Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([O:14][CH3:15])(=[O:13])[CH3:12].CO.C(OC)(=O)CC(C)=O>>[C:1]([CH2:12][C:11]([O:14][CH3:15])=[O:13])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1
Reactant: COC(C)=O
Agent: COC(=O)CC(C)=O
Solvent: CO
Product: COC(=O)CC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A 1-I flask fitted with a mechanical stirrer, reflux condenser, and nitrogen sweep (to protect the Na), was immersed in a water bath to control temperature (i.e., to provide heat and to cool if need be). In the flask was placed 272.3 g (2 moles) of methyl benzoate; 74.1 g (1 mole) of methyl acetate; 1 gm. atom--23 g., Na; and 32 g (1 mole) of methanol (to react with the Na and to initiate the reaction). The flask was purged with nitrogen and was maintained under a positive nitrogen pressure throughout the reaction. The solution was heated to 80°-85° C. overnight, during which time all the Na metal was consumed. The resulting yellow heterogeneous solution was cooled to room temperature and poured into a separatory funnel containing 130 ml of concentrated hydrochloric acid and 200 g. of crushed ice. This was shaken and the lower aqueous phase removed. (In this step the Na in the Na methyl benzoyl acetate reacts with the HCl and is removed as NaCl.) The residual material was then washed with water, 2×100 mls, saturated NaHCO3 olution, 2×100 mls, and finally 2×100 mls of saturated brine (NaCl). (Byproduct methanol leaves with the water in the water washes.) The residual yellow organic phase was then transferred to a distilling flask and fractionated through a 12-inch Vigreux column at 0.5 mm Hg pressure. A forerun containing methyl benzoate and methyl acetoacetate was collected at 37°-42° C. at 0.5 mm Hg. This was followed by a fraction of 82.5 g. methyl benzoyl acetate boiling at 81°-84° C. at 0.5 mm Hg. Yield of the pure product methyl benzoyl acetate based on Na was 46.3%, as a water white liquid.
Reaction SMILES: Br[CH:2]([C:6]1[CH:7]=[CH:8][C:9]([O:16][CH3:17])=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:11]=1)[C:3](=O)[CH3:4].[C:18]([NH:21][C:22]([NH2:24])=[S:23])(=[O:20])[CH3:19]>C(O)C>[CH3:17][O:16][C:9]1[CH:8]=[CH:7][C:6]([C:2]2[S:23][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[N:24][C:3]=2[CH3:4])=[CH:11][C:10]=1[S:12](=[O:14])(=[O:13])[NH2:15]
Reactant: CC(=O)NC(N)=S
Reactant: COc1ccc(C(Br)C(C)=O)cc1S(N)(=O)=O
Solvent: CCO
Product: COc1ccc(-c2sc(NC(C)=O)nc2C)cc1S(N)(=O)=O

Procedure:
5-(1-Bromo-2-oxo-propyl)-2-methoxy-benzenesulfonamide (Example 30b) (0.2 g, 0.64 mmol) and N-acetylthiourea (0.075 g, 0.64 mmol) in ethanol (3 ml) are stirred at 70° C. for 4 hours. The mixture is concentrated and the residue is recrystallised from ethanol to give an off-white solid. MH+ (ESMS): Mp 341.9° C.
Reaction SMILES: [O-]S([O-])(=O)=O.[Ca+2].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:14]([O-])([OH:16])=[O:15].[N+](C1C=CC=CC=1)([O-])=O>C(Cl)(Cl)Cl>[N+:14]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:13])([O-:16])=[O:15]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A 100g portion of soluble anhydrite was added to a solution of 32.9g toluene in 100 ml chloroform. Then a 22.6g portion of anhydrous nitric acid was added to the dispersion over a 30-minute period. Stirring at 25°C was continued for an additional 2 1/2 hour period. Nitrobenzene was added before the last half hour period and was used as the internal standard. Gas chromatographic analysis showed a 93.2% yield of nitrotoluene with the proportion being 49.1% ortho, 2.1% meta, and 48.8% para.
Reaction SMILES: [F:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:3]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(F)c2N2CCOCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(CN2CCNCC2)c1N1CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[3-fluoro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate (1.00 g, 2.64 mmol, 1.00 equiv), dichloromethane (20 mL). The mixture was cooled to 0° C. Trifluoroacetic acid (2 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 0.600 g (crude) of 4-[2-fluoro-6-(piperazin-1-ylmethyl)phenyl]morpholine as light yellow oil. LCMS (ESI, m/z): 280 [M+H]+.
Reaction SMILES: Cl[C:2]1C(F)=C(C(F)=C[CH:9]=1)C=O.[Br:12][C:13]1[C:18]([CH:19]=[O:20])=[C:17]([F:21])[C:16]([Cl:22])=[CH:15][CH:14]=1>>[Br:12][C:13]1[C:18]([C:19](=[O:20])[CH:2]=[CH2:9])=[C:17]([F:21])[C:16]([Cl:22])=[CH:15][CH:14]=1
Reactant: O=Cc1c(F)ccc(Cl)c1F
Reactant: O=Cc1c(Br)ccc(Cl)c1F
Product: C=CC(=O)c1c(Br)ccc(Cl)c1F

Procedure:
1-(6-Bromo-3-chloro-2-fluorophenyl)prop-2-en-1-one was prepared using a procedure analogous to intermediate 1 except that 3-chloro-2,6-difluorobenzaldehyde was replaced with 6-bromo-3-chloro-2-fluorobenzaldehyde. 1H NMR (500 MHz, CDCl3) δ 7.33-7.41 (m, 2H), 6.64 (dd, J=17.6, 10.2 Hz, 1H), 6.25 (d, J=10.7 Hz, 1H), 6.07 (d, J=17.6 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[Li]CCCC.Cl>C1COCC1.C1(C)C=CC=CC=1>[F:19][C:17]1[CH:18]=[C:2]([B:20]([OH:25])[OH:21])[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:16]=1
Reactant: Fc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1cc(F)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: -20 °C
Yield: 180.1 %

Procedure:
2-(3-Bromo-5-fluorophenoxy)-5-(trifluoromethyl)pyridine (2 g, 0.005 mol) and tri-isopropyl borate (1.6 mL, 0.007 mol) were dissolved in dry THF (40 mL) and toluene (10 mL) under inert atmosphere and cooled to −78° C. n-BuLi (4.48 mL, 0.005 mol) was then added dropwise at −78° C. The reaction was warmed to −20° C. and 2N HCl (2 mL) was added and then the mixture was warmed to RT. The reaction mixture was concentrated and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (2.71 g, 70%); m/z (300.4, M− H−).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[C:17]([F:26])[CH:16]=3)[CH2:12][NH:11][CH2:10]2)[O:6][N:5]=1)[CH3:2].C(N(CC)CC)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36].O>ClCCl>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[C:17]([F:26])[CH:16]=3)[CH2:12][N:11]([C:35]([O:37][C:38]3[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=3)=[O:36])[CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: CCOc1noc(C2CNCC(c3ccc(OC(F)(F)F)c(F)c3)C2)n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1noc(C2CC(c3ccc(OC(F)(F)F)c(F)c3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
195 mg (0.48 mmol) of 3-(3-ethoxy-1,2,4-oxadiazol-5-yl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]piperidine were initially charged in 4.5 ml of dichloromethane, cooled to 0° C. and admixed with 0.27 ml (193 mg, 1.91 mmol) of triethylamine and 96 mg (0.48 mmol) of 4-nitrophenyl chloroformate. The reaction mixture was stirred at RT for 1 hour and admixed with water, and the organic phase was removed. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 290 mg (94% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[NH:8][CH:7]=[C:6]2[C:13]1[N:21]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41].C1CCCCC1.[C:50]([O:53]CC)(=[O:52])[CH3:51]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:51][C:50]([OH:53])=[O:52])[N:8]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:7]=[C:6]2[C:13]1[N:21]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=1
Reactant: COC(=O)CBr
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c[nH]c2cc1O
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCCCC1
Product: COC(=O)Cn1cc(-c2cc3cccnc3n2S(=O)(=O)c2ccc(C)cc2)c2cc(OC)c(OCC(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97 %

Procedure:
A solution of 5-methoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-6-ol (0.043 g; 100 μmol), in solution in dimethylformamide (10 ml), is placed in a 1.3×10 cm hemolysis tube, then potassium carbonate (0.027 g; 200 μmol) is added and the mixture is agitated at ambient temperature for 5 minutes. Methyl bromoacetate (0.028 ml; 300 μmol) is added and the mixture is then heated at 50° C. for 4 hours, the TLC control (eluent: 50/50 v/v cyclohexane/ethyl acetate) showing that the reaction has come to an end. The reaction mixture is run into 5 ml of distilled water and the reaction mixture is then extracted with ethyl acetate (15 ml). The combined extracts are washed with water (20 ml), dried over magnesium sulfate, filtered, and evaporated to give a crude compound which is purified by chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (60/40 v/v). The fractions containing the expected compound are combined and evaporated to give the methyl ester of {5-methoxy-1-methoxycarbonylmethyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-6-yloxy}acetic acid (0.056 g; 97%), the characteristics of which are as follows:
Reaction SMILES: [O:1]1CCCC1.[O:6]1[CH2:8][CH:7]1[CH2:9][N:10]([CH2:20][CH:21]1[CH2:23][O:22]1)[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].S(=O)(=O)(O)O.[Cl-].[Na+]>C(OCC)(=O)C>[OH:22][CH2:23][CH:21]1[O:1][CH:7]([CH2:8][OH:6])[CH2:9][N:10]([S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])[CH2:20]1
Reactant: O=S(=O)(c1ccccc1)N(CC1CO1)CC1CO1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)N1CC(CO)OC(CO)C1
Reaction time: 144 h

Procedure:
Tetrahydrofuran (40 mL) was added to N,N-bis(2-oxiranylmethyl)benzenesulfonamide (from step (i) (alternative A) above; 10 g, 37.1 mmol), followed by dilute sulfuric acid (10 mL of 1 M), and the mixture stirred for 6 days (reaction is complete within 1 day). Solid sodium chloride (3 g) and ethyl acetate (40 mL) were added, and the mixture stirred for 1 hour. The organic phase was separated and washed with aqueous ammonium chloride (10 mL of 10%). The organic phase was concentrated under reduced pressure before toluene was added (50 mL). The mixture was concentrated again to leave the title compound as a crude oil (10.65 g). This material was employed directly in subsequent reactions without any further purification.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]#[N:22])=[N:6][N:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[CH:8]=1)(=O)[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].O1CCC[CH2:31]1>C1(C)C=CC=CC=1.CCOCC>[C:21]([C:5]1[C:4]([C:1]([CH3:31])=[CH2:2])=[CH:8][N:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:6]=1)#[N:22]
Reactant: CC(=O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Reactant: C1CCOC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=C(C)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-acetyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.75 g) in tetrahydrofuran (5 ml) cooled to −40° C. under an atmosphere of nitrogen was added μ-chloro-μ-methylene-[bis(cyclopentadienyl)titanium]dimethylaluminium (5.18 ml of a 0.5M solution in toluene) and the mixture was stirred for 15 minutes then allowed to warm to room temperature. After 2 hours at room temperature 0.1M aqueous sodium sulphate solution was added dropwise until effervescence ceased. The reaction mixture was diluted with ether (50 ml), washed with aqueous sodium sulphate solution, dried and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane: hexane (1:1). Combination and evaporation of suitable fractions provided the title compound as a tan solid m.p. 63-64° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19].ClC(Cl)C.Cl>N1C=CC=CC=1>[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][S:18](=[O:20])(=[O:19])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reaction time: 0.33 h

Procedure:
8.96 g (50 mmol) of 4-fluoro-2-trifluoromethylaniline is dissolved in 100 ml of pyridine and under cold conditions combined under stirring with 9.52 g (50 mmol) of 3-chlorosulfonylpropionic acid methyl ester (98.5%). The mixture is agitated for 20 minutes, heated for 4 hours to 40° C., and the pyridine is exhausted under vacuum. The residue is distributed between dichloroethane and 4N hydrochloric acid. The organic solution is washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is purified by column chromatrography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])(=O)=O)=CC=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCS(C)(=O)=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
(4-Chloro-2-nitro-phenyl)-(3-methanesulfonyl-propyl)-carbamic acid tert-butyl ester was prepared according to Scheme 1. To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF (5 mL) was added NaH (170 mg, 4.3 mmol, 60 wt %). The mixture was stirred for 30 min at RT, then 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (0.75 g, 2.56 mmol) was added. The solution was heated to 50° C. and stirred for overnight. After cooled to RT, H2O (30 mL) was added and the solution was extracted with DCM (40 mL×3). The organic layer was dried over anhydrous and concentrated. The residue was purified by prep-TLC (DCM) to give tert-butyl 4-chloro-2-nitrophenyl(3-(methylsulfonyl)propyl)carbamate (360 mg, yield: 69%) as pale oil. MS obsd. (ESI+) [(M+H)+]: 393.0.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(C(C)C)CC)(C)C>CN(C=O)C.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>[CH3:14][Si:13]([C:11]#[C:12][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1)([CH3:16])[CH3:15]
Reactant: Brc1cnc2cnccn12
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnc2cnccn12
Temperature: 50 °C
Yield: 91.7 %

Procedure:
A mixture of 3-bromoimidazo[1,2-a]pyrazine (0.15 g, 0.76 mmol; prepared according to J. Bradac, et al. J. Org. Chem. (1977), 42, 4197-4201), 0.09 g (0.91 mmol) of ethynyltrimethylsilane, 0.044 g (0.038 mmol) of Pd(PPh3)4, 0.014 g (0.076 mmol) of Cul, and 0.26 mL (1.52 mmol) of diisopropylethylamine in 3.8 mL of DMF was heated at 50° C. overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide 0.15 g of product: 216 m/z (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]([NH2:24])=S)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1.O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]#[N:24])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(NC(N)=S)ccc1-n1cccn1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(NC#N)ccc1-n1cccn1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 87 %

Procedure:
A mixture of the compound (315 mg) obtained in Example 2c, p-toluenesulfonyl chloride (190 mg) and pyridine (2 ml) was stirred at room temperature for 70 minutes. Water was added to the reaction mixture and extraction with methylene chloride was conducted. The organic layer was washed with brine, dried with anhydrous sodium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1) to give the titled compound (yield, 87%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
To a solution of N-butyl-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (73 mg, 0.25 mmol) in anhydrous acetonitrile (5 mL) was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (75 mg, 0.25 mmol) and N,N-diisopropylethylamine (43 μL, 0.25 mmol). The resulting solution was heated at reflux under nitrogen for 2 h and then cooled to room temperature. The solvent was removed in vacuo and the residue diluted with water (10 mL) and extracted with CH2Cl2 (30 mL). The organic extract was separated by hydrophobic frit and the solvent removed in vacuo. Purification by SPE (Silica, 5 g) eluting 99:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (105 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[N:12]([CH:13]=1)[CH:11]=[CH:10][CH:9]=[CH:8]2)([O:3][CH3:4])=[O:2].[C:14]([O:17][CH2:18][C:19](Cl)=[O:20])(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:18][C:19]([C:13]1[N:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][C:5]=1[C:1]([O:3][CH3:4])=[O:2])=[O:20])(=[O:16])[CH3:15]
Reactant: COC(=O)c1cc2ccccn2c1
Reactant: CC(=O)OCC(=O)Cl
Product: COC(=O)c1cc2ccccn2c1C(=O)COC(C)=O

Procedure:
Following the procedure of Example 3, reaction of 2-carbomethoxyindolizine with acetoxyacetyl chloride gave 3-acetyloxyacetyl-2-carbomethoxyindolizine (IX). Reaction of IX with 1.5 equiv of anhydrous hydrazine in dry ethanol gave 4-hydroxymethylpyridazino[4,5-b]indolizin-1-one which upon refluxing with excess POCl3 gave 1-chloro-4-chloromethylpyridazino[4,5-b]indolizine (X). Compound X (1.0 g, 4.0 mmol) was combined with excess N,N-diethylaminopropylamine (2.68 mL, 17 mmoL) in N-methylpyrrolidinone (2 mL) containing TEA (0.74 mL, 1.2 equiv.) and 1.2 equiv. of ammonium chloride (vigorous initial reaction with gas evolution). When the reaction subsided the stirred reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the volatiles were removed by vacuum distillation. The residue was dissolved in methylene chloride and extracted with water (3 times), dried (MgSO4), and the solvent evaporated. The residue was purified by flash column chromatography on silica gel eluting with 20% methanol in methylene chloride containg 2% ammonium hydroxide. The isolated free base was converted to the tetra hydrochloride salt using ethereal HCl in ether m.p. 120°-123° C.
Reaction SMILES: [C@H:1]12[CH2:28][C@H:4]([N:5]([C:7]3[N:12]=[C:11]([C:13]4[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=4)[N:10]=[C:9]4[N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:21]=[CH:22][C:8]=34)[CH2:6]1)[CH2:3][O:2]2.C(N(CC)CC)C.ClC(Cl)(O[C:40](=[O:46])[O:41][C:42](Cl)(Cl)Cl)Cl.N(C1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C[C@@H]4C[C@H]3CO4)N=2)=CC=1)=[C:49]=[O:50]>ClCCl.C(O)CO>[OH:50][CH2:49][CH2:42][O:41][C:40](=[O:46])[NH:17][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:10]=[C:9]3[N:20]([CH2:23][C:24]([F:26])([F:27])[F:25])[N:21]=[CH:22][C:8]3=[C:7]([N:5]3[CH2:6][C@@H:1]4[CH2:28][C@H:4]3[CH2:3][O:2]4)[N:12]=2)=[CH:19][CH:18]=1
Reactant: Nc1ccc(-c2nc(N3C[C@@H]4C[C@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C=Nc1ccc(-c2nc(N3C[C@@H]4C[C@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Solvent: CCN(CC)CC
Solvent: OCCO
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc(N3C[C@@H]4C[C@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1)OCCO
Reaction time: 8 h

Procedure:
A solution of 4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (26 mg, 0.07 mmol) in dichloromethane (2 mL) was treated with triethylamine (86 μL), followed by a solution of triphosgene (10 mg, 0.03 mmol) in dichloromethane (1 mL). After the passage of 20 minutes, the appropriate nucleophile—in the case, ethylene glycol (excess)—was added to the (1S,4S)-5-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (“isocyanate”) mixture. After standing overnight at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 15% acetonitrile/85% of 0.1% aqueous trifluoroacetic acid to 88% acetonitrile to provide 2-hydroxyethyl(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)carbamate. MS (ES+): 479.2 (M+H)+