Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([O-:18])(=O)=[O:16].[Na+].CC(C)=O.P(Cl)(Cl)([Cl:26])=O>CC(N(C)C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([Cl:26])(=[O:18])=[O:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
59 g of sodium 2-(2-methoxyethoxy)-5-nitrobenzenesulfonate prepared as described in Synthesis Example 1 was added to a mixture of 200 ml of acetone and 75 ml of phosphorous oxychloride and 75 ml of dimethylacetamide was added dropwise to the mixture with stirring while the reaction mixture was maintained at 30° to 40° C. After completion of the dropwise addition, the reaction mixture was allowed to stand while stirring until it cooled to room temperature. The reaction mixture was then poured into 600 ml of ice water, stirred for 30 minutes and the crystals thus-precipitated were recovered by filtration. The crystals were washed with 100 ml of water and air-dired.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8](=[N:23][OH:24])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8](=[N:23][O:24][CH3:26])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:21])[F:20])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCC(=NO)c1ncc(Br)cc1Cl)c1ccccc1C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 23 h
Yield: 69.3 %

Procedure:
To a suspension of 200 mg of N-[2-(5-bromo-3-chloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 189 mg of potassium carbonate in 1 ml of N,N-dimethylformamide, 97 mg of iodomethane was added, and the mixture was stirred at room temperature for 23 hours. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with ethyl acetate (20 ml×2), the resulting organic layers were combined, washed with water (10 ml×2) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 143 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](=O)[CH3:21])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:34][OH:35].[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](=[N:34][OH:35])[CH3:21])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1)=NO

Procedure:
630 mg (1 mM) of 1-(2-(bis-(4-fluorophenyl)-methoxy)-ethyl)-4 -(3-ketobutyl)piperazine (prepared as described in example 19) was suspended in 2 5 ml of ethanol at room temperature. A solution of hydroxylamine hydrochloride in 1 ml of water was added, followed by the dropwise addition of 240 mg of potassium hydroxide dissolved in 1 ml of water. The mixture was heated at reflux for 1 h, the solvent was evaporated, and the residue was dissolved by the addition of 5 ml of water and 5 ml of methylene chloride. The aqueous phase was extracted three times with methylene chloride, and the organic extract was washed with water, dried, and evaporated in vacuo. The residual oil was dissolved in ethanol, and a crude dimaleate salt was precipitated by addition of an ethanolic solution of 417 mg of maleic acid. The crude salt (405 mg) was recrystallized from 50 ml of hot ethanol to yield the dimaleate salt of the title compound as colourless crystals, melting at 161°-162° C. Analytical data were in accordance with the proposed structure. H-NMR spectrum indicated the presence of two stereoisomers in the ratio of 2.5:1.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].CN([CH:13]=[O:14])C>>[O:14]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9])[C:13]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCCCBr
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: BrCCCCCOc1ccccc1
Reaction time: 4 h
Yield: 40 %

Procedure:
To a well-stirred suspension of sodium hydride (15.3 g, 0.32 mol; 50% oil dispersion) in dry DMF (500 ml) containing (25 g, 0.26 mol), was added dropwise 1,5-dibromopentane (122.3 g, 0.53 mol). After the addition was complete, the reaction mixture was stirred at 60°-70° C. for 4 hours. Most of the DMF was next removed under reduced pressure, and the residue was dissolved in ethyl acetate (250 ml). The organic extract was washed successively with a 5% sodium hydroxide solution, water and brine. After drying the organics over anhydrous magnesium sulfate, all volatiles were removed. The residual yellow liquid was then distilled under reduced pressure, and the pure product was collected at 118°-125° C./1 mm as a clear colorless liquid (26 g, 40% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[Br:13]Br.OS([O-])=O.[Na+]>C(Cl)(Cl)Cl>[Br:13][C:10]1[S:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1
Reactant: c1ccc(Nc2nccs2)nc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Brc1cnc(Nc2ccccn2)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of N-(pyridin-2-yl)thiazol-2-amine (9.76 g, 55.07 mmol) in degassed chloroform (180 mL) was added bromine (3.11 mL, 60.6 mmol, 1.1 eq) at 23° C. The reaction was stirred for 15 minutes and followed by LC/MS. Bromine (2×0.3 mL) was added until reaction completed. The mixture was cooled to 0° C. and 10% aq. NaHSO3 (150 mL) was added. The suspension changed color and the solid was filtered, washed with water and vacuum dried overnight. The title compound was obtained as a solid (10.79 g, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.94-6.99 (1H, m), 7.04 (1H, d, J=8.34 Hz) 7.45 (1H, s), 7.74 (1 H, td, J=7.83, 1.77 Hz), 8.31 (1 H, d, J=5.31 Hz), 11.54 (1 H, s). LC/MS (M+H)+: 256, 258; (M−H)−: 254, 256.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=2[C:25]([OH:27])=O)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.C(Cl)(=O)C(Cl)=O.ClCCl>C1COCC1.CN(C=O)C>[ClH:1].[Cl:1][C:2]1[N:3]2[C:4](=[N:22][C:23]3[C:24]([C:25]2=[O:27])=[C:28]([F:32])[CH:29]=[CH:30][CH:31]=3)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C)cc3c(Nc4cccc(F)c4C(=O)O)nc(Cl)nc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Product: Cl
Reaction time: 0.25 h
Yield: 186.1 %

Procedure:
To a solution of 2-({2-chloro-6-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzoic acid (439 mg, 0.924 mmol) in THF (15 mL) and DMF (few drops) was added 2M oxalyl chloride solution in dichloromethane (0.56 mL, 1.13 mmol) dropwise. After ˜15 min, LCMS analysis shows reaction complete so reaction mixture was cooled in an ice bath and filtered via a buchner funnell and thet solid was washed with THF and dried under reduced pressure to afford 5-chloro-8-fluoro-2-methyl-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl salt (423 mg, 0.86 mmol) as a yellow solid. ESIMS (M+H)+=457.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21](O)=[O:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O1CCCC1.O>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CO
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a solution of (2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (5.00 g, 15.56 mmol) in tetrahydrofuran (50 mL) at −10° C. was added N-methylmorpholine (1.882 mL, 17.11 mmol). To this solution was added slowly isobutyl chloroformate (2.34 g, 2.25 mL, 17.11 mmol). The resulting mixture was stirred for 30 minutes and filtered, and the filtrate was added to a solution of sodium borohydride (1.18 g, 31.1 mmol) in water (1.5 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes, and the reaction was quenched by the addition of a saturated solution of NH4Cl. The mixture was extracted with ethyl acetate, and the organic extract was washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-2% methanol in dichloromethane to give the title compound as a colorless oil (3.93 g, 82%). 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 7.36 (d, J=7.4 Hz, 2 H), 7.30 (t, J=7.3 Hz, 2 H), 7.23 (t, J=7.2 Hz, 1 H), 4.50 (s, 2 H), 4.20-4.29 (m, 2 H), 3.92-4.00 (m, 1 H), 3.80-3.87 (m, 2 H), 3.50-3.59 (m, 1 H), 2.16-2.30 (m, 2 H), 1.47 (s, 9 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:9]=1[C:10]([N:12]=[S:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[O:11].[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:43])[F:42])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH:17]([CH3:18])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=3[CH3:24])=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:42])[F:43])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(Cl)cc(C(=O)N=S(C(C)C)C(C)C)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc(C(=O)N=S(C(C)C)C(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 68.1 %

Procedure:
To a suspension of potassium carbonate (9.73 g, 70.0 mmol, 1.10 equiv) and 2-amino-5-chloro-N-(diisopropyl-λ4-sulfanylidene)-3-methyl-benzamide (18.7 g, 62.4 mmol, 1.00 equiv) in toluene (80 mL) a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (20.1 g, 64.1 mmol, 1.03 equiv.) in toluene (40 mL) was added at 60° C. After 35 minutes at 60° C., the reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (50 mL), 0.1 M HCl (50 mL), dried over Na2SO4 and concentrated. The crude product was recrystallized from methyl tert-butyl ether to yield the title compound (24.4 g, 66%). The crystalline material was analyzed by means of DSC and by means of X-ray powder diffractometry (XRPD). The data revealed that form I of Va-2 was obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].O1CCOCC1.C(=O)([O-])O.[Na+].[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35]>C(Cl)(Cl)Cl>[CH3:32][N:33]([CH3:38])[S:34]([N:5]1[CH2:6][CH2:7][C@@H:2]([CH3:1])[C@@H:3]([N:8]2[C:12]3=[C:13]4[CH:19]=[CH:18][NH:17][C:14]4=[N:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:20])[CH2:4]1)(=[O:36])=[O:35]
Reactant: C[C@@H]1CCNC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CCN(S(=O)(=O)N(C)C)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Reaction time: 2 h
Yield: 36.7 %

Procedure:
To a solution of rel-1-[(3R,4R)-4-methylpiperidin-3-yl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (80 mg), dioxane (1.6 mL) and 4M saturated aqueous sodium hydrogencarbonate (2.4 mL) was added dimethylsulfamoyl chloride (51 mg) at ambient temperature. The mixture was stirred for 2 hours then chloroform (8 mL) was added. The organic layer was separated and dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give rel-(3R,4R)—N,N,4-trimethyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidine-1-sulfonamide (41 mg) as a colorless solid.
Reaction SMILES: [C:1]([O:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-])=[O:5].C(Cl)(=O)C(Cl)=O>>[OH:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([O:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18])=[O:11]
Reactant: CCCCC=COC(=O)c1ccccc1C(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Product: CC/C=C\CCOC(=O)c1ccccc1CO
Reaction time: 2.5 h
Yield: 31.8 %

Procedure:
1 g (4.03 mmol) monohexenyl phthalate was heated at reflux in 6 ml oxalyl chloride (17.3 eq.) for 1.5 h. The excess oxalyl chloride was distilled under vacuum. The crude acid chloride was then diluted in 10 ml dichloromethane cooled to 0° under argon, and introduced dropwise on a solution of 2.07 g (2 eq.) nBuNBH4 in 10 ml dichloromethane. The reaction mixture was maintained under stirring at O for 2.5 h. The mixture was then poured over 5% KHSO4 and cold ethyl ethyl acetate, and extracted. Chromatography of the crude product over silica gel (85:15 cyclohexane/AcOEt) yielded 0.3 g (32%) (Z)-3-hexenyl 2-hydroxymethylbenzoate containing about 10% phthalide, in the form of a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2].[N:32]1([CH2:38][CH2:39][CH2:40]O)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:40][CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccc(Cl)cc3)c2)cc1Cl
Reactant: OCCCN1CCOCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCCCN3CCOCC3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (293 mg; 0.62 mmol) was dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 3-morpholin-4-yl-propan-1-ol (75 mg; 0.52 mmol) and tributyl-phosphine (0.23 mL; 0.93 mmol) was added followed by 1,1′-(Azodicarbonyl)dipiperidine (0.38 g; 1.5 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 16 h, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 600.4 (M+); Rt: 2.2 min.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][CH2:7][OH:8])[CH2:4][OH:5].O.[C:10]1(C)[CH:15]=CC(S(O)(=O)=O)=C[CH:11]=1.C(N(CC)CC)C>CC(C)=O>[CH3:11][C:10]1([CH3:15])[O:5][CH2:4][CH:3]([CH2:6][CH2:7][OH:8])[CH2:2][O:1]1
Reactant: OCCC(CO)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CCO)CO1
Reaction time: 15 h
Yield: 220.6 %

Procedure:
To an acetone (30 ml) solution of the 2-(hydroxymethyl)butane-1,4-diol (3.4 g, 28.3 mmol) obtained in accordance with the method described in J. Med. Chem., 30 (9), 1636-1642 (1987), p-toluenesulfonic acid monohydrate (244 mg, 2.83 mmol) was added at room temperature and the mixture was stirred for 15 hours. To the reaction mixture, triethylamine (394 μl, 2.83 mmol) was added and the mixture was concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (1.0 g, yield: 22%) as a light yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C:18](=[CH:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH:14]=[CH:15]1)[CH2:10][CH2:9]3.[C-]#[C-].[Li+].[Li+].[CH3:27][C:28](C)=O>C1COCC1>[C:27]([C@:3]1([OH:22])[C@@H:2]([CH3:1])[CH2:7][C@H:6]2[C@H:8]3[C:18](=[CH:19][CH2:20][C@:4]12[CH3:5])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH:14]=[CH:15]1)[CH2:10][CH2:9]3)#[CH:28]
Reactant: CC(C)=O
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)C1=O
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C#C[C@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Reaction time: 0.5 h

Procedure:
16β-Methylandrosta-1,4,9(11)-triene-3,17-dione (IB, U.S. Pat. No. 3,010,958, 20 g) is added in THF (60 ml) to the lithium acetylide at -40°. When the reaction is complete, acetone (24 ml) is added. The mixture is warmed while bubbling nitrogen thru the slurry to remove excess acetylene. Water (25 ml) is slowly added. Water (105 ml) is then added more quickly creating two phases which are separated. The aqueous phase is washed with THF (50 ml); the organic phases (pH is 9) are combined, washed with aqueous sulfuric acid and concentrated to 350 ml. Heptane (200 ml) is added, the mixture heated to 80° and held for 30 min. The mixture is cooled slowly to 30° and then to 18° for one hr. The mixture is filtered, the solid washed with heptane (20 ml) and then dried under reduced pressure with heat to give the title compound.
Reaction SMILES: [OH-].[Na+].CC1(C)C(C)(C)OB([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)O1.[NH2:21][C:22]1[N:27]=[CH:26][C:25](Br)=[CH:24][N:23]=1>C1COCC1.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>[NH:15]1[C:16]2[C:12](=[C:11]([C:25]3[CH:24]=[N:23][C:22]([NH2:21])=[N:27][CH:26]=3)[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Nc1ncc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2cccc3[nH]ccc23)cn1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Pd(PPh3)4 (285 mg, 0.25 mmol) and a freshly prepared sodium hydroxide solution (985 mg in 12 mL of water) were added to a mixture of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole (2 g, 8.21 mmol) and 2-amino-5-bromopyrimidine (1.71 g, 9.85 mmol) in THF (30 mL). The reaction mixture was degassed and then purged three times with nitrogen and then refluxed overnight with stirring under nitrogen. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (300 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give 1.4 g (82%) of 5-(1H-indol-4-yl)-pyrimidin-2-ylamine as a white solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=2)[CH2:4]1)#[N:2]>CO.ClCCl.[Pd]>[NH2:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]([C:1]#[N:2])[CH2:11]2
Reactant: N#CC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: N#CC1Cc2ccc(N)cc2C1
Yield: 103.9 %

Procedure:
A solution of 2-cyano-5-nitroindane (11.90 g, 63.3 mmol) in methanol/dichloromethane=1:1 (200 ml) was hydrogenated over 10% palladium on charcoal (1.2 g) at 30 p.s.i and 20° C. for 5 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 5-amino-2-cyanoindane (10.4 g) which was used directly for the next reaction. A portion, recrystallised from ethanol, formed pinkish needles, m.p. 73°-76° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:3]=1[O:4][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(OCC)C>[CH3:14][Si:13]([CH3:15])([CH3:16])[C:10]1[CH:11]=[CH:12][C:2]([CH3:1])=[C:3]([OH:4])[CH:9]=1
Reactant: Cc1ccc([Si](C)(C)C)cc1O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc([Si](C)(C)C)cc1O
Reaction time: 0.08 h
Yield: 53.2 %

Procedure:
To a solution of 2-methyl-5-(trimethylsilyl)phenoxytrimethylsilane (Intermediate 2; 5 g) in diethyl ether (40 mL) at room temperature was added tetrabutylammonium fluoride (TBAF; 19.3 mL, 1.0 M solution, 19.3 mmol). The reaction was stirred at this temperature for 5 minutes and then water (40 mL) was added. The mixture was extracted with diethyl ether (2×40 mL) and the combined organic extracts were dried (magnesium sulphate), concentrated under reduced pressure and purified by column chromatography (SiO2; light petroleum to 9:1 light petroleum-diethyl ether) to give the title compound as a colourless oil (1.9 g, 56%). Rf=0.32 (9:1 light petroleum-diethyl ether). 1H NMR δH 0.26 (9 H, s), 2.27 (3 H, s), 4.62 (1 H, s), 6.93 (1 H, d, J=1.0 Hz), 7.02 (1 H, dd, J=7.3, 1.0 Hz), 7.15 (1 H, d, J=7.3 Hz).
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].[CH3:5][C@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:12]1[CH:17]=[C:16]([CH2:18]OS(C)(=O)=O)[N:15]=[C:14]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:32])=[CH:26][CH:25]=2)[N:13]=1>C(#N)C.N12CCCN=C1CCCCC2>[CH3:5][C@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:12]1[CH:17]=[C:16]([CH2:18][S:4][CH:1]([CH3:3])[CH3:2])[N:15]=[C:14]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:32])=[CH:28][CH:29]=2)[N:13]=1
Reactant: CC(C)S
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)SCc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Isopropyl mercaptan (0.075 mL) was dissolved in acetonitrile (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL). The reaction was allowed to stir at room temperature for 15 minutes then 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]-3-phenyl-urea (228 mg) in acetonitrile (5 mL) added. The reaction was stirred for 30 minutes then concentrated in vacuo. The residue was chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired compound (78 mg) as a gum.