Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=[C:17]3[N:25](S(C4C=CC(C)=CC=4)(=O)=O)[CH:26]=[CH:27][C:16]=23)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=[C:17]3[NH:25][CH:26]=[CH:27][C:16]=23)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1NC1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cnc2[nH]ccc2c1NC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
A mixture of methyl 4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (667 mg, 1.26 mmol, 1.0 eq) and Cs2CO3 (824 mg, 2.52 mmol) in THF/MeOH (1:1, 5 mL) was stirred at rt for 16 h. The solvent was removed in vacuo and the residue suspended in H2O/MeOH (1:1, 5 mL) and treated with NaOH (77 mg, 1.92 mmol, 2 eq) and then heated to 80° C. for 16. The solvent was reduced in vacuo and adjusted to pH 4-5. The precipitate was filtered to give the title compound (263 mg, yield: 76%) as a brown solid which was used without further purification. ESI-MS (M+H) 361.18.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.[C:24]([C:28]1[N:33]=[C:32]([N:34]=[CH:35]N(C)C)[C:31]([C:39]#[N:40])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C(O)(=O)C>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([S:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:2]([NH:1][C:39]2[C:31]3[CH:30]=[CH:29][C:28]([C:24]([CH3:25])([CH3:26])[CH3:27])=[N:33][C:32]=3[N:34]=[CH:35][N:40]=2)[CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C=Nc1nc(C(C)(C)C)ccc1C#N
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2c(Nc3cc(OCc4ccccc4)ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 25 °C

Procedure:
The product from Example 27A was heated at 130° C. in acetic acid with the product from Example 127A for 15 minutes, the mixture was then cooled to room temperature, the solvent removed and the residue purified by column chromatography on silica gel to provide the title product. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.38 (s, 9H) 5.11 (s, 2H) 6.60-6.74 (m, 2H) 6.94 (d, J=7.35 Hz, 1H) 7.06-7.19 (m, 3H) 7.27-7.50 (m, 6H) 7.78 (d, J=8.09 Hz, 1H) 8.56 (s, 1H) 8.75 (s, 1H) 9.64 (s, 1H) 9.95 (s, 1H); MS (ESI+) m/z 509 (M+H)+.
Reaction SMILES: [OH-].[Na+:2].P([O-])([O-])([O-])=O.[Na+:8].[Na+].[Na+].[CH:11]1[C:16]([C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:15][CH:14]=[C:13]([NH:29][CH2:30][C:31]2[CH:32]=[N:33][C:34]3[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([NH2:42])[C:35]=3[N:36]=2)[CH:12]=1>[Cl-].[Na+]>[Na:2][Na:8].[CH:15]1[C:16]([C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:11][CH:12]=[C:13]([NH:29][CH2:30][C:31]2[CH:32]=[N:33][C:34]3[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([NH2:42])[C:35]=3[N:36]=2)[CH:14]=1
Reactant: [Na+]
Agent: Nc1nc(N)c2nc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Product: [Na][Na]

Procedure:
Clean glassware to be used with 2 M NaOH for 3-5 minutes and the rinse thoroughly with deionized water. Prepare a first saline buffer by adding 2.7017 grams of dibasic sodium phosphate, USP to 5 liters of 0.9% sodium chloride for injection, USP. Prepare a second saline buffer by adding 1.39 grams of monobasic sodium phosphate, USP to 1 liter of 0.9% sodium chloride for injection, USP. While stirring the first saline buffer solution, slowly add the second saline buffer solution until the final pH is 7.9-8.1. Record the final volume. Add sufficient aminopterin salt, preferably the disodium salt, to provide 0.4 mg/ml aminopterin (i.e. 2 mg aminopterin per 5 ml) and filter through a 0.2 micron membrane filter, desiccate by freeze drying to a solid powder, and package under sterile conditions in 10-ml vials that are sealed from the atmosphere. Resuspend with the appropriate amount of sterile water at the time of administration.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[Br:15]Br>ClCCl>[Br:15][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1ccc(C)c(SCCC(=O)O)c1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1cc(SCCC(=O)O)c(C)cc1Br
Temperature: 5 °C
Yield: 99 %

Procedure:
25.23 g (0.12 mol) of the title compound of Example 1, Step A was dissolved in 250 mL of dichloromethane and cooled to 5° C. A solution of 19.12 g (0.12 mol) of bromine in 25 mL of dichloromethane was added dropwise over 45 minutes, keeping the reaction temperature at 5° C. The reaction was then allowed to warm to room temperature, diluted with 200 mL of dichloromethane and washed twice with 400 mL of water. The organice layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 34.35 g of the title compound of step A as a white solid melting at 105-107° C. 1H NMR (CDCl3): δ2.33 (s,3H), 2.34 (s, 3H), 2.67 (t, 2H), 3.10 (t, 2H), 7.18 (s, 1H), 7.36 (s, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19].[H-].[Na+]>>[C:18]([O:22][C:23](=[O:26])[CH2:24][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:15]=2)[CH:11]=[CH:12]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(O[Si](C)(C)C(C)(C)C)cc21

Procedure:
In analogy to the procedure described in example 1 b], 6-(tert-butyl-dimethyl-silanyloxy)-1H-indole was reacted with bromo-acetic acid tert-butyl ester in the presence of sodium hydride to obtain [6-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid tert-butyl ester as colorless liquid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2cc(Cl)sc2n1
Product: Clc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,6-dichloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-chloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([OH:7])=[O:6])[CH3:3].O[N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[O:15]=[C:10]1[CH2:11][CH2:12][C:13](=[O:14])[N:9]1[O:6][C:5](=[O:7])[CH2:4][N:2]([CH3:3])[CH3:1]
Reactant: CN(C)CC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CN(C)CC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5.15 g (50 mMol) Dimethylamino-acetic acid 15 was added to 5.75 g (50 mMol) N-hydroxy-succinimide and 11.05 g (55 mMol) dicyclohexyl-carbodiimide in 100 ml CH2Cl2 at 0° C. The reaction mixture was stirred for 20 h at RT. The residue was filtered and the filtrate was evaporated in vacuum to dryness. The residue was then dissolved in diethylether, mixed with A-Kohle. The solution was filtered off and evaporated. The obtained oil was dissolved in a small amount of diethylether to get a crystallization of the product. The cooled crystal solution was filtered off. The crystals were once again dissolved in Diethylether, treated with A-Kohle and the solution was filtered off. Those purification steps were repeated several times until the obtaining of a pure product in 1H-NMR
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6][NH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>CN(C)C=O>[CH3:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][N:7]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6]1
Reactant: COCCOCCBr
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)OC
Temperature: 30 °C
Reaction time: 18 h

Procedure:
Dimethyl 4-nitro-1H-pyrazole-3,5-dicarboxylate (9.53 g, 41.6 mmol) and potassium carbonate (3.44 g, 25 mmol) were dissolved in N,N-dimethylformamide (140 mL) under nitrogen. The mixture was then treated with a solution of 1-bromo-2-(2-methoxyethoxy)ethane (9.90 g, 54 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 30° C. for 18 hours and then allowed to cool to room temperature. Additional 1-bromo-2-(2-methoxyethoxy)ethane (9.90 g, 54 mmol) and potassium carbonate (3.44 g, 25 mmol) were added and the reaction mixture allowed to stir at 30° C. for 4 hours. The reaction mixture was concentrated in vacuo and the residue taken up in ethyl acetate (200 mL) and water (200 mL). The aqueous was separated and washed with ethyl acetate (200 mL), the organics were combined and washed with water. The organic layer was dried over magnesium sulphate and concentrated in vacuo to yield the title product. 1H NMR (CDCl3, 400 MHz) δ: 3.25 (s, 3H), 3.38 (m, 2H), 3.50 (m, 2H), 3.80 (t, 2H), 3.92 (s, 3H), 3.93 (s, 3H), 4.77 (t, 2H). MS APCI+ m/z 333 [MH]+
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: BrCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nnc(SCCCCc2ccccc2)s1
Yield: 56 %

Procedure:
A solution of 320 mg of 2-amino-5-mercapto-1,3,4-thiadiazole, 430 mg of 1-bromo-4-phenylbutane and 350 mg of potassium carbonate in 5 ml of N,N-dimethylformamide was stirred overnight at room temperature. After dilution with ethyl acetate, the reaction mixture was washed in sequence with water, 1N sodium hydroxide, water and saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was recrystallized from ethyl acetate to give 300 mg of 2-amino-5-[(4-phenylbutyl)thio]-1,3,4-thiadiazole. Melting point 111° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:20])[CH:8]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][N:40]=[C:39](S(C)(=O)=O)[N:38]=2)=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:20])[CH:8]=1)[C:39]1[N:38]=[C:37]([C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)[CH:42]=[CH:41][N:40]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(Cl)cc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Yield: 23.2 %

Procedure:
To a mixture of the ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (686 mg, 2.46 mmol) and N,N-diisopropylethylamine (285 μL, 1.64 mmol) was added 4-(4-chlorophenyl)-2-(methylsulfonyl)pyrimidine (439 mg, 1.64 mmol) and the resultant mixture heated at 100° C. for 16 h in a reactivial. The cooled reaction mixture were then treated with N,N-diisopropylethylamine (285 μL, 1.64 mmol) and heated for a further 16 h at 100° C. in the reactivial. The cooled reaction mixtures were diluted with CH2Cl2 (30 mL), washed with water (20 mL), the aqueous extracted with CH2Cl2 (30 mL), the CH2Cl2 extracts combined and the solvent removed in vacuo. Purification by Biotage™ chromatography (silica, 90 g) eluted with 10:1 cyclohexane:EtOAc gave the title compound as a colourless gum (178 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][NH:29]3)O1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:25]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:26]=3[CH:27]=[CH:28][NH:29]4)=[CH:7][N:6]=1)[CH2:10]2
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Brc1cnc(O[C@H]2CN3CCC2CC3)nc1
Product: c1cc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)c2cc[nH]c2c1

Procedure:
The product of Example 11A (170 mg, 0.6 mmol) was coupled with 4-(4,4,5,5-tetra-methyl-[1,3,2]dioxaborolan-2-yl)-1H-indole ((ref. WO02055517, 146 mg, 0.6 mmol) according to the procedure in Example 8A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.10) as a solid (76 mg, yield, 40%). 1H NMR (300 MHz, CD3OD) δ 1.50-1.64 (m, 1H), 1.67-1.93 (m, 2H), 2.05-2.19 (m, 1H), 2.25-2.33 (m, 1H), 2.73-3.12 (m, 5H), 3.39-3.50 (m, 1H), 5.17-5.25 (m, 1H), 6.55 (dd, J=3.4, 1.0 Hz, 1H), 7.11 (dd, J=7.1, 1.0, Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.35 (d, J=3.1 Hz, 1H), 7.44-7.49 (m, 1H), 8.85 (s, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]3[C:18]4[N:19]=[C:20](Cl)[N:21]=[CH:22][C:17]=4[S:16][CH:15]=3)=[O:13])[C:5]=2[N:4]=[CH:3]1.[C@@H:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30].O.ClCCl>O1CCOCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]3[C:18]4[N:19]=[C:20]([NH:30][C@@H:25]5[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]5[NH2:31])[N:21]=[CH:22][C:17]=4[S:16][CH:15]=3)=[O:13])[C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2c(NC(=O)c3csc4cnc(Cl)nc34)cccc21
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cn1cnc2c(NC(=O)c3csc4cnc(N[C@@H]5CCCC[C@@H]5N)nc34)cccc21
Yield: 37.9 %

Procedure:
To a solution of 0.041 g (0.119 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid(1-methyl-1H-benzoimidazol-4-yl)-amide in 1.19 mL of dioxane was added 0.082 g (0.716 mmole) of cis-cyclohexane-1,2-diamine. The mixture was heated at 100 degrees for over night. Water and dichloromethane were added, separated. The aqueous layer was washed with dichloromethane twice. The organic layer was washed with aqueous sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-0.7 N ammonia solution in methanol (gradient 100:0-90:10) gave 0.019 g of 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid (1-methyl-1H-benzoimidazol-4-yl)-amide as a light yellow solid. MH+/Z=422
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH2:17]([C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[CH3:18].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:17]([C:19]1[N:20]([C:2]2[N:3]=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=2)[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[CH3:18]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Clc1nc(N2CCOCC2)c2ncsc2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2ncsc2n1
Temperature: 120 °C

Procedure:
A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (3.0 g, 11.7 mmol), 2-ethylbenzimidazole (1.88 g, 12.9 mmol), tris(dibenzylideneacetone)dipalladium (534 mg, 0.60 mmol), XPhos (1.11 g, 2.34 mmol) and Cs2CO3 (7.62 g, 23 4 mmol) in dioxane (60 mL) was purged with argon then heated at 120° C. for 16 h in a sealed tube. The reaction mixture was filtered through Celite®, and the filtrated partitioned between EtOAc and H2O. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:DCM, 0-90%) followed by recrystallisation from iPrOAc affording the title compound (3.17 g, 74%). LCMS (method A): RT 2.74 min [M+H]+ 367.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[C:24][Si](C)(C)C)=[C:19]([N+:29]([O-:31])=[O:30])[CH:18]=3)[N:16]=2)[N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:13][N:12]3[CH:14]=2)=[CH:18][C:19]=1[N+:29]([O-:31])=[O:30])#[CH:24]
Reactant: C[Si](C)(C)C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 81.8 %

Procedure:
A stirred mixture of 6-(2-fluorophenyl)-2-(3-nitro-4-((trimethylsilyl)ethynyl)phenyl)imidazo[1,2-b]pyridazine (0.250 g, 0.58 mmol) in acetonitrile (100 mL) containing catalytic cesium carbonate (0.101 mmol) in water (0.031 mL) is heated at 60° C. for 4 hours. The mixture is concentrated to dryness then purified via chromatography using CH2Cl2 to afford the title product (0.170 g, 82%) as a yellow solid: Rf 0.40 (CH2Cl2); LCMS (m/z)=359.4 [M+H]+, tR=3.02 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=[N:21][CH2:22][CH:23](O)[C:24]([O:27][CH3:28])([CH3:26])[CH3:25])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+].O>C(#N)C>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[N:10]2[C:23]([C:24]([O:27][CH3:28])([CH3:25])[CH3:26])=[CH:22][N:21]=[C:9]12)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(C)(C)C(O)CN=C1N[C@H](C)[C@H](c2ccccc2)C[C@@H]1NC(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(C)(C)c1cnc2n1[C@H](C)[C@H](c1ccccc1)C[C@@H]2NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 1 h
Yield: 19.2 %

Procedure:
To a solution of tert-butyl{(3S,5S,6R)-2-[(2-hydroxy-3-methoxy-3-methylbutyl)imino]-6-methyl-5-phenylpiperidin-3-yl}carbamate (196 mg, 0.47 mmol) in acetonitrile (4.7 mL) was added pyridinium dichromate (880 mg, 2.34 mmol), and the mixture was stirred 1 h at 70° C. The mixture was cooled to ambient temperature and saturated aqueous sodium bicarbonate was added. Water was added, and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 95% water/acetonitrile→15% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (36 mg). MS 400.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].[C:24]1(=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[NH:25]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:25]2[C:26](=[O:33])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]2=[O:34])[CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(O)c1ccc(F)c(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(c1ccc(F)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 301 (0.0754 g, 0.219 mmol), isoindoline-1,3-dione (0.0387 g, 0.263 mmol) and PPh3 (0.127 g, 0.482 mmol) in THF cooled to 0° C. was added DEAD (0.0760 mL, 0.482 mmol) and the reaction warmed to RT and stirred overnight. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4) filtered and concentrated to an oil. The crude oil was purified by SiO2 chromatography to afford 0.0507 g (49%) of (2R)-tert-butyl 2-(2-(3-chloro-4-fluorophenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)pyrrolidine-1-carboxylate (303) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2.BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2
Reactant: O=C1CCc2cccc(Br)c2C1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc2cccc(Br)c2c1
Yield: 207.1 %

Procedure:
In two side by side reactions, 8-bromo-2-tetralone (7.0 g, 31.25 mmol) and N-bromosuccinimide (5.84 g, 32.8 mmol) were combined in carbon tetrachloride and refluxed 45 min. The reactions were cooled, filtered through diatomaceous earth (Celite™), and combined for workup. The organic solution was washed with saturated aqueous sodium bicarbonate and brine followed by drying through phase separating filter paper (1PS) and concentrated to give 14.44 g (104% crude) of 8-bromo-2-naphthol as a brown solid which was suitable for further reaction. A sample dissolved in methylene chloride and treated with activated carbon, concentrated, and triturated with hexane had: mp 96°-100° C.; 1HNMR (250 MHz, CDCl3) δ 7.79-7.73 (m, 3H), 7.56 (d, J=4.5 Hz, 1H), 7.22-7.14 (m, 3H). HRMS m/e calculated for C10H7BrO: 221.9680. Observed m/e: 221.9664.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.[Br:26]N1C(=O)CCC1=O.CCOCC.O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[S:22][C:23]([Br:26])=[CH:24][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cccs1
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccc(Br)s1
Reaction time: 1.5 h

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(thien-2-yl)pyrazole (0.153 g) in acetonitrile (12 ml) was added N-bromosuccinimide (0.068 g). The mixture was left at room temperature for 1.5 hours and then poured into ether (50 ml) and water (50 ml). The layers were separated and the aqueous phase extracted with a second portion of ether (50 ml). The combined organic layers were washed with water (25 ml), then dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as an off-white solid, m.p. 214° C.