Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cnn(C)c3)c2n1C
Temperature: 140 °C
Yield: 79.6 %

Procedure:
A mixture of 4-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]-pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.069 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 30 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 427 as a white solid (0.081 g, 81%). LCMS (Method K): RT 2.50 min [M+H]+ 392.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.24 (1H, s), 7.92 (1H, s), 7.67-7.59 (2H, m), 7.31 (2H, s), 7.12-7.08 (1H, m), 5.64 (1H, m), 3.93 (3H, s), 3.17 (3H, s), 1.58 (3H, d, J=6.74 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:9][CH2:10][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC1(c2ccc(Br)cc2)CCNCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 4-(4-bromophenyl)-4-methylpiperidine (285) (4.1 g, 16 mmol) in DCM (20 mL) was added (BOC)2O (5.7 g, 26 mmol). The resulting mixture was stirred at RT for 30 min before being diluted with water (10 mL). The mixture was extracted with DCM (10 mL×2). The combine organic layers were washed with brine, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 20% EtOAc in PE to give tert-butyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (286) (5 g, 88%) as colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:24]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1c(Cl)cccc1Cl
Yield: 29.1 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and 2,6-dichlorobenzoyl chloride (Aldrich, 0.2 mL, 1.4 mmol) in 25 mL THF were processed as in Example 132 to afford the title compound (0.12 g, 0.32 mmol, 30% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.28 (s, 6H), 3.27 (s, 3H), 3.74 (t, J=4.6 Hz, 2H), 4.34-4.44 (m, 2H), 7.19 (dd, J=8.8, 6.8 Hz, 1H), 7.28-7.34 (m, 2H); MS (DCI/NH3) m/z 359 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: N#Cc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (200 mg, 0.42 mmol) in 1,4-dioxane (1.5 mL) was added 6-bromonicotinonitrile (123 mg, 0.67 mmol), Pd(PPh3)2Cl2 (30 mg, 0.042 mmol), and Cs2CO3 (1 mL, 2 M) were added. The vessel was sealed with a septum and placed into the microwave cavity. Microwave irradiation of 100 W was used, and the temperature being ramped from rt to 120° C. Once this temperature was reached, the reaction mixture was held at this temperature for 30 min. After the mixture was cooled to rt, the mixture was filtered. The filtrate was extracted with EtOAc (4×20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile (120 mg, 62%). LC-MS Method 2 tR=1.33, m/z=398; 1H NMR (CDCl3): 1.13 (s, 3H), 1.19 (s, 3H), 1.58 (d, 3H), 2.22 (m, 2H), 2.27 (m, 2H), 2.40 (m, 1H), 2.89 (m, 1H), 3.49 (s, 1H), 5.73 (m, 1H), 7.11 (d, 2H), 7.28-7.38 (m, 5H), 7.80 (m, 3H), 8.00 (d, 1H), 8.93 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:27](=[O:36])[N:28]([CH3:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C=1>>[CH3:19][C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][C:27](=[O:36])[N:28]([CH3:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:3][CH:4]=2)[O:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Cc1c(-c2ccccc2)c(=O)oc2cc(O)ccc12
Agent: [I-]
Product: Cc1c(-c2ccccc2)c(=O)oc2cc(OC(=O)N(C)c3ccccc3)ccc12
Yield: 62.3 %

Procedure:
The title compound (120 mg, 52% yield, white solid) was prepared from 7-hydroxy-4-methyl-3-phenyl-chromen-2-one (126 mg, 0.50 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (175 mg, 0.51 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH2:13][CH2:14][OH:15])[CH3:12].[Li]CCCC.[CH3:21][S:22]SC>O1CCCC1>[CH3:12][C:5]1([CH2:13][CH2:14][OH:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([S:22][CH3:21])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: CC1(CCO)CCOc2ccc(Br)cc21
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(C)(CCO)CCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.8 %

Procedure:
To a chilled (−78° C.) solution of 1 g (3.7 mmol) of 2-(6-bromo-4-methylchroman-4-yl)ethanol in 10 mL of dry tetrahydrofuran was added 3.25 mL (8 mmol) of a 2.5 M solution of n-BuLi in hexanes. After 10 minutes, 0.66 mL (7.4 mmol) of dimethyldisulfide was added and the reaction was warmed to room temperature. After 30 minutes, the reaction was cooled to −78° C., quenched with saturated aqueous ammonium chloride, warmed to room temperature and extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with ethyl acetate-hexanes (0-30% gradient) to afford 0.43 g (50%) of 2-(4-methyl-6-methylsulfanylchroman-4-yl)ethanol as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[CH3:12][CH:13](O)[CH3:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:1][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:13]([CH3:14])[CH3:12]
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Reactant: CC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)n1cnc2c(Cl)nc(F)nc21
Reaction time: 8 h
Yield: 63.8 %

Procedure:
6-Chloro-2-fluoro-9H-purine (517.7 mg, 3 mmol), 2-propanol (198.3 mg, 3.3 mmol), PPh3 (866 mg, 3.3 mmol) was mixed under N2 in a 50 mL round-bottom flask at 0° C. DEAD (575 mg, 3.3 mmol) was added via syringe dropwise to the mixture. The temperature was raised to r. t. and the mixture was stirred overnight. Sovent was removed in vacuo and the resulting residue was chromatographed on silica gel (CH2Cl2/EtOAc, 4:1, Rf 0.62). The product was obtained as a white solid (411 mg, 64%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]([CH3:28])([CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:21]#[N:22]>>[C:21]([C:20]([NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])#[N:22]
Reactant: CC(N)(C#N)CS(C)(=O)=O
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CC(C#N)(CS(C)(=O)=O)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-Amino-3-methanesulfonyl-2-methyl-propionitrile (example 80a) as starting materials and isolated (1.22 g, 98%); MS (ESI, m/z): 406.6 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])(=[O:35])=[O:34])[C:27]=2[F:44])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[C:27]([F:44])=[C:28]([NH:32][S:33]([C:36]3[C:37]([F:43])=[CH:38][CH:39]=[CH:40][C:41]=3[F:42])(=[O:34])=[O:35])[CH:29]=[CH:30][CH:31]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(N)n3)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(-c2sc(C3CCNCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[5-(2-amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (94 mg, 0.145 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to give 52 mg of the title compound. MS (ESI): 547.1 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)C=CC=CC=1>>[C:1]1([N:9]2[C:10]3[C:15](=[C:14]([CH2:18][N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)[CH:13]=[CH:12][CH:11]=3)[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: C=O
Product: c1ccc(-c2nn(-c3ccccc3)c3cccc(CN4CCNCC4)c23)cc1
Yield: 155.8 %

Procedure:
By the procedure similar to that described in Example 19, 3-phenylindazole (2.91 g), paraformaldehyde (0.50 g) and N-phenylpiperazine (4.87 g) were treated to obtain 4.3 g of 1-N-phenylpiperazinomethyl-3-phenylindazole having a melting point between 109°-110° C after recrystallization from ethanol.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]([O:18]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:22][NH2:23]>C(O)C>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]([NH:22][NH2:23])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of Example 1B (2.65 g, 10 mmol) in ethanol (20 mL) was treated with hydrazine hydrate (3.12 mL, 100 mmol), heated to reflux for 18 hours, cooled to room temperature, and filtered. The resulting solid was washed with ethanol and dried under vacuum to provide 1.86 g (74%) of the desired product of sufficient purity for subsequent use.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.N([O-])=O.[Na+].[BrH:16]>O.[Cu]Br>[Br:16][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Br
Reactant: Nc1nc2ccc(F)cc2s1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc2nc(Br)sc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Slurry 2-amino-6-fluorobenzothiazole (0.255mol) in water (325mL), heat to reflux and add 48% hydrobromic acid (130mL). Maintain at reflux for 20 minutes, cool to 0° C. and add a solution of sodium nitrite (17.56g, 0.255mol) in water (90mL), maintaining a temperature of 0° C. Stir at 0° C. for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03g,0.293mol) in 48% hydrobromic acid (86mL) and water (225mL). Stir at room temperature for 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-6-fluorobenzothiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[NH2:16].P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[C:13]([F:12])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(N2CCOCC2)c(F)c1)c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A mixture of 5-chlorosalicylic acid (0.30 g, 1.738 mmol), 3-fluoro-4-morpholinoaniline (compound of Reference Example 74; 0.34 g, 1.738 mmol), phosphorus trichloride (0.08 ml, 0.869 mmol) and toluene (6 ml) was refluxed for 1.5 hours. The reaction mixture was cooled to the room temperature, and extracted with ethyl acetate after addition of water. The ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with diisopropyl ether to give the title compound (0.30 g, 49%) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C=O)C.O>[CH2:13]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH:6]=[CH:7]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2ccn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A solution of 6-bromoindole (5.0 g, 26 mmol) in dry DMF (45 mL) was cooled in an ice bath. Sodium hydride (2.2 g of 60% dispersion in oil, 55 mmol) was added. After stirring for 30 minutes under nitrogen at room temperature, the reaction mixture was cooled in an ice bath, and benzyl bromide (6.1 mL, 51 mmol) was added. After stirring for one hour at room temperature, the reaction mixture was poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was then washed with water and brine, then dried over anhydrous magnesium sulfate and evaporated to dryness. Purification of the residue by flash chromatography using hexane as an eluant and drying for 30 minutes at 60° C. yielded 1-benzyl-6-bromo-1H-indole (5.83 g, 80%) as a waxy solid, mp: 85-88° C. Mass spectrum (+ESI, [M+H]+) m/z 286; 1HNMR (500 MHz, DMSO-d6): δ 7.7 (d, 1H, J=0.61 Hz), 7.50-7.55 (m, 2H), 7.30 (t, 2H, J=7.3 Hz), 7.2-7.25 (m, 1H), 7.2 (d, 2H, J=8.4 Hz), 7.15 (dd, 1H, J=8.4 Hz and 1.7 Hz), 6.5 (dd, 1H, J=3.1 Hz and 0.77 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]([CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]([CH3:9])=[O:8].[OH-].[Na+].CN(C)[CH:24]=[O:25]>O>[NH:6]([CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:24]=[O:25])[C:7]([CH3:9])=[O:8]
Reactant: CN(C)C=O
Reactant: CC(=O)NCc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)NCc1ccc2[nH]cc(C=O)c2c1
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Phosphorus oxychloride (0.38 ml, 0.004 mol) was slowly added at 0° C. under nitrogen atmosphere to anhydrous N,N-dimethylformamide (1.9 ml, 0.025 mol). The mixture was stirred for 15 minutes and a solution of 5-acetamino methylindole (0.73 g, 0.0039 mol) in anhydrous N,N-dimethylformamide (4 ml) was added dropwise below 2° C. The mixture was stirred at room temperature for 3 h and diluted with an equal volume of water. The solution was neutralized (pH 8) with 1 N aqueous solution of sodium hydroxide. The mixture was evaporated to dryness under reduced pressure and the residue was recrystallized from ethyl acetate to afford 0.5 g (60%) of the entitled product (mp 182–184° C.).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2.Cl[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:24][C:23]([F:26])([F:25])[C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:13][CH2:12][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:11]3)[CH:22]=1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1cc(NCc2ccc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 130 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
{[2-(Trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 34, 100 mg, 0.467 mmol), 4-chloro-6-(trifluoromethyl)pyrimidine (Intermediate 26, 128 mg, 0.700 mmol) and potassium carbonate (142 mg, 1.027 mmol) were dissolved in DMSO (1 mL). The reaction mixture was stirred in the microwave for 1 hour at 130° C. The LC/MS showed product. The reaction mixture was poured into water and the product was extracted with ethyl acetate. Traces of water were removed with a phase separator. The solvent was removed under reduced pressure. Purification was done by MDAP. The most pure fractions were combined and diluted with DCM and washed with aqueous sodium bicarbonate. Traces of water were removed with a phase separator. The solvent was removed under reduced pressure to give the title compound (20 mg);
Reaction SMILES: [N+:1]([CH:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]2[CH2:16][CH2:17][CH:5]1[CH:6]=[CH:7]2)([O-:3])=[O:2].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].O1CCOCC1>C(O)(C)(C)C>[N+:1]([C:4]1([CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]2[CH2:16][CH2:17][CH:5]1[CH:6]=[CH:7]2)([O-:3])=[O:2]
Reactant: C=CC(=O)OC
Reactant: O=[N+]([O-])C1C2C=CC(CC2)C1c1ccccc1
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: COC(=O)CCC1([N+](=O)[O-])C2C=CC(CC2)C1c1ccccc1

Procedure:
Variant B: 0.18 mole of 2-nitro-3-phenyl-bicyclo[2.2.2]-oct-5-ene, 0.18 mole of methyl acrylate and 3.8 ml of Triton B in 50 ml of tert.-butanol and stirred for 24 hours, a further 0.18 mole of methyl acrylate and 70 mlof dioxan are then added and the mixture is heated to the reflux temperature for 24 hours. After cooling, the reaction mixture crystallizes. A little ethanol is added, the mixture is neutralized with 2N hydrochloric acid and the crystal sludge is filtered. Recrystallization of the crystals from isopropanol with the addition of animal charcoal gives crystals of melting point 127°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.I[CH2:31][CH:32]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:31][CH:32]2[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:33]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(F)ccc34)cnc21
Reactant: CC(C)(C)OC(=O)N1CC(CI)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Cn2nc(-c3cnc4c(n3)c(C=O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)C1
Yield: 63.6 %

Procedure:
2-(6-Fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (225 mg, 547 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (162 mg, 547 μmol) and cesium carbonate (534 mg, 1.64 mmol) in dimethylformamide (4 mL) were heated in a microwave at 150° C. for 30 min. The mixture was partitioned between ethyl acetate and water. Then the organic phase was washed with water 3 times, dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((6-fluoro-3-(7-formyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (202 mg, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.[Br-].C[S+](C)[CH:20]=[C:21]=[CH2:22].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][C:11](=[O:16])[C:12]3[C:21]([CH3:22])=[CH:20][O:15][C:13]=3[CH2:14]2)=[CH:7][CH:8]=1
Reactant: C=C=C[S+](C)C
Reactant: COc1ccc(C2CC(=O)CC(=O)C2)cc1
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C2CC(=O)c3c(C)coc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.5 %

Procedure:
A mixture of 5-(4-methoxyphenyl)cyclohexane-1,3-dione (0.95 g), dimethyl-1,2-propadien-1-yl sulfonium bromide (1.5 g), sodium ethoxide (0.31 g) and ethanol (10 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (20 ml), and to the solution was added p-toluenesulfonic acid(0.85 g). The mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate, and the mixture was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 6-(4-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.14 g).