Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[C:16]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:3][C:2]([F:1])([F:14])[F:15])[C:5](=[O:13])[CH2:6]2)(=[O:18])[CH3:17]
Reactant: O=C1Cc2ccccc2N1CC(F)(F)F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)CC(=O)N2CC(F)(F)F

Procedure:
To a solution of 1-(2,2,2-trifluoro-ethyl)-1,3-dihydro-indol-2-one (2.0 g, 9.3 mmol) and acetyl chloride (0.86 mL, 12 mmol) in carbon disulfide (40 mL) was added aluminum trichloride (7.4 g, 56 mmol) by portions. The mixture was heated to reflux for 3 hours, then cooled. The liquid phase was decanted and the residue was quenched carefully with ice, then water. The solids were filtered, washed with water, dried and recrystallized from acetone/hexanes to give a pale pink solid, mp 170-171° C. Yield 1.23 g (51%).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][O:12][CH3:13])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].CCOCC.CCCCCC.II>C1COCC1.CO>[CH3:13][O:12][CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COCCC1(C(=O)OC)CCCC1
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CO
Product: COCCC1(C(=O)O)CCCC1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 1-(2-methoxyethyl)cyclopentane carboxylate methyl ester (7.987 g, 42.9 mmol) in a mixture of THF (170 mL) and methanol (170 mL) was added 1 N sodium hydroxide (170 mL). The mixture was heated to 40° C. for 2 h at which point TLC (ether:hexane 1:1, iodine chamber) analysis indicated the absence of starting material and the mixture was cooled to room temperature. The solvent was removed under vacuum and the residue was diluted with water (100 mL) and was extracted with ether (2×200 mL) to remove any neutral impurities. The basic aqueous layer was acidified with 1 N hydrochloric acid and the product was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine solution and dried over sodium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the residue was dried under high vacuum to afford 6.183 g (82%) of a light brown oil. HR MS (C9H16O3): Obs. mass, 172.0154. Calcd. mass, 172.0126 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:11]=1[NH2:22].[C:23](OCC)(=[O:27])[C:24]([CH3:26])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:22]=[C:24]([CH3:26])[C:23](=[O:27])[N:16]([C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCOC(=O)C(C)=O
Reactant: COC[C@@H](C)Nc1ncnc(-c2ccc(OC)cc2Cl)c1N
Solvent: CCO
Product: COC[C@@H](C)n1c(=O)c(C)nc2c(-c3ccc(OC)cc3Cl)ncnc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
(R)-6-(2-Chloro-4-methoxy-phenyl)-N4-(2-methoxy-1-methyl-ethyl)-pyrimidine-4,5-diamine (0.26 g, 0.82 mmol) was diluted in ethanol (8 ml) and ethyl pyruvate was added (0.92 ml, 8.2 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 6.0 mg of (R)-4-(2-chloro-4-methoxy-phenyl)-8-(2-methoxy-1-methyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 570a). 1H NMR (300 MHz, CDCl3) δ ppm 9.09 (s, 1 H), 7.43 (d, J=8.79 Hz, 1 H), 7.09 (d, J=2.56 Hz, 1 H), 6.97 (dd, J=8.79, 2.56 Hz, 1 H), 4.39 (m, 3H), 3.91 (s, 3 H), 3.73 (dd, J=10.07, 5.31 Hz, 2 H), 3.35 (s, 3H), 2.53 (s, 3 H), 1.62 (6, J=6.96 Hz, 3 H). MS (AP) 375.2 [(M+H)+, 100].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1)[C:7](=[O:28])[CH:6]=[CH:5]2.[CH3:29][O-:30].[Na+]>CO.O.C(OCC)(=O)C>[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([O:30][CH3:29])=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]2=[O:28])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3cc(Cl)ncc32)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2ccc(=O)n(CCN3CCC(N)CC3)c2cn1
Temperature: 150 °C
Yield: 64 %

Procedure:
A solution of tert-butyl {1-[2-(6-chloro-2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 129, 335 mg, 0.83 mmol) was treated with a solution of sodium methoxide in methanol (0.5 M, 4 mL). The reaction was sealed in a tube and heated at 150° C. for 4 hours using microwave irradiation. The reaction was diluted with water and ethyl acetate. The layers were separated. The aqueous phase was washed with ethyl acetate twice. The organic extracts were combined dried over magnesium sulfate and evaporated at reduced pressure to give 116 mg (64%) of the crude product as a yellow oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.NC(N)=[S:22].[OH-].[Na+].Cl>O.C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:6][C:2](=[S:22])[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: NC(N)=S
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1oc(=S)[nH]c1-c1ccc(Cl)cc1
Yield: 100 %

Procedure:
A mixture of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (5.72 g), thiourea (4.57 g) and ethanol (70 ml) was stirred under reflux for 30 minutes. An aqueous solution of 2N sodium hydroxide (40 ml) was added to the reaction mixture, and stirred under reflux for an additional 30 minutes. Water was added to the reaction mixture, which was then neutralized with 6N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 3-[4-(4-chlorophenyl)-2-thioxo-4-oxazolin-5-yl]propionic acid (5.41 g, yield: 96%). This was recrystallized from ethanol to give colorless needles. mp 196-197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide to yield an off-white solid (2.8%). LCMS: m/z=493.22 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.48 (d, 1H, J=8.3 Hz), 8.06 (s, 1H), 7.72 (d, 1H, J=1.8 Hz), 7.52 (d, 1H, J=7.6 Hz), 7.17 (m, 5H), 3.56 (m, 2H), 3.37 (s, 2H), 2.98 (m, 3H), 2.29 (m, 2H), 2.01 (m, 2H), 1.30 (m, 6H), 1.06 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12](O)=[O:13])=[CH:9][C:8]([C:15]([F:18])([F:17])[F:16])=[CH:7][CH:6]=2.S(Cl)([Cl:23])=O>>[F:1][C:2]([F:20])([F:19])[C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12]([Cl:23])=[O:13])=[CH:9][C:8]([C:15]([F:18])([F:17])[F:16])=[CH:7][CH:6]=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(C(F)(F)F)[nH]c2ccc(C(F)(F)F)cc12
Product: O=C(Cl)c1c(C(F)(F)F)[nH]c2ccc(C(F)(F)F)cc12
Temperature: 70 °C

Procedure:
A mixture of 500 mg (1.68 mmol) of the indolecarboxylic acid from Step 4 and 20 ml of thionyl chloride was heated for 3 at 70° C. The excess of thionyl chloride was removed under reduced pressure and the remaining crude acid chloride was dissolved in 30 ml of dry dichloromethane. This solution was used in the next step.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[SH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17]>>[CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([SH:12])[CH:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc(S)c1
Reactant: CC(C)Oc1ccc(N)cc1
Product: CC(C)Oc1ccc(NC(=O)c2cccc(S)c2)cc1

Procedure:
The entitled compound was obtained according to the method of Example 92 but using 4-isopropoxyaniline and 3-mercaptobenzoic acid as the starting materials.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.[Si]([O:35][CH2:36][CH2:37][CH:38]=O)(C(C)(C)C)(C)C>>[CH:23]([N:18]1[C:17]([C:11]2[S:12][C:13]3[CH2:14][CH2:15][O:16][C:7]4[CH:6]=[C:5]([CH:3]5[CH2:4][N:1]([CH2:38][CH2:37][CH2:36][OH:35])[CH2:2]5)[CH:27]=[CH:26][C:8]=4[C:9]=3[N:10]=2)=[N:21][C:20]([CH3:22])=[N:19]1)([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(CCCO)C4)ccc2-3)n(C(C)C)n1

Procedure:
Following the procedures for 519, 8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-(tert-butyldimethylsilyloxy)propanal to give 526. MS (ESI+) 440.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:13]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.B>C1COCC1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH3:9])=[CH:13][C:14]=1[S:20]([N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)(=[O:22])=[O:21]
Reactant: COc1ccc(C(=O)N[C@H](C)c2cccc(Cl)c2)cc1S(=O)(=O)N1CCOCC1
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(CN[C@H](C)c2cccc(Cl)c2)cc1S(=O)(=O)N1CCOCC1
Yield: 18.1 %

Procedure:
To a solution of (R)—N-(1-(3-chlorophenyl)ethyl)-4-methoxy-3-(morpholinosulfonyl)benzamide 43 (0.948 g, 2.16 mmol) in THF (9 mL) at room temperature was added borane (0.124 g, 8.96 mmol) (9 mL, 1 M in THF). The reaction mixture was heated to reflux for 24 h, quenched with 1 M NaOH, and diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 50% to 100% EtOAc in hexanes) gave (R)—N-(4-methoxy-3-(morpholinosulfonyl)benzyl)-1-(3-chlorophenyl)ethanamine 44 (0.166 g, 18.1% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.35 (d, J=6.5 Hz, 3H), 3.21-3.24 (m, 4H), 3.55-3.63 (m, 2H), 3.71-3.78 (m, 4H), 3.91 (s, 3H), 6.97 (d, J=8.6 Hz, 1H), 7.20-7.29 (m, 3H), 7.33 (s, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.78 (s, 1H). Mass spectrum: calculated for C20H25ClN2O4S 424.1. found 425.2 (M++1).
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[NH2:17][CH2:16][CH2:15][CH2:14][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ccccn1
Agent: Cl
Product: NCCCN(c1ccccc1)c1ccccn1

Procedure:
A mixture of N-[3-(N-phenyl-N-pyrid-2-ylamino)-propyl]phthalimide, (3.1 g) and conc. hydrochloric acid (30 ml) were heated under reflux for 21 hr. Phthalic acid was filtered off on cooling and the solvent was evaporated from the filtrate. The residue was dissolved in water and the solution extracted at pH 1 with chloroform. The pH was raised to pH 13 (NaOH) and the solution extracted again with ether. The ether extracts were dried (K2CO3) and the ether was evaporated to give 2-[N-(3-aminopropyl)-N-phenylamino]pyridine, 1.84 g as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[C:5]([N+:15]([O-])=O)[C:4]=1[NH:18][C:19](=O)[CH3:20]>CC(O)=O.[Fe]>[CH3:1][O:2][C:3]1[C:4]2[N:18]=[C:19]([CH3:20])[NH:15][C:5]=2[CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1
Reactant: COc1cc(N2CCOCC2)cc([N+](=O)[O-])c1NC(C)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc(N2CCOCC2)cc2[nH]c(C)nc12
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a refluxing solution of combined batches of N-(2-methoxy-4-morpholino-6-nitrophenyl)acetamide (2.06 g) in HOAc (60 mL) was added iron powder (1.18 g) and the mixture was stirred at reflux temperature overnight. It was cooled to room temperature and filtered. The filtrate was concentrated in-vacuo and the residue was washed with EtOAc:petroleum ether=1:1 to afford crude product as a solid (1.73 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.56 (s, 3H), 3.12 (t, 4H, J=4.8 Hz), 3.88 (t, 4H, J=4.8 Hz), 3.94 (s, 3H), 6.39 (s, 1H), 6.62 (s, 1H); LC-MS: m/e=248 [M+1]+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([Cl:38])[C:11]([NH:18][CH2:19][CH:20]([OH:37])[CH2:21][O:22][CH:23]3[CH2:26][N:25](C(OCC4C=CC=CC=4)=O)[CH2:24]3)=[C:12]([F:17])[CH:13]=2)[N:8]([C:39]2[C:44]([F:45])=[CH:43][C:42]([F:46])=[C:41]([NH2:47])[N:40]=2)[CH:7]=1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([Cl:38])[C:11]([NH:18][CH2:19][CH:20]([OH:37])[CH2:21][O:22][CH:23]3[CH2:26][NH:25][CH2:24]3)=[C:12]([F:17])[CH:13]=2)[N:8]([C:39]2[C:44]([F:45])=[CH:43][C:42]([F:46])=[C:41]([NH2:47])[N:40]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2nc(N)c(F)cc2F)c2c(Cl)c(NCC(O)COC3CN(C(=O)OCc4ccccc4)C3)c(F)cc2c1=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cn(-c2nc(N)c(F)cc2F)c2c(Cl)c(NCC(O)COC3CNC3)c(F)cc2c1=O
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a slurry of 10% Pd on carbon (2.1 g) in MeOH (20 mL) was added a solution of 11 (13.7 g, 20.3 mmol) in MeOH (230 mL). The mixture was hydrogenated at 1 atm. for 1 h, filtered over Hyflo and evaporated yielding 12 as beige crystals (10.3 g, 93%). Mp. 148-152° C.; 1H NMR (300 MHz, DMSO-d6): δ 1.27 (3H, t, J=7.1 Hz), 3.27 (1H, d, J=5.0 Hz), 3.28-3.80 (10H, m), 4.19 (1H, br. s), 4.21 (2H, q, J=7.1 Hz), 5.86 (1H, s), 6.74 (2H, s), 7.84 (1H, d, J=13.8 Hz), 7.94 (1H, dd, J=9.7, 9.0 Hz), 8.43 (1H, s); 13C NMR (75 MHz, CDCl3): δ 14.1, 48.4 (d, JF=10 Hz), 53.6, 60.2, 68.4, 70.4 (d, JF=4 Hz), 72.1, 106.4 (d, JF=6 Hz), 111.0, 111.3 (d, JF=23 Hz), 113.6 (dd, JF=23, 21 Hz), 118.9 (d, JF=6 Hz), 133.8 (d, JF=13 Hz), 134.2, 139.5 (d, JF=12 Hz), 143.3 (dd, JF=248, 4 Hz), 145.0 (dd, JF=259, 5 Hz), 145.6 (d, JF=14 Hz), 149.3 (d, JF=245 Hz), 149.5, 163.5, 171.0; IR: (KBr) 1697, 1614, 1496, 1457 cm−1; ES-HRMS m/z: (M++1H) calcd. for C23H24ClF3N5O5 542.1413. found 542.1391.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[C:14]2[C:23]([CH2:24][N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:22][C:21]3[C:20]([CH3:31])([CH3:30])[CH2:19][CH2:18][C:17]([CH3:33])([CH3:32])[C:16]=3[CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].[Cl-].[NH4+]>C(O)C>[F:1][C:2]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[C:14]2[C:23]([CH2:24][N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:22][C:21]3[C:20]([CH3:31])([CH3:30])[CH2:19][CH2:18][C:17]([CH3:33])([CH3:32])[C:16]=3[CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(/C=C/c2cc3c(cc2Cn2cccn2)C(C)(C)CCC3(C)C)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(Cn3cccn3)c(/C=C/c3ccc(C(=O)O)c(F)c3)cc21
Yield: 44.1 %

Procedure:
A slurry of 199 mg (0.446 mmol) of Methyl 2-fluoro-4-[(E)-2-[5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate, 1.5 mL ethanol and 1 mL of 2M aqueous sodium hydroxide was stirred for 16 hours. The mixture was neutralized with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was then washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting 145 mg of residue was triturated in methanol to provide 85 mg (44%) of 2-Fluoro-4-[(E)-2-[5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro naphthalen-2-yl)vinyl]benzoic acid 47.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12](Cl)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[C:6]([CH3:18])[CH:5]=[C:4]([O:19][CH3:20])[N:3]=1.O1CCOCC1.[CH2:27]([NH2:29])[CH3:28]>C(OCC)(=O)C>[Br:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:29][CH2:27][CH3:28])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[C:6]([CH3:18])[CH:5]=[C:4]([O:19][CH3:20])[N:3]=1
Reactant: CCN
Reactant: COc1cc(C)c(NC(=O)c2cccnc2Cl)c(Br)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCNc1ncccc1C(=O)Nc1c(C)cc(OC)nc1Br
Temperature: 140 °C
Yield: 44.2 %

Procedure:
A mixture of N-(2-bromo-6-methoxy-4-methyl-3-pyridinyl)-2-chloro-3-pyridinecarboxamide (2.1 g), dioxane (10 ml), and ethylamine (0.5 g) was heated to 140° C. in a sealed tube for 5 hours. The cooled mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried (anhydrous magnesium sulfate) and concentrated. The product was purified on a silica gel column (methylene chloride/ethyl acetate, 99:1) and crystallized by trituration with diisopropyl ether to give 0.95 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl-].[NH4+].C(OCC)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCC(=O)O)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CCCO)cc1OC
Reaction time: 8 h

Procedure:
A solution of 6.0 g (28.5 mmol) 3-(3,4-dimethoxyphenyl)-propionic acid in 120 ml anhydrous THF is cooled to 0° C. and treated within 15 minutes with 42.75 ml borane THF complex (1 M solution). Stirring is continued overnight at rt. The resulting clear solution is cooled with an ice/water bath and hydrolyzed by the addition of 100 ml saturated ammonium chloride solution. Extractive work-up with diethyl ether furnishes a colourless oil, which is purified by chromatography (hexane/ethyl acetate) to yield a colourless oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27][N:28]([CH2:36][CH2:37][O:38][CH3:39])C(=O)OC(C)(C)C)[CH:25]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27][NH:28][CH2:36][CH2:37][O:38][CH3:39])[CH:25]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)=[O:43])[CH2:3][CH2:2]1
Reactant: COCCN(CCn1cc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cn1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCCn1cc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cn1
Reaction time: 0.75 h
Yield: 342.8 %

Procedure:
To a solution of 246 (722 mg, 0.18 mmol) in DCM (30 mL) was added TFA (7 mL) and the reaction mixture was stirred for 45 min. The reaction mixture was concentrated, diluted with water and 4M NaOH to pH 11 and extracted with AcOEt. The extract was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 50 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 15/85 over 20 CV), to produce a material that upon trituration with AcOEt, afforded the title compound 247 (3.15 mg, 0.617 mmol, 52% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.71 (s, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.33 (s, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.72 (d, J=2.4 and 13.6 Hz, 1H), 7.68 (s, 1H), 7.35 (t, J=9.2 Hz, 1H), 7.22-7.16 (m, 1H), 6.57 (d, J=2.4 Hz, 1H), 6.53 (d, J=5.6 Hz, 1H), 4.21 (t, J=6.0 Hz, 2H), 3.36 (t, J=5.6 Hz, 2H), 2.98 (s, 3H), 2.97 (t, J=6.0 Hz, 2H), 2.68 (t, J=5.6 Hz, 2H), 2.59-2.50 (m, 1H), 0.68-0.62 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 511.54 (M+H).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br>>[F:4][C:5]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH:2][NH2:3]
Reactant: NN
Reactant: Fc1cccc(CBr)c1F
Solvent: O
Product: NNCc1cccc(F)c1F

Procedure:
Preparation takes place in analogy to that described in Example 1 A from 2.74 g (54.75 mmol) of hydrazine hydrate and 3.02 g (14.60 mmol) of 2,3-difluorobenzyl bromide. For work up, the residue is purified by flash chromatography (mobile phase: dichloromethane:methanol 30:1–10:1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:21])([CH3:20])[CH3:19])[C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:21])([CH3:19])[CH3:20])[C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)=[O:30]
Reactant: CSc1nccc(-c2cnc3c(C(C)(C)O)cccn23)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2cnc3c(C(C)(C)O)cccn23)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A solution of 2-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyridin-8-yl]-propan-2-ol (0.5 g) in DCM (100 mL) was cooled to 0° C., and MCPBA (0.376 g) was added. The reaction mixture was stirred at 0° C. for 2 h, then quenched with 10% Na2S2O3 (aq). The organic layer was washed with NaHCO3 (sat'd aq), separated, and dried over Na2SO4, filtered, concentrated, and titurated with EtOAc and filtered to provide 2-[3-(2-methylsulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyridin-8-yl]-propan-2-ol (0.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2[CH2:16]O)=[CH:4][C:3]=1[CH3:18].S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH2:16][C:9]1[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:18])[CH:4]=1
Reactant: Cc1cc(C)c(CO)c(-c2ccc(F)c(C)c2)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(CCl)c(-c2ccc(F)c(C)c2)c1
Reaction time: 1 h

Procedure:
4'-Fluoro-2-hydroxymethyl-3,3',5-trimethyl-1,1'-biphenyl (2.77 g, 11.3 mmoles) was added in divided portions to thionyl chloride (10 ml) and then heated with stirring in an 80° bath for one hour. The reaction was then diluted with 50 ml of dry toluene and the solvent was evaporated in vacuo to leave 3.27 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[I:10]N1C(=O)CCC1=O.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+]>C(Cl)Cl>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:6]([I:10])=[C:4]([CH:3]=1)[NH2:5]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(N)cc1Br
Agent: F[B-](F)(F)F
Agent: [IH2+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(I)c(N)cc1Br
Yield: 83.6 %

Procedure:
A solution of 3-bromo-4-methylaniline (5.00 g, 26.9 mmol), N-iodosuccinimide (4.53 g, 20.2 mmol) and bis(pyridine)iodonium tetrafluoroborate (2.70 g, 7.26 mmol) in DCM (100 mL) was stirred at room temperature overnight. The mixture was diluted with DCM, washed sequentially with saturated aqueous NaHSO3 and water, and dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 1%, 2% and 3%), to provide 5-bromo-2-iodo-4-methylaniline as a yellow solid (5.27 g, 63% yield). Mass spectrum m/z 312, 314 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J=0.6 Hz, 1H), 6.94 (s, 1H), 4.17-3.91 (br.s, 2H), and 2.25 (s, 3H).