Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=1[OH:17].IC>C1COCC1.CCCCCC>[CH3:1][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=1[OH:17]
Reactant: [Li]C(C)(C)C
Reactant: Oc1c(Br)cccc1C(F)(F)F
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(F)(F)F)c1O
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
t-Butyllithium (1.7 ml of a 1.8M solution of hexane; 3 equiv.) is added to THF (1 ml) and cooled to -78° C. under argon with stirring, and a solution of 2-bromo-6-trifluoromethylphenol in dry THF (1 ml; 1 mmol) is added dropwise via syringe. The reaction is stirred 30 minutes, and then iodomethane (340 mg; 2.4 equiv.) is added dropwise via syringe at -78° C. under argon, with stirring. The mixture is allowed to warm to 0° C. with stirring over 15 minutes, and stirring is continued for 45 minutes more. The reaction is then quenched with 1N HCl (3 ml) and extracted from 1N HCl (10 ml) with 3×10 ml portions of ether. The combined ether portions are washed with water (3×20 ml portions: pH tests neutral), and the solution is then dried (MgSO4), filtered, and concentrated in vacuo to give crude 2-methyl-6 -trifluoromethylphenol, which is chromatographed on silica gel with 5% ether in petroleum ether to give pure product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl.O>[C:25]1([C:22]2[CH:23]=[CH:24][N:10]3[C:11]=2[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:13][C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH:7]=[N:6][CH:5]=2)=[N:9]3)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.1 %

Procedure:
2-(5-Aminopyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80.0 mg, 0.201 mmol) was dissolved in CH2Cl2 (10 mL) and pyridine (0.0500 mL, 0.610 mmol) was added, followed by methanesulfonyl chloride (26.0 mg, 0.221 mmol). The reaction mixture was stirred at room temperature for 3 h then diluted with water (10 mL) and the aqueous solution was extracted with CH2Cl2 (25×2 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-64 as described in general methods) to obtain N-(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)methanesulfonamide (20.0 mg, 20.0%). LCMS Condition B-39: retention time 2.02 min, [M+1]=471.80. HPLC Condition B-32: retention time 6.96 min, Purity 99.40%. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.11 (s, 3H), 4.92 (d, J=4.8 Hz, 2H), 6.82 (d, J=2.8 Hz, 1H), 7.31 (dd, J=4.4 Hz, J=8.8 Hz, 2H), 7.46-7.61 (m, 8H), 7.79 (dt, J=2.0 Hz, J=7.6 Hz, 1H), 7.92 (d, J=2.8 Hz, 1H), 8.40 (d, J=4.0 Hz, 1H), 8.44 (t, J=2.4 Hz, 1H), 9.15 (d, J=2.0 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:25])([F:24])[C:5]1[CH:6]=[C:7]([C:11]2[C:12](=[O:23])[CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][C:15]=2[NH2:16])[CH:8]=[CH:9][CH:10]=1.[CH2:26](Br)[CH:27]=[CH2:28]>O.C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[F:3][C:4]([F:24])([F:25])[C:5]1[CH:6]=[C:7]([C:11]2[C:12](=[O:23])[CH:13]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][C:15]=2[NH:16][CH2:28][CH:27]=[CH2:26])[CH:8]=[CH:9][CH:10]=1
Reactant: C=CCBr
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)C1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)C1
Temperature: 25 °C

Procedure:
One gram of sodium hydroxide in 4.0 ml of water is added to a mixture of 4.0 g of 2-(3-trifluoromethylphenyl)-3-amino-5-phenyl-2-cyclopentenone in 80 ml of methylene chloride at room temperature followed by the addition of 1.46 g of allyl bromide and 0.27 g of benzyltriethylammonium chloride. The resulting two-phase mixture is stirred at room temperature until the reaction is completed. The reaction mixture is washed three times with water, dried over magnesium sulfate and concentrated in vacuo. The residue is typically purified by chromatography to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][C:13]1[O:14][C:15]2[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=2[C:17]=1[C:18]1[N:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=1.CCN(C(C)C)C(C)C>ClCCl.O1CCCC1.CO.[OH-].[Na+]>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:24][C:21]1[CH:20]=[N:19][C:18]([C:17]2[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[O:14][C:13]=2[CH3:12])=[CH:23][N:22]=1)=[O:5]
Reactant: Cc1oc2ccccc2c1-c1cnc(N)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc2ccccc2c1-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (8.0 mg, 35 μmol) was added to a stirred solution of 249 (13 mg, 0.1 mmol) and Hünig's base (37 μL, 28 mg, 0.2 mmol) in dichloromethane (0.5 mL) at room temperature. The reaction was stirred for 0.5 h. The solution was diluted with tetrahydrofuran (0.6 mL), methanol (0.3 mL) and 2 M sodium hydroxide solution (0.1 mL). The mixture was stirred and heated to 50° C. for 20 min then cooled to room temperature, diluted with dichloromethane (10 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-20% ethyl acetate in hexane) provided 250 (7.0 mg, 54%) as a solid: LRESIMS m/z 366.1 [M+H]+, calcd. for C20H14F2N3O2 366.1.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:26](=[O:30])[N:27]([CH3:29])[CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl.[Li+].[Cl-]>CC(O)C.O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:26](=[O:30])[N:27]([CH3:28])[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCC4)c3n2)nc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CC(C)O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 147.9 %

Procedure:
To a suspension of methyl 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate (1.0 g, 2.4 mmol) in 2-propanol (60 mL) were added LiOH (0.29 g, 5.0 eq) and water (12 mL) and the resulting mixture was stirred at 60° C. for 1 h. After cooling to room temperature, the reaction mixture was treated with 1N HCl (12.24 mL, 5 eq) and concentrated in vacuo which gave 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid as a light yellow solid (1.40 g) in 95% yield as the LiCl (5 equiv) co-salt and was used for the next reaction without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.30 (br s, 1H), 11.24 (br s, 1H), 9.03 (s, 1H), 8.88 (d, J=2.2 Hz, 1H), 8.31 (dd, J=8.7, 2.2 Hz, 1H), 8.11 (d, J=8.7 Hz, 1H), 6.81 (s, 1H), 4.79 (m, 1H), 3.06 (s, 6H), 2.41 (m, 2H), 2.02 (m, 4H), 1.67 (m, 2H); MS m/z 395.4 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C@H:11]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:14]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([CH2:47][CH3:48])=[CH:43][CH:42]=3)[CH:34]=2)[C@@H:13]([OH:49])[C@@H:12]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CI.[NH4+].[Cl-].Cl[C:64]1C=CC([C@@H]2[C@@H](OC)[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=CC=1CC1C=CC(CC)=CC=1>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:26]([O:25][C@@H:15]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@@H:12]([CH2:50][O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[C@H:13]([O:49][CH3:64])[C@H:14]1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][CH3:48])=[CH:45][CH:46]=2)[CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3[C@@H](O)[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Reactant: CCc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)[C@@H]3OC)ccc2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1ccc(Cc2cc([C@H]3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@@H](COCc4ccccc4)[C@@H]3OC)ccc2Cl)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
NaH (157 g, 1.5 eq, 60% containing in oil) was added into the solution of (1R,2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)cyclohexanol (4, R=Et, 2 g, 2.61 mmol) in anhydrous THF (10 mL) at 0° C. TBAI (0.1 eq) and CH3I (760 mg, 2 eq) were added into the reaction mixture after stirring for 1 h at the same temperature and the reaction mixture was stirred overnight at rt. Sat aq. NH4Cl was added to quench the reaction and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was evaporated to dryness. The residue (yellow oil, 2.05 g) was dissolved in THF:CH3OH=2:1, treated with 1,2-dichlorobenzene (1% mol ratio) and Pd/C (10%, 1/1 weight ratio), and stirred over 2 h under H2 atmosphere at room temperature. The reaction was monitored by LC-MS until completion. The mixture was filtered, and the filtrate was evaporated to dryness and purified by preparative HPLC to give target compound 16 (987 mg, (white solid, yield of 90.0%). 1H-NMR (400 MHz, CD3COCD3): δ 7.32-7.34 (2H, m), 7.22 (1H, dd, J=2.4, 8.0 Hz), 7.12 (4H, dd, J=8.4 Hz), 4.15 (2H, s), 3.93-3.98 (1H, m), 3.70-.3.75 (1H,m), 3.65-3.67 (1H, m), 3.54-3.60 (2H, m), 3.37 (1H, t, J=10.4 Hz), 3.30 (1H, t, J=8.8 Hz), 2.84 (3H, s), 2.52-2.65 (3H, m), 1.51-1.58 (1H, m), 1.17 (3H, t, J=7.2 Hz); MS (ESI+): 421 [M+H]+, 438 [M+NH4]+, 841 [2M+H]+, 858 [2M+NH4]+, (ESI+): 465 [M+HCOO]−.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[CH3:20])=[CH:14]/[C:15]([O:17]CC)=O)=[CH:9][CH:8]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(Cl)(Cl)Cl.C(=O)=O.C([Mg]Cl)(C)C.[NH4+].[Cl-]>C1COCC1.O>[CH3:27][O:26][N:25]([CH3:24])[C:15](=[O:17])/[CH:14]=[C:13](/[C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:21])[F:22])=[CH:12][CH:11]=1)\[CH3:20]
Reactant: CNOC
Reactant: CCOC(=O)/C=C(\C)c1ccc(OCCCC(F)(F)F)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: O=C=O
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)/C=C(\C)c1ccc(OCCCC(F)(F)F)cc1
Temperature: -61 °C
Reaction time: 1.5 h
Yield: 57.9 %

Procedure:
A solution of Intermediate 11B (2.67 g, 8.44 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.65 g, 16.9 mmol) in anhydrous THF (35 mL) was cooled to −61° C. (CHCl3/dry ice) under an atmosphere of Ar. To this solution was added 0.5 M isopropylmagnesium chloride (16.9 mL, 33.8 mmol) in THF slowly via a syringe. The reaction was stirred at −61° C. for 1.5 h, warmed to −20° C. (sat'd aq NaCl/ice) and stirred for 40 min, then warmed to 0° C. and stirred for 20 min. The reaction was poured into 10 mL of sat'd aq NH4Cl and 12 mL of water, and then extracted with EtOAc. The organic layer was washed with sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc in hexanes to provide Intermediate 11C (1.62 g, 58%) as a light brown oil. LCMS Anal. Calc'd for C16H20F3NO3 331.33, found [M+H] 332.2.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH3:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[CH:18]=[C:17]([CH2:19][CH3:20])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[N:15]=1.CCCCCCC.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:12]1[C:13]2[CH:18]=[C:17]([CH2:19][CH3:20])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[N:15]=[C:10]([CH3:9])[N:11]=1
Reactant: CCc1cc2c(Cl)nc(C)nc2n1Cc1ccccc1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: CCc1cc2c(OCC(=O)OC)nc(C)nc2n1Cc1ccccc1
Temperature: 60 °C
Yield: 62.6 %

Procedure:
To a suspension of 240 mg (10.0 mmol) of sodium hydride in 15 mL of benzene was added 783 mg (8.69 mmol) of methyl glycolate and 1.91 g (6.68 mmol) of 2-methyl-4-chloro-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine. The mixture was heated at 60° C. and monitored by TLC (silica, 7:3 heptane-ethyl acetate) for conversion to product. After 5 days the reaction was cooled to ambient temperature and partitioned by the addition of 10 mL of 2 M sodium hydrogen sulfate and 30 mL of ethyl acetate. The aqueous phase was extracted with 10 mL of ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated to 2.5 g of oil. The residue was purified by flash chromatography (200 g silica, 7:3 heptane-ethyl acetate) to provide 1.42 g (62%) of [[2-methyl-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.27 (t, J=7.4 Hz, 3H), 2.57 (q, J=7.4 Hz, 2H), 2.60 (s, 3H), 3.80 (s, 3H), 5.08 (s, 2H), 5.44 (s, 2H), 6.34 (s, 1H), 7.02 (d, J=7.1 Hz, 2H), 7.25 (m, 3H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[CH2:24]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[CH2:24]2)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1
Reactant: N[C@@H]1CCC[C@H](O)C1
Reactant: COC(=O)c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cnc(Cl)nc1N[C@@H]1CCC[C@H](O)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a stirring solution of methyl 2,4-dichloropyrimidine-5-carboxylate (4.00 g, 19.32 mmol) in THF (85 mL) was added DIEA (3.37 mL, 19.32 mmol). The resulting mixture was cooled to −78° C. in a dry ice/acetone bath. A solution of (1S,3R)-3-aminocyclohexanol (2.448 g, 21.25 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) in 40 mL THF was added at such a rate that the temperature remained at −78° C. The resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was then concentrated to dryness and diluted with 200 mL ethyl acetate and 75 mL of a 1:1 mixture of water and an aqueous saturated sodium bicarbonate solution. The layers were separated and the aqueous layer back-extracted with 100 mL ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil that solidified upon standing. The solid was triturated with diethyl ether (5 mL), filtered, rinsed with diethyl ether (5 mL) and dried in vacuo to afford methyl 2-chloro-4-((1R,3S)-3-hydroxycyclohexylamino)pyrimidine-5-carboxylate (3.7 g, 12.95 mmol, 67% yield) that was used without further purification. MS (ESI) m/z 286.0 [M+1]+.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:12])[CH:8]=[CH:9][CH2:10][OH:11].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:11][CH2:10]/[CH:9]=[CH:8]\[CH2:7][OH:12]
Reactant: OCC=CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC/C=C\COC1CCCCO1
Temperature: 0 °C
Reaction time: 48 h
Yield: 481.9 %

Procedure:
Dihydropyrane (9.1 ml, 100 mmol) was added dropwise to a cooled (0° C.) solution of 2-butene-1,4-diol (8.8 g, 10 mmol) and pyridinium paratoluenesulfonate (0.25 g, 10 mmol) in anhydrous dichloromethane:tetrahydrofuran (2:1). The mixture was stirred two days at 0° C. then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate:hexane 3:7) to give 8.3 g of the title compound (49%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([N:19]2[C:23]3[N:24]=[C:25]([CH3:41])[N:26]=[C:27]([N:28]4[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35]OS(C)(=O)=O)[CH2:30][CH2:29]4)[C:22]=3[C:21]([CH3:42])=[C:20]2[CH3:43])=[C:14]([CH3:44])[CH:13]=1.[Na+].[I-].OS([O-])(=O)=O.[K+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([C:6]#[N:7])[CH2:35][CH2:34][CH:31]1[CH2:32][CH2:33][N:28]([C:27]2[C:22]3[C:21]([CH3:42])=[C:20]([CH3:43])[N:19]([C:15]4[C:16]([CH3:18])=[CH:17][C:12]([Br:11])=[CH:13][C:14]=4[CH3:44])[C:23]=3[N:24]=[C:25]([CH3:41])[N:26]=2)[CH2:29][CH2:30]1)[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: Cc1nc(N2CCC(CCOS(C)(=O)=O)CC2)c2c(C)c(C)n(-c3c(C)cc(Br)cc3C)c2n1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)CCC1CCN(c2nc(C)nc3c2c(C)c(C)n3-c2c(C)cc(Br)cc2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.4 %

Procedure:
Under N2 atmosphere, to a solution of cyanoacetic acid ethyl ester (93 mg) in THF (3 mL) was added sodium hydride (33 mg) and the mixture was stirred for 30 minutes. Methanesulfonic acid 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethyl ester (300 mg) was added, and the mixture was heated at reflux for 3 hours. Cyanoacetic acid ethyl ester (93 mg) was added, and the reaction mixture was heated at reflux for 1 hour. And then NaI (7 mg) was added, and the mixture was heated at reflux for 2 hours. After cooling to room temperature, 5% aqueous KHSO4 solution was added into the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=4/1) to obtain the title compound (57 mg) as a colorless oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]([F:9])([F:19])[F:20])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.6 %

Procedure:
Benzyl bromide (66.17 ml, 95.35 g, 0.56 mol) was added to a mixture of 4-(trifluoromethoxy)phenol (90.26 g, 0.51 mol) and potassium carbonate (140.97 g, 1.2 mol) in dimethylformamide (160 ml) and the mixture was stirred at room temperature for 72 hours. The mixture was poured into water (1.5 l) and extracted with ethyl acetate (3×500 ml). The combined organic fractions were washed with aqueous sodium carbonate (saturated, 500 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (133.5 g, 99%). 1H NMR (360 MHz, CDCl3) δ 7.39 (5H, m), 7.14 (2H, d, J=9.0 Hz), 6.95 (2H, d, J=9.0 Hz), and 5.05 (2H, s).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[C:7]([CH3:31])=[C:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)[C:9]([CH:16]([CH3:18])[CH3:17])=[N:10]2.[OH-].[Li+]>O1CCCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:5]([CH2:4][C:3]([OH:32])=[O:2])=[C:6]2[C:11]=1[N:10]=[C:9]([CH:16]([CH3:17])[CH3:18])[C:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)=[C:7]2[CH3:31]
Reactant: COC(=O)Cc1ccc(Cl)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(Cl)ccc(CC(=O)O)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.9 %

Procedure:
A solution of [8-chloro-2-isopropyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yl]acetic acid methyl ester (0.04 g) in tetrahydrofuran (3.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.3 mL), and the resulting mixture was stirred at room temperature for six hours. The mixture was concentrated under reduced pressure and the pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid (3.0 mL). The mixture was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (5:95 to 98:2 by volume) to afford title compound as white solid (0.024 g).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:20]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([CH3:14])=[CH:16][CH:17]=1)[CH2:11]2
Reactant: Cc1ccc(CN)cc1
Reactant: COC(=O)c1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(CN2Cc3cccc(Cl)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol,), 4-methyl benzylamine (0.102 mL, 0.8 mmol), and K2CO3 (0.276 g, 2.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-chloro-2-(4-methyl-benzyl) 2,3-dihydro-isoindol-1-one (0.06 g, 34%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.22 (s, 2H), 4.78 (s, 2H), 7.12-7.46 (m, 7H). GC-MS: m/z 271 (M)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:11]=2[CH2:10][CH2:9]1.O1CCOCC1CN1CCC2C=C(OC)C(N)=CC=2CC1.Cl[C:42]1[N:47]=[C:46]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[S:55]([N:58]([CH3:60])[CH3:59])(=[O:57])=[O:56])[C:45]([Cl:61])=[CH:44][N:43]=1>>[Cl:61][C:45]1[C:46]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[S:55]([N:58]([CH3:60])[CH3:59])(=[O:57])=[O:56])=[N:47][C:42]([NH:19][C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([CH2:7][CH:2]4[CH2:3][O:4][CH2:5][CH2:6][O:1]4)[CH2:9][CH2:10][C:11]=3[CH:18]=2)=[N:43][CH:44]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCN(CC1COCCO1)CC2
Agent: COc1cc2c(cc1N)CCN(CC1COCCO1)CC2
Product: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CC2COCCO2)CC3)ncc1Cl

Procedure:
3-1,4-Dioxinan-2-ylmethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine, prepared in a similar manner as 3-1,4-Dioxinan-2-ylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine of Example 636b, was reacted with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide, in a similar manner as Example 601b, to yield desired product 2-[5-Chloro-2-(3-[1,4]dioxan-2-ylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N,N-dimethyl-benzenesulfonamide as a lyophylate (38%); 1H NMR (400 MHz, DMSO-d6) δ 9.82 (bs, 1H), 9.56 (s, 1H), 9.29 (s, 1H), 8.51 (bs, 1H), 8.29 (s, 1H), 7.84 (d, J=8.08 Hz, 1H), 7.71 (m, 1H), 7.46-7.37 (m, 3H), 7.08 (d, J=6.57 Hz, 1H), 4.07 (m, 1H), 3.82-3.60 (m, 6H), 3.48 (bs, H2O), 3.3-2.9 (m, 9 H), 2.75 (m, 1H), 2.65 (s, 6H); MS (m/e) 573.16 (M+H).