Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:18][C:19](=[O:36])[CH2:20][CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[CH2:11]([O:18][C:19](=[O:36])[CH2:20][CH2:21][C:22](=[CH2:1])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCC(=O)OCc1ccccc1)CCC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(CCC(=O)OCc1ccccc1)CCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Methyltriphenylphosphonium bromide (536 mg, 1.5 mmol) was suspended in anhydrous THF (1.0 mL) at −5C. A THF solution of NaHMDS (1.0 M, 1.5 mL, 1.5 mmol) was added dropwise to keep the temperature below 0° C. The mixture was stirred at 0° C. for 0.5 h before cooled to −78° C. To this ylid solution was added a solution of dibenzyl-4-oxopimelate (354 mg, 1.0 mmol) in THF (1.0 mL) dropwise to keep the temperature below −50° C. The temperature was allowed to rise to room temperature in 1.5 h with stirring after addition. The reaction mixture was then poured in icy water (25 mL) and extracted with Et2O (2×25 mL). The organic layer was washed with brine (20 mL) and dried over Na2SO4. The solvent was removed under vacuum and the residue was subjected to silica chromatography (EtOAc/hexanes, up to 1/10) to give compound B4 (197 mg). The yield was 56%. 1H NMR (200 MHz, CDCl3) δ 7.37 (m, 10H), 5.11 (s, 4H), 4.78 (d, 2H, J=1.1 Hz), 2.53 (m, 4H), 2.39 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 173.3, 146.6, 136.4, 129.0, 128.7, 110.5, 66.9, 33.2, 31.6; MS (MALDI-TOF) calcd (M+Na+) 375.4, found 375.6.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][C@H:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[C:15]([CH3:16])[C:7]=2[C@@H:6]([CH2:5][C:4]([OH:19])=[O:3])[O:10]1
Reactant: CCOC(=O)C[C@H]1OB(O)c2cc(OC)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c2c(c1)B(O)O[C@@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3R)-(1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.68 g, 2.57 mmol) in THF (7 mL) was added a solution of LiOH (0.31 g, 12.87 mmol) in water (7 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours then acidified to pH 2 using 6M hydrochloric acid and extracted with EtOAc. The organic extracts were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (0-5% MeOH in DCM) to give (3R)-(1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid as an off white solid (0.45 g, 74%). mp 48.2-50° C. 1HNMR (400 MHz, DMSO-d δ 9.10 (s, 1H), 7.02 (d, J=2.34 Hz, 1H), 6.83 (d, J=1.76 Hz, 1H), 5.42 (dd, J=9.67, 2.64 Hz, 1H), 3.73 (s, 3H), 3.01 (dd, J=15.38, 2.49 Hz, 1H), 2.24 (s, 3H), 2.03 (m, 1H). MS (ESI) m/z: 235 (M−1)−. HPLC purity: 98.31% (Maxplot), 97.78% (220 nm).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])([O-])=O>CCO>[NH2:1][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]
Reactant: N#Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Solvent: CCO
Product: N#Cc1cccc(Oc2ccccc2N)c1
Yield: 98.9 %

Procedure:
A solution of 3-(2-nitrophenoxy)benzonitrile (1.21 g, 5 mmol, 1.0 equiv) in 30 mL of EtOH was treated with SnCl22H2O (3.38 g, 3 equiv) at reflux for 4 h. The volatile was evaporated and the residue was redissolved in EtOAc, washed with saturated aqueous NaHCO3 and 1N NaOH. The organic layer was dried over MgSO4, filtered and evaporated to give 3-(2-aminophenoxy)benzonitrile (1.04 g, 99%). MS found for C13H11N2O (M+H)+: 211.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[NH2:7])([CH3:3])[CH3:2].O[CH2:14][CH:15]([CH2:17]O)O.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>O.C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[C:6]2[C:8]([CH:14]=[CH:15][CH:17]=[N:7]2)=[CH:9][C:10]=1[O:11][CH3:12])([CH3:3])[CH3:2]
Reactant: OCC(O)CO
Reactant: COc1ccc(N)cc1C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2cccnc2cc1C(C)C
Temperature: 100 °C
Yield: 54.3 %

Procedure:
A mixture of 3-isopropyl-4-methoxyaniline (4.22 g, 23.6 mmol), 5.87 g (63.7 mmole) of glycerol and 3.25 g (14 mmol) of As2O5 was heated to 100° C. with stirring At 100° C., 4.0 mL of concentrated H2SO4 was added dropwise. The mixture was heated at 150-160° C. for six hours, then cooled to 80° C., and 20 mL water was added, followed by aqueous saturated NaHCO3 until the mixture reached pH7-8. The mixture was diluted with 100 mL of water and 300 mL of ethyl acetate and the solution mixture was decanted from insolubles. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography with silica eluting with 20% ethyl acetate in hexanes to give 2.58 g of 7-isopropyl-6-methoxyquinoline, together with 0.65 g of 6-hydroxy-7-isopropylquinoline as a minority product.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:11][C:12]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15]2)=[O:13])[CH:4]=1.Cl>CO.O1CCOCC1>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:11][C:12]([N:14]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15]2)=[O:13])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)COCc2cc(C(F)(F)F)ccn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCN(C(=O)COCc2cc(C(F)(F)F)ccn2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [(3S)-1-({[4-(trifluoromethyl)pyridin-2-yl]methoxy}acetyl)pyrrolidin-3-yl]carbamate (300 mg, 0.74 mmol) in methanol (3 mL) was added a 4.0 M solution of HCl in 1,4-dioxane (6 mL). After being stirred for 0.5 h at room temperature, the solution was concentrated under vacuum to give the title compound. MS (M+H) 304.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]([C:17]([C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)=[O:18])=[CH:7]1.[CH3:29][NH:30][CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]([C:17]([C:19]2[CH:20]=[N:21][C:22]([N:30]([CH3:31])[CH3:29])=[CH:23][CH:24]=2)=[O:18])=[CH:7]1
Reactant: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Reactant: CNC
Product: CN(C)c1ccc(C(=O)c2cn(Cc3cccc(Cl)c3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Example 141, from 151 mg (0.37 mmol) of 1-(3-chloro-benzyl)-3-(6-chloro-pyridine-3-carbonyl)-1H-quinolin-4-one and 2 mL 2 M dimethylamine solution. Yield: 127 mg of a yellow powder. LC-MSD, m/z for C24H20ClN3O2 [M+H]+=418.1, 420.1; HPLC retention time: 1.6 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1OC.[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:14]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
60.6 g (324.2 mmol) of 2-bromoanisole was added dropwise to a dichloromethane solution (350 ml) containing 51.8 g (388.6 mmol) of aluminum chloride and 45.6 g (324.3 mmol) of benzoyl chloride which was cooled to 0° C. After addition, the resulting mixture was stirred for 2 hours. After a reaction, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (21) as 61.3 g (210.7 mmol, yield of 75%) of a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH:14]=[CH2:15]>O1CCCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH:14]=[CH2:15])[N:3]=1
Reactant: C=CCC(C)(C)CN
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: C=CCC(C)(C)CNc1nc(Cl)cc(Cl)n1
Reaction time: 4 h

Procedure:
4.59 (25 mmoles) of 2,4,6-trichloropyrimidine are added to a solution of 6.23 g (55 mmoles) of 5-amino-4,4-dimethyl-1-pentene in 50 ml of tetrahydrofuran at room temperature, the reaction mixture is stirred at the same temperature for 4 hours, then evaporated. The evaporation residue is distributed between 60 ml of chloroform and 5 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 10 ml of water each, then dried and evaporated. The evaporation residue is subjected to chromatography on a silica gel column by using mixtures of hexane and ethyl acetate as eluents. Elution with a 19:1 hexane/ethyl acetate mixture gives 4,6-dichloro-2-[(2,2-dimethyl-4-penten-1-yl)amino]pyrimidine as an oily product in a yield of 2.62 g (40.3%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[C:14]([OH:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:23]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[C:14]([O:20][CH3:23])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2ccc(CO)c(O)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(CO)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To 190 mg of 4-hydroxy-5-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 1 mL of iodomethane, 200 mg of K2CO3 and 3 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent gave 200 mg of 4-methoxy-5-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.CCO>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(-c2nnnn2C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(-c2nnnn2C)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
10% Pd on carbon (7 mg, 0.268 mmol) was added to a solution of 5-(3-methoxy-4-nitrophenyl)-1-methyl-1H-tetrazole (Preparation 195, 63 mg, 0.268 mmol) in EtOAc (1.2 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. EtOH (0.5 mL) was added and the reaction mixture was stirred for 1.5 hours. The reaction was filtered and the filtrate concentrated in vacuo to afford the title product as a white solid (52 mg, 95%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([S:13]([C:16]2[C:17]([CH2:27][CH3:28])=[N:18][N:19]3[C:24](Cl)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([CH2:27][CH3:28])=[N:18][N:19]3[C:24]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: CCc1nn2c(N3CCNCC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 27.7 %

Procedure:
0.64 g (7.4 mmol) of piperazine in 10 ml of DMF was added to a solution of 1.0 g (3 mmol) of 3-benzenesulphonyl-7-chloro-2-ethyl-5-methyl-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and stirred at 60° for 2 hrs. The DMF was evaporated in a high vacuum, the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with 50 ml of CH2Cl2 and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 9:1) and crystallization from EtOH yielded 0.32 g (27%) of 3-benzenesulphonyl-2-ethyl-5-methyl-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 150-150.8°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1C[O:16][CH2:15]C1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:15](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: C1CCOC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
To a solution of 2-amino-5-methoxy-benzoic acid (1.2 g, 7 mmol) in anhydrous THF (50 mL) triethylamine (1.0 mL, 7 mmol) was added and the mixture was cooled down to 0° C. Then triphosgene (2.0 g, 7 mmol) was added portion wise and the reaction allowed to reach room temperature and left stirring for 18 hours. 1 mL of H2O was carefully added to the mixture and the solvent was removed under reduced pressure. The residue was precipitated from H2O, affording 1.3 g of the titled compound (96% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13]>>[Cl:9][C:10]1[CH:11]=[C:12]([NH:13][C:2]2[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: Nc1cccc(Cl)c1
Product: Nc1cc(Nc2cccc(Cl)c2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 105A from 6-chloro-pyrimidin-4-ylamine and 3-chloroaniline.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[CH:20][N:21]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])(C)(C)C.[Cl:31]N1C(=O)CCC1=O>C(#N)C.O1CCCC1>[Cl:31][C:20]1[N:21]=[C:17]([C@@H:8]([NH2:7])[C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[NH:18][C:19]=1[C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[F:29]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc(I)cc2F)[nH]1
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)[C@H](N)c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1
Reaction time: 1 h

Procedure:
To a solution of {(1S,2S)-1-[5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-carbamic acid tert-butyl ester (1.10 g, 2.11 mmol) in 10:1 v/v acetonitrile/tetrahydrofuran (20 mL) under an atmosphere of nitrogen was added N-chlorosuccinimide (352 mg, 2.64 mmol) and the mixture was refluxed for 24 hours. The reaction was concentrated in vacuo, diluted with ethyl acetate (60 mL) and washed with saturated sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. To a solution of the crude product in dichloromethane (20 mL) under an atmosphere of nitrogen was added trifluoroacetic acid (6 mL) and the mixture was stirred for one hour. The reaction mixture was concentrated in vacuo then basified with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (2×50 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (1S,2S)-1-[4-chloro-5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propylamine which was used in the subsequent step without further purification (860 mg, 89%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:17]=[C:16](F)[C:15]([C:19]2[S:23][C:22]([NH2:24])=[N:21][N:20]=2)=[C:14]([F:25])[CH:13]=1>C1COCC1>[CH2:3]([O:10][C:16]1[CH:17]=[C:12]([Br:11])[CH:13]=[C:14]([F:25])[C:15]=1[C:19]1[S:23][C:22]([NH2:24])=[N:21][N:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1nnc(-c2c(F)cc(Br)cc2F)s1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nnc(-c2c(F)cc(Br)cc2OCc2ccccc2)s1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 37.5 %

Procedure:
A stirred suspension of NaH (60% dispersion in mineral oil, 151 mg, 3.77 mmol) in THF (10 mL) was cooled under nitrogen in an ice bath. To this suspension was added a solution of benzyl alcohol (0.372 mL, 3.59 mmol) in THF (5 mL) drop-wise. On completion of addition, the resulting suspension was stirred at ice bath temperature for 5 minutes, then room temperature for 10 minutes, before being slowly added to a stirred, ice-bath cooled suspension of 5-(4-bromo-2,6-difluorophenyl)-1,3,4-thiadiazol-2-amine (1 g, 3.42 mmol) in THF (20 mL). The resulting yellow/brown suspension was stirred at ice bath temperature for 15 minutes, room temperature for 1 hour then heated at 50° C. for 18 hours. The reaction was quenched by addition of saturated NH4Cl(aq) (30 mL), diluted with water (30 mL), and extracted with EtOAc (100 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated onto silica gel and the crude material was purified by flash chromatography using an 80 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a pale yellow solid (488 mg, 37% yield). LC-MS: Rt 1.19 min; MS m/z 282.0 M+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 7.27-7.47 (m, 9H), 5.28 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](=[N:14]O)[CH3:13])=[CH:10][N:11]=2)[CH:2]=1.[C:16](=[O:19])([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](=[N:14][O:19][C:16]3[N:11]=[CH:7][CH:3]=[CH:2][N:1]=3)[CH3:13])=[CH:10][N:11]=2)[CH:2]=1
Reactant: CC(=NO)c1cnc(-c2cccnc2)s1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(=NOc1ncccn1)c1cnc(-c2cccnc2)s1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A suspension of 1-[2-(3-pyridyl)thiazol-5-yl]ethanone oxime (76 mg, 0.33 mmol) and cesium carbonate (330 mg, 1.0 mmol) in acetonitrile (10 ml) was stirred at ambient temperature and treated with 2-chlopyrimidine (60 mg, 0.5 mmol). The reaction was monitored by TLC and LC/MS until ca. 70% completion, and then concentrated in vacuo. The solid residue was stirred with ethyl acetate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with ethyl acetate:MeOH (95:5), to give isomer B of 1-[2-(3-pyridyl)thiazol-5-yl]-N-pyrimidin-2-yloxy-ethanimine (46 mg, 46%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH3:36][C:37]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:43][C:37]5([CH3:36])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(N)CCCCC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCCCC4)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 29.1 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (70 mg, 0.22 mmol) in 6 mL of DMF were added EDCI (64 mg, 0.33 mmol) and DMAP (42 mg, 0.34 mmol), followed by the addition of 1-methylcyclohexanamine hydrochloride (50 mg, 0.33 mmol) in one portion at room temperature and stirred for 16 hours. The reaction mixture was poured into 35 mL of water, and filtered to give a crude product, which was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 55% acetonitrile/45% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 88% acetonitrile/12% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclohexyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (26 mg, 28.4%) as a pale yellow solid. MS: (M+H)+=407; 1H NMR (300 MHz, DMSO): δ 12.68 (s, 1H), 9.10 (s, 1H), 8.45-8.40 (m, 2H), 7.85 (s, 1H), 7.71 (d, 1H, J=9.9 Hz), 7.20-7.14 (m, 1H), 4.17 (s, 3H), 2.33-2.29 (m, 2H), 2.03-2.00 (m, 1H), 1.53-1.46 (m, 10H).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:15]12[CH:23]([N:24]3[CH2:27][C:26]([CH2:50][C:51]#[N:52])([N:28]4[CH:32]=[C:31]([C:33]5[C:34]6[CH:41]=[CH:40][N:39](COCC[Si](C)(C)C)[C:35]=6[N:36]=[CH:37][N:38]=5)[CH:30]=[N:29]4)[CH2:25]3)[CH:19]([CH2:20][NH:21][CH2:22]1)[CH2:18][O:17][CH2:16]2.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([N:21]1[CH2:20][CH:19]2[CH:23]([N:24]3[CH2:25][C:26]([CH2:50][C:51]#[N:52])([N:28]4[CH:32]=[C:31]([C:33]5[C:34]6[CH:41]=[CH:40][NH:39][C:35]=6[N:36]=[CH:37][N:38]=5)[CH:30]=[N:29]4)[CH2:27]3)[CH:15]([CH2:16][O:17][CH2:18]2)[CH2:22]1)=[O:6]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5C6CNCC5COC6)C4)c3)ncnc21
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2C3COCC2CN(C(=O)c2ccnc(C(F)(F)F)c2F)C3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a mixture of 3-fluoro-2-(trifluoromethyl)isonicotinic acid (50.0 mg, 0.239 mmol) and {1-(3-oxa-7-azabicyclo[3.3.1]non-9-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (128 mg, 0.239 mmol) in DMF (2 mL) were added triethylamine (0.100 mL, 0.717 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (127 mg, 0.287 mmol). The mixture was stirred at room temperature for 2 hours. Direct purification with prep-LCMS (pH=10) afforded 50 mg (30% yield) of the desired product. LCMS found: 696.3 (M+1)+.
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[N:17][CH:16]=2)=[CH:9][CH:8]=1.[Br:22]Br.O>C(O)(=O)C>[Br:22][CH:14]([C:15]1[CH:20]=[CH:19][N:18]=[N:17][CH:16]=1)[C:13]([C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=1)=[O:21]
Reactant: BrBr
Reactant: O=C(Cc1ccnnc1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccc(F)cc1)C(Br)c1ccnnc1
Reaction time: 0.5 h

Procedure:
0.70 g (5.2 mmol) of sodium acetate is added to a solution of 1.02 g (4.70 mmol) of 1-(4-fluorophenyl)-2-pyridazin-4-ylethanone in 20 ml of acetic acid and then 0.26 ml (5.2 mmol) of bromine in solution in a few ml of acetic acid is added dropwise (slight exotherm). After 30 minutes at ambient temperature, the reaction medium is cooled and 60 ml of water are added. The product is extracted with diethyl ether. The cooled organic phase is washed with an aqueous solution of sodium hydrogen carbonate, dried over sodium sulfate and filtered. This solution (approximately 50 ml) is used rapidly, as it is, in the rest of the synthesis.