17]=1)=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H](N)CNC(=O)c1cc2n(n1)CCN(CCC1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CNC(=O)c1cc2n(n1)CCN(CCC1CCN(C(=O)OC(C)(C)C)CC1)C2=O)NC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetic anhydride (70 ml, 0.76 mmol), was added to a cooled (0°) solution of 4-3 (350 mg, 0.69 mmol) in 10 ml THF. The resulting solution was allowed to warm to room temperature and stirred for 18 h, then concentrated, and the residue was dissolved in 50 ml ethyl acetate and washed successively with NaHCO3, H2O, 10% KHSO4, H2 O, and brine (25 ml each). The organic layer was dried over Na2 SO4 and evaporated giving a colorless residue which was chromatographed on silica gel with 3% CH3OH/CH2Cl2 to yield 4-4 as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([O-:13])=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.[OH-].[Li+]>CO.O>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)[O-])cnc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3.2 g (10 mmol) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]imidazo[4,5-b]pyridine-6-carboxylate in 150 mL methanol was mixed with a solution of 1.5 g lithium hydroxide in 20 mL water and stirred for 24 hours at room temperature. Then the mixture was diluted with 50 mL of water, the alcohol was distilled off and the aqueous phase was washed with ethyl acetate. After acidification with dilute hydrochloric acid, the mixture was extracted several times with dichloromethane/methanol (9:1), the organic phase was dried with sodium sulfate and the solvent was distilled off. Yield: 2.1 g beige solid (70% of theory); Rf value: 0.38 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][S:43](CN1C=CC(N)=N1)(=[O:45])=[O:44]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][S:43]([CH3:42])(=[O:45])=[O:44])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cn1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (166 μL, 0.33 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (46 μL, 0.39 mmol) was added to the solution at 0° C. After 1 h, 1-methanesulfonylmethyl-1H-pyrazol-3-ylamine (0.30 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-methanesulfonylmethyl-1H-pyrazol-3-yl)-propionamide (133 mg, 90%) as a white solid: ESI-LRMS m/e calcd for C20H26ClN3O5S2 [M+] 487.1, found 488.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.22 (m, 2H, CH2), 1.43-1.94 (m, 8H, 4×CH2), 2.09-2.29 (m, 1H, CH), 2.86 (s, 3H, SO2CH3), 3.27 (s, 3H, SO2CH3), 3.58 (t, J=7.5 Hz, 1H, CH), 5.25 (s, 2H, NCH2), 6.87 (d, J=2.5 Hz, 1H, Ar), 7.48 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.54 (d, J=2.5 Hz, 1H, Ar), 7.61 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.1 Hz, 1H, Ar), 8.10 (brs, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:19])=[O:12]
Reactant: CO
Reactant: O=C(O)CCCc1ccccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1ccccc1O

Procedure:
4-(2-Hydroxyphenyl)butyric acid (1 g, 5.55 mmol) was dissolved in 20 mL anhydrous methanol, and 5 mL sulfuric acid. The mixture was heated to reflux for 6 hours. After aqueous workup, 1.14 g of methyl 4-(2-hydroxyphenyl)butyrate was obtained. 1H NMR (CDCl3): 1.92 (q, 2H), 2.40 (t, 2H), 2.65 (t, 2H), 3.72 (s, 3H), 6.84 (m, 2H), 7.10 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[C:16](OC(=N)C(Cl)(Cl)Cl)([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[C:6]([O:8][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C(=O)O)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)OC(C(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of compound 2 (500 mg, 1.83 mmol) in toluene (2.5 mL) was added t-butyl-trichloroacetimidate (0.33 mL). The reaction was stirred at room temperature for 5 hours. The solid precipitate was filtered off and washed with toluene. The filtrate was concentrated in vacuo to provide compound 3 which was used in the next reaction without further purification.
Reaction SMILES: COC(=O)[N:4]([CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[CH3:13])[CH2:5][CH2:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9].[Br-].[CH2:23]1[CH2:27]OC[CH2:24]1>>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([CH:12]([NH:4][CH2:5][CH2:6][C:7]([OH:11])([CH2:27][CH:23]=[CH2:24])[CH:8]([CH3:9])[CH3:10])[CH3:13])=[CH:19][CH:18]=1
Reactant: C1CCOC1
Reactant: COC(=O)N(CCC(=O)C(C)C)C(C)c1ccc(Br)cc1
Agent: [Br-]
Product: C=CCC(O)(CCNC(C)c1ccc(Br)cc1)C(C)C
Reaction time: 8 h

Procedure:
To a solution of [1-(4-bromo-phenyl)-ethyl]-(4-methyl-3-oxo-pentyl)-carbamic acid methyl ester (1.78 g, 5 mmol) in dried THF (20 mL) was added allymagnesium bromide (1 M, 25 mL, 25 mmol) dropwise at −78° C. The mixture was stirred overnight. The reaction was quenched with aqueous sat. NH4Cl. The mixture was extracted with EtOAc. The organic phase was dried over Na2SO4, and condensed to give 3-{2-[1-(4-bromo-phenyl)-ethylamino]-ethyl}-2-methyl-hex-5-en-3-ol (2.2 g, crude).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:24]2[CH:25]=[CH:26][NH:27][C:28]=2[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1Cl
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1Cl

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6,7-dichloro-3-(piperidin-4-yl)-1H-indole (0.80 g, 3.0 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.64 g, 3.1 mmol) and potassium carbonate (0.83 g, 6.0 mmol). The product was isolated as a tan foam. Yield 278mg, 21%. mp 160-165° C. FDMS m/e=441 (M+ of free base).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23]O)[CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[Br:48][CH2:23][CH2:22][CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:9]2[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[CH:3]=3)=[CH:13][C:12]([Cl:14])=[CH:11][N:10]=2)[CH2:16][CH2:17]1
Reactant: O=C(Nc1cc(Cl)cnc1N1CCC(CCCO)CC1)c1cccc(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)cnc1N1CCC(CCCBr)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.3 %

Procedure:
A mixture of 0.080 g (0.20 mmol) of the above amide and 0.056 g (0.22 mmol) of triphenylphosphine in anhydrous methylene chloride (10 mL), under an atmosphere of nitrogen, is stirred at room temperature for 20 minutes. To this mixture is added 0.071 g (0.22 mmol) of carbon tetrabromide and the resulting mixture is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is purified by flash silica gel chromatography to give 0.037 g (40%) of N-[4-(3-bromo-propyl)-5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-3-chloro-benzamide.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:41]=[C:40]4[C:36]([C:37]([NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54])=[N:38][N:39]4COCC[Si](C)(C)C)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:41]=[C:40]4[C:36]([C:37]([NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54])=[N:38][NH:39]4)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)ccc12
Temperature: 66 °C

Procedure:
14 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.2 g of N-[6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 17 hours. The heating is then stopped and 75 cm3 of ethyl acetate are added. This mixture is washed with 50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with cyclohexane/ethyl acetate (80/20 by volume) and collecting 30 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 2×2 cm3 of diisopropyl ether. This mixture is filtered through a sinter funnel to give, after drying (90 Pa; 50° C.), 220 mg of N-[6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of a white solid melting at 220° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:5]([CH2:18][OH:19])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].CC(C)=[O:31].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Br:1][C:2]1[C:3](=[O:28])[N:4]([C:20]2[C:21]([F:27])=[CH:22][CH:23]=[CH:24][C:25]=2[F:26])[C:5]([C:18]([OH:31])=[O:19])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=c1c(Br)c(OCc2ccc(F)cc2F)cc(CO)n1-c1c(F)cccc1F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Temperature: 0 °C
Yield: 65 %

Procedure:
In a 100 ml round bottom flask, 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one (1.70 g, 3.7 mmol) was dissolved in acetone (10 mL) and cooled to 0° C. in ice bath. To the reaction was added 1M acetone solution of Jones (5 ml, excess amount). Additional Jones reagent was added over time (approximately 6 hours) until the reaction was complete. The reaction was then concentrated down to dryness. The residue was then taken up in ethyl acetate (10 mL) and washed with brine. The dark yellow to brown colored crude product was purified by dissolving in 1N aqueous NaOH. The remaining organic impurities were removed by extracting with diethyl ether. The organic layers were discarded and the aqueous layer was acidified with dilute HCl (til pH app 1) to precipitate the pure acid which was then filtered and triturated with ether to obtain 1.17 g (65%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (q, J=9.41 Hz, 1H), 7.57-7.50 (m, 1H), 7.34 (dt, J=10.11, 2.78 Hz, 1H), 7.28-7.23 (m, 3H), 7.18 (dt, 8.90, 2.42 Hz, 1H), 5.47 (s, 2H). ES-HRMS m/z 471.9814 (M+H calcd for C19H11BrF4NO4, requires 471.9808)
Reaction SMILES: C([O:8][C:9]1[C:10]([F:29])=[C:11]([F:28])[CH:12]=[C:13]2[C:18]=1[N:17]([CH:19]1[CH2:21][CH2:20]1)[CH:16]=[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:14]2=[O:27])C1C=CC=CC=1.CCO>C1COCC1.[Pd]>[CH:19]1([N:17]2[C:18]3[C:13](=[CH:12][C:11]([F:28])=[C:10]([F:29])[C:9]=3[OH:8])[C:14](=[O:27])[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16]2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OCc3ccccc3)c(F)c(F)cc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2c(O)c(F)c(F)cc2c1=O
Yield: 47.4 %

Procedure:
A solution of ethyl 8-(benzyloxy)-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (3.00 g, 7.51 mmol) in THF (60 mL)-EtOH (10 mL) was hydrogenated under atmospheric pressure over 10% Pd/C (300 mg) at room temperature for 2 h. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. The crude product washed with Hexane and dried to yield ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxoquinoline-3-carboxylate (1.10 g, 47%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[C@H:10]([C:15]#[N:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[OH:19]>C(Cl)(Cl)Cl.CC(O)=O.O=[Pt]=O>[C:11]([OH:13])(=[O:19])[CH3:12].[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[C@H:10]([CH2:15][NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C#N
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN
Reaction time: 16 h

Procedure:
80.3 A suspension of (3S,4S)-3-cyano-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg) in 15 ml of EtOH, 0.3 ml of chloroform, 0.38 ml of AcOH and 8 mg of PtO2 was hydrogenated at 22° C. and atmospheric pressure for 16 h. The suspension was filtered and the filtrate evaporated to give 188 mg of (3R,4S)-3-aminomethyl-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester acetate. Colorless semisolid. MS 231.3 ([M+H]+)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:10][CH2:11][CH2:12]Br>>[Br:10][CH2:11][CH2:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: BrCCBr
Reactant: c1ccc2[nH]ccc2c1
Product: BrCCn1ccc2ccccc21

Procedure:
The procedure is as for Example 39 using as substrate 1H-indole and 1,2-dibromoethane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])O[C:10]=1[C:17]([NH:19][CH:20]1[CH2:23][CH2:22][CH2:21]1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH2:25]>CO>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:25]([CH3:24])[C:10]=1[C:17]([NH:19][CH:20]1[CH2:23][CH2:22][CH2:21]1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)o1
Solvent: CO
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)n1C
Temperature: 72.5 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of the compound from example 4 (2.616 g, 8.35 mmol, 1.0 equiv) in methanol (10 ml) was quickly added methylamine (2M in methanol, 20 ml, 40 mmol, 4.79 equiv). The sealed tube was stirred overnight at 70-75° C. The resulting brown solution was evaporated to dryness and purified by chromatography (EtOAc, then 1:4 MeOH/EtOAc) provided the titled compound (1.70 g, 62.24%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([OH:15])=O)[CH2:10][NH:9][C:8]=2[CH:16]=1.[Br:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=1[NH2:22].N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1>[Br:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:13]([CH:11]1[O:12][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:17])=[CH:16][C:8]=2[NH:9][CH2:10]1)=[O:15]
Reactant: Cc1ccc(N)c(Br)c1
Reactant: O=C(O)C1CNc2cc(OC(F)(F)F)ccc2O1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CC1CCCO1
Product: Cc1ccc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
6-(Trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (600 mg, 2.28 mmol) and 2-bromo-4-methyl-aniline (424 mg, 286 μL, 2.28 mmol) were dissolved in 2-methyltetrahydrofuran (7 mL) and pyridine (461 μL, 5.70 mmol). T3P (2902 mg, 2.7 mL of 50% w/w solution, 4.56 mmol) was added and the reaction was stirred for 30 min at room temperature. Purification by silica gel chromatography (10-100% ethyl acetate/hexanes) provided N-(2-bromo-4-methylphenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (743 mg, 76% yield). LC/MS m/z 432.4 [M+H]+.
Reaction SMILES: CS(C)=O.C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[C:23]([C:39]#[N:40])=[C:24]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[S:25][C:26]=1[C:27]1[NH:28][CH2:29][CH:30]([CH3:32])[N:31]=1.[OH-].[NH4+]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[C:23]([C:39]#[N:40])=[C:24]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[S:25][C:26]=1[C:27]1[NH:28][CH:29]=[C:30]([CH3:32])[N:31]=1
Reactant: CC1CNC(c2sc(N3CCOCC3)c(C#N)c2-c2ccc(Cl)cc2Cl)=N1
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c[nH]c(-c2sc(N3CCOCC3)c(C#N)c2-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To DMSO (32.0 uL, 0.000451 mol) in DCM (3 mL, 0.05 mol) at −78° C. was added oxalyl chloride (38.2 uL, 0.000451 mol) and the mixture was stirred for 30 min. 4-(2,4-dichlorophenyl)-5-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)-2-morpholinothiophene-3-carbonitrile (19 mg, 0.000045 mol) in DCM (1.5 mL, 0.023 mol) was added. After 1 h, TEA (0.188 mL, 0.00135 mol) was added and the mixture was stirred for another 30 min. 33% ammonium hydroxide (33:67, ammonia:Water, 0.117 mL) was added and the reaction mixture was warmed to room temperature. The mixture was purified by column chromatography to afford 4-(2,4-dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)-2-morpholinothiophene-3-carbonitrile (4.04 mg, 21%). LCMS: (FA) ES+ 419.13, ES− 417.17. 1H NMR (400 MHz, d1-chloroform) δ: 7.61 (d, 1H), 7.42 (dd, 1H), 7.34 (d, 1H), 6.61 (s, 1H), 3.88-3.84 (m, 4H), 3.62-3.57 (m, 4H), 2.21 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[N:27]4[CH:28]=[CH:29][N:30]=[C:26]4[CH:25]=[C:24]([C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[N:23]=3)[CH:19]=[N:18]2)[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)#[N:2].C(Cl)[Cl:38].Cl.O1CCOCC1>>[ClH:38].[CH3:36][N:34]1[CH:35]=[C:31]([C:24]2[N:23]=[C:22]([C:20]3[CH:19]=[N:18][N:17]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]4)[CH:21]=3)[N:27]3[CH:28]=[CH:29][N:30]=[C:26]3[CH:25]=2)[CH:32]=[N:33]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCN(C(=O)OC(C)(C)C)CC4)c3)n2)cn1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCNCC4)c3)n2)cn1
Reaction time: 1.5 h
Yield: 107.8 %

Procedure:
Tert-butyl 4-(cyanomethyl)-4-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Example 21; 17 mg, 0.035 mmol) was dissolved in DCM (170 μL, 0.035 mmol) and treated with 4N HCl in dioxane (170 μL, 0.70 mmol). After 90 minutes, the reaction mixture was concentrated in vacuo to afford 2-(4-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-4-yl)acetonitrile hydrochloride (16 mg, 98% yield). MS (apci) m/z=388.3 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C=O)C>[I:11][C:10]1[C:3]2[C:2]([NH:22][CH:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[CH3:21])=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: COc1ccc(C(C)N)cc1
Reactant: Clc1ncnc2scc(I)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(C)Nc2ncnc3scc(I)c23)cc1
Yield: 50.1 %

Procedure:
A mixture of 4-chloro-5-iodothieno[2,3-d]pyrimidine (100 mg, 0.34 mmol) and 1-(4-methoxyphenyl)ethylamine (69 mg, 0.37 mmol) and triethylamine (87 μL, 0.9 mmol) in DMF (2.0 mL) was allowed to react for 15 hours at 25° C., then 3 hours at 50° C. The reaction mixture was filtered through a cotton plug and purified by HPLC (Gilson system; Phenomenex column: Luna 5μ C18(2), 150×21.20 mm, 5μ micro) with water/acetonitrile gradient. Appropriate fractions were pooled to provide 70 mg of tan solid.