Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:7]([NH:14][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCl
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of chloromethyltrimethylsilane (325g, 370ml, 2.65 mole) and benzylamine (835g, 850ml, 7.78 mole) was heated at 120° C. (oil bath temperature) for 2h. A white solid began appearing after only 10 minutes and a viscous mixture eventually resulted. The reaction mixture was allowed to cool, then basified with potassium carbonate solution and extracted twice with ether. The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was purified by distillation. The excess benzylamine was removed in the first fractions (b.p. 47-62° C. at 2mmHg). The title compound (D16) was obtained as a colourless oil (380g, 74%) b.p. 75-80° C. at 2mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][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]=[N:6][C:7]=1[Cl:8].[CH3:23][C:24]([CH3:30])([CH3:29])[CH:25]=[CH:26][CH:27]=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.CCOC(C)=O>[CH3:23][C:24]([CH3:30])([CH3:29])[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1[CH:3]=[C:4]([O:9][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]=[N:6][C:7]=1[Cl:8]
Reactant: C=CC=CC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)C=CC=Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Reaction time: 96 h
Yield: 26.7 %

Procedure:
A solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (480 mg, 1.2 mmol), 5-(5,5-dimethyl-1,3-hexadiene (200 mg, 1.8 mmol), Pd(OAc)4 (25 mg), tris(o-tolyl)phosphine (125 mg), and triethylamnine (2.5 mL) in acetonitrile (5 mL) was sealed in a tube and headed at 100° C. for 4 days. The solution was then diluted with EtOAc, and the mixture was extracted with water and aqueous NaHCO3 solution. The organic layer was dried and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:Et2O 100:5-100:15 to afford the title compound (135 mg, 43% yield). MS (CI/NH3) m/z 421 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.08 (s, 9H), 1.48 (s, 9H), 1.89 (m, 2H), 2.00 (m, 2H), 3.38 (m, 2H), 3.95 (m, 1H), 4.13 (m, 1H), 4.23 (m, 1H), 5.99 (m, 1H), 6.22 (m, 1H), 6.71 (m, 1H), 6.95 (m, 1H), 7.74 (br s, 1H).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[F:15][C:16]([F:20])([F:19])[CH2:17][NH2:18].C(O)(=O)C>CO>[F:15][C:16]([F:20])([F:19])[CH2:17][NH:18][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1
Reactant: NCC(F)(F)F
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(CNCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Add sodium cyanoborohydride (957 mg, 15.24 mmol) to a stirred solution of 4-cyanobenzaldehyde (500 mg, 3.81 mmol), 2,2,2-trifluoroethylamine (0.3 mL, 3.81 mmol) and acetic acid (0.44 mL, 7.62 mmol) in methanol (5 mL). Stir the mixture overnight at room temperature. Partition the mixture between 1N aqueous NaOH and DCM. Extract the aqueous phase twice with DCM. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the desired intermediate (749 mg, 92%) suitable for use without further purification. MS (ES+) m/z: 215 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>CN1C(=O)CCC1.CC(OC)(C)C>[CH2:25]([NH:29][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CN
Reactant: OC(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: COC(C)(C)C
Product: CC(C)CNc1ccc2ncc(C(O)c3ccc4ncccc4c3)n2n1
Temperature: 160 °C
Reaction time: 7 h

Procedure:
(rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanol (Stage 1.1, 80 mg, 0.257 mmol) and KF (30 mg, 0.515 mmol) were suspended in NMP (2 mL). Isobutylamine (129 μL, 1.287 mmol) was then added and the RM was stirred at 160° C. for 7 h. The mixture was diluted with TBME and washed with water (3×). The aqueous layer was then extracted with TBME (3×). The combined layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Flashmaster) to afford the title compound as a yellow foam (tR 4.11 min (conditions 4), MH+=348.0, 1H-NMR in DMSO-d6: 8.86 (m, 1H); 8.32 (m, 1H); 8.02 (m, 1H); 7.94 (d, 1H); 7.80 (m, 1H); 7.61 (d, 1H); 7.51 (dd, 1H); 7.31 (s, 1H); 6.88 (t, 1Ht); 6.61 (d, 1H); 6.24 (m, 1H); 6.12 (d, 1H); 2.98 (m, 2H); 1.82 (m, 1H); 0.86 (m, 6H)).
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[O:7][CH:6]([OH:8])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].O>O>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:12])[OH:7])[OH:11])[OH:10])[OH:9]
Reactant: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Frozen flocculated cells are immersed in water or a glucose syrup. The cell mass is allowed to thaw and is gently crushed by mechanical means or stirring to give particles of approximately uniform size. This slurry is then subjected to vacuum conditions for approximately 30 minutes to remove occluded gases from the cell particles. A jacketed column of 1-inch diameter is partially filled with water or glucose syrup and the degassed slurry is then poured into the column. The packed column is heated to 60° C. and a 2 M solution of glucose having a pH of 8.0 and containing 0.004 M MgCl2. 6H2O is passed through the column at flow rates which are regulated to give the degree of glucose conversion desired. Conversions ranging up to 50% are attainable by this process.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(ON=O)CC(C)C.[Cl:16][C:17]1[CH:23]=[CH:22][C:20](N)=[C:19]([S:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])=[CH:27][C:26]=2[Cl:36])[CH:18]=1>C(#N)C.O>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:19]([S:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])=[CH:27][C:26]=2[Cl:36])[CH:18]=1
Reactant: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2N)c(Cl)c1
Reactant: CCOC(=O)CS
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CSc1ccc(Cl)cc1Sc1ccc(S(=O)(=O)CC)cc1Cl
Temperature: 60 °C

Procedure:
Ethyl mercaptoacetate (0.11 ml) followed by isoamylnitrite (0.16 ml) were added to a solution of the product from step (iii) (0.35 g) in dry acetonitrile (20 ml) and heated at 60° C. for 10 h. The mixture was diluted with water, extracted with diethylether, the organics dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 1:1, yield 0.10 g.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][NH:40][CH3:41]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:40]([CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])[CH3:41])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Yield: 55.8 %

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and N,N,N′-trimethylethylenediamine (200 mg, 1.98 mmol) as starting materials to afford the title compound as a colourless oil (241 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:31][CH2:32][CH:33]=[C:34]1[C:40]2[CH:41]=[CH:42][CH:43]=[N:44][C:39]=2[CH2:38][O:37][C:36]2[CH:45]=[CH:46][C:47]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:48][C:35]1=2>C(O)(C)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[CH:6]1[CH2:10][CH2:9][N:8]([CH2:31][CH2:32][CH:33]=[C:34]2[C:40]3[CH:41]=[CH:42][CH:43]=[N:44][C:39]=3[CH2:38][O:37][C:36]3[CH:45]=[CH:46][C:47]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:48][C:35]2=3)[CH2:7]1
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1

Procedure:
To a solution of [(4-Chloro-benzyl)-pyrrolidin-3-yl-amino]-acetic acid methyl ester (188 mg, 0.67 mmol) in isopropanol (5 mL) was added 2,6-lutidine (186 uL, 1.6 mmol), and a catalytic amount of potassium iodide. The resultant solution was heated at 80° C. and to it was added 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (149 mg, 0.4 mmol) portionwise over 0.5 h. The reaction solution was heated overnight then partitioned between water and ethyl acetate. The product was purified on SiO2 (ethyl acetate:Methanol:triethylamine 95:4.5:0.4) and isolated as a film. LCMS (retention time=1.84, ES+; 576); 1H NMR (CD3OD): δ 8.46 (1H,d), 7.76 (1H, d), 7.45 (2H, m), 7.23 (5H, m), 6.74 (1H, d), 6.15 (1H, m), 3.72 (2H, m), 3.60 (4H, s), 3.30 (6H, m), 2.78 (4H, m), 2.42 (2H, m), 2.05 (1H, m), 1.82 (1H, m), 1.50 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](SC)=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[C:14]#[N:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH:22](N)([CH3:24])[CH3:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([CH:22]([CH3:24])[CH3:23])=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[C:14]#[N:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CC(C)N
Reactant: COc1cc(NC(SC)=C(C#N)S(C)(=O)=O)cc(OC)c1
Product: COc1cc(NC(=C(C#N)S(C)(=O)=O)C(C)C)cc(OC)c1

Procedure:
3-(3,5-dimethoxyphenylamino)-2-methanesulfonyl-3-methylsulfanyl-2-propenenitrile (0.263 g, 0.8 mmol) was stirred in isopropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in Example 17, 2) to give the title compound syrup, 209 mg (77%). Mp 135-136.5° C. 1H NMR (200 MHz, CDCl3): δ=1.15 (s, 6H), 3.10 (s, 3H), 3.5 (m, 1H), 3.78 (s, 6H), 6.25 (br s, 2H), 6.33 (br s, 1H); Analysis: calc. for C15H21N3O4S: C, 53.08%; H, 6.24%; N, 12.38%. Found: C, 53.38%; H, 6.26%; N, 12.31%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[C:6](=[O:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1c(OCC)cc[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(OCC)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (60 g, 0.284 mol), 4-fluoro phenylboronic acid (120 g, 0.853 mol), Cu(OAc)2 (113 g, 0.568 mol) and pyridine (88 g, 1.137 mol) in DCM (500 mL) was stirred at RT for 4 h open to air. The reaction mixture was filtered and the solids were washed with water. The filtrate was extracted with DCM (2×250 mL). The combined organics were dried over Na2SO4 and concentrated to afford ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate. The product was carried forward without further purification. (77 g, 95% yield).
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])/[CH:12]=[CH:13]/[CH3:14].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[NH2:6][C:5]1[C:4]([F:10])=[CH:3][C:2](/[C:13](/[CH3:14])=[CH:12]/[C:11]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([F:9])[CH:7]=1
Reactant: C/C=C/C(=O)OCC
Reactant: Nc1cc(F)c(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C(\C)c1cc(F)c(N)cc1F
Temperature: 110 °C
Reaction time: 48 h
Yield: 29 %

Procedure:
A mixture of 4-bromo-2,5-difluoroaniline (5.0 g), ethyl crotonate (4.98 ml), palladium acetate (54.0 mg), tris(2-methylphenyl)phosphine (442 mg), and triethylamine (33.4 ml) was stirred at 110° C. in a nitrogen atmosphere for 48 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The obtained residue was separated with ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (5% ethyl acetate/n-hexane) to give Compound 10a (1.69 g, 29%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C(NC1C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8](=[O:15])[C:9](=[N+:37]=[N-:38])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-(3-chloro-2-fluorophenyl)-3-oxopropanoate (1.30 g, 5.31 mmol), triethylamine (0.618 g, 6.11 mmol, 1.15 equiv), and 4-acetamidobenzenesulfonyl azide (1.40 g, 5.85 mmol, 1.1 equiv) were combined in acetonitrile (15 mL). After stirred at ambient temperature for 30 minutes, the mixture was concentrated in vacuo and the residue was treated with sodium hydroxide (25 mL, 2 M aqueous) and extracted with twice chloroform. The combined organic extracts were washed once with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 40:60; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[O:5][CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2](=[O:1])[C:3]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=3)=[CH:4][O:5]2)=[CH:10][CH:9]=1)#[CH:13]
Reactant: C[Si](C)(C)C#Cc1ccc2c(=O)c(-c3ccc(NS(C)(=O)=O)cc3)coc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc2c(=O)c(-c3ccc(NS(C)(=O)=O)cc3)coc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-(4-oxo-7-((trimethylsilyl)ethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide (1.8 g, 4.37 mmol) was dissolved in a 1:1 mixture of methanol/tetrahydrofuran (6 ml), potassium carbonate (121 mg, 0.2 eq) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed the solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate in the presence of water. The organic phase was dried over magnesium sulfate, filtered, and solvent removed under reduced pressure to afford N-(4-(7-ethynyl-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:28]/[O:29][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][NH:24][CH2:25][CH2:26][OH:27])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:45](N2C=NC=C2)=[O:46])C=1>C(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:28]/[O:29][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])/[C:15](=[O:16])[NH:17][C@H:18]2[C@@H:19]([CH2:23][N:24]3[CH2:25][CH2:26][O:27][C:45]3=[O:46])[NH:20][C:21]2=[O:22])[N:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCO)cs1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2CCOC2=O)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Prepared according to PCT Int. Appl. 2011061760. A solution of tert-butyl 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-(((2-hydroxyethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (92 mg, 0.161 mmol) in Chloroform (806 μl) was treated with CDI (131 mg, 0.806 mmol) After stirring at rt for 3 h it was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (MeOH-DCM, 0-10%), affording the title compound (91 mg, 95%) as an orange oil. LCMS: Rt=0.86 min, m/z=597.2 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:20])=O>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCOCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: ClCCOCc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 2-benzyloxyethanol (11.7 g) and pyridine (6.08 g) in dichloromethane (50 ml) was added thionyl chloride (6.7 ml) under ice-cooling, and the resulting mixture was stirred at refluxing temperature for 2.5 hr. Ice-water was added to the reaction mixture, and the organic layer was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform) to give 10.3 g of 2-benzyloxyethyl chloride.
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH:25]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]1)[N:5]1[CH:9]=[C:8]([C:10]2[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[CH:13]=[C:12]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[N:11]=2)[CH:7]=[N:6]1)#[N:2].C(Cl)[Cl:39].Cl.O1CCOCC1>>[ClH:39].[CH3:24][N:22]1[CH:23]=[C:19]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:4]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH2:3][C:1]#[N:2])[CH:9]=3)[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[CH:13]=2)[CH:20]=[N:21]1.[CH3:24][N:22]1[CH:23]=[C:19]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:4]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH2:3][C:1]#[N:2])[CH:9]=3)[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[CH:13]=2)[CH:20]=[N:21]1
Reactant: ClCCl
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CCN(C(=O)OC(C)(C)C)CC4)c3)n2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CCNCC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 4-(2-cyano-1-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (59.4 mg, 0.118 mmol) was dissolved in DCM (592 μL, 0.118 mmol). To this was added 4N HCl in dioxane (296 μL, 1.18 mmol) and stirred at ambient temperature for 1 hour. Complete conversion was observed after 1 hour and the reaction mixture was concentrated to dryness to afford the HCl salt of 3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-(piperidin-4-yl)propanenitrile (56.0 mg, 99.7% yield). MS (apci) m/z=402.3 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]=1[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]([CH3:25])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[Li]CCCC.[Cl:38][Si:39](Cl)([CH3:41])[CH3:40]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11]([CH:10]=[C:9]([CH3:25])[CH:8]2[Si:39]([Cl:38])([CH3:41])[CH3:40])=[C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2cc(C(C)(C)C)c(OCC(C)C)c(-c3ccccc3)c2C1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1=Cc2c(cc(C(C)(C)C)c(OCC(C)C)c2-c2ccccc2)C1[Si](C)(C)Cl
Temperature: -20 °C
Reaction time: 10 h
Yield: 100.3 %

Procedure:
To a solution of 16.8 g (50.2 mmol) of 5-tert-butyl-6-isobutoxy-2-methyl-7-phenyl-1H-indene in 200 ml of toluene 20.1 ml (50.5 mmol) of 2.5 M nBuLi in hexanes was added at room temperature. The formed viscous solution was stirred for 10 h, and then 10 ml of THF was added. The resulting mixture was stirred for 1 h at 65° C., then cooled to −20° C., and 32.5 g (252 mmol, 5 eq.) of dichlorodimethylsilane was added in one portion. This mixture was warmed to room temperature, refluxed for 0.5 h, and then filtered through glass frit (G3). The precipitate was additionally washed by 2×30 ml of toluene. The combined filtrate was evaporated to dryness to give 21.5 g (99%) of (6-tert-butyl-5-isobutoxy-2-methyl-4-phenyl-1H-inden-1-yl)(chloro)dimethylsilane which was further used without an additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(O)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][S:18]([C:21]2[C:22](=[O:23])[O:10][C:5]3[C:6]([CH:7]=2)=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:19])=[O:20])=[CH:25][CH:26]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3cc(Cl)ccc3oc2=O)cc1
Yield: 66 %

Procedure:
A solution of 5-chlorosalicylaldehyde (1 mmol) and 2-(4-methoxybenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 66% yield of the title compound; m.p. 224-226° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21][CH3:22])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>>[C:28]1([O:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH3:22])[CH:12]=[CH:13][C:5]=2[O:4][C:1](=[O:3])[CH3:2])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(F)ccc1-c1ccc(OC(C)=O)c(C(=O)O)c1
Reactant: Oc1ccccc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(F)ccc1-c1ccc(OC(C)=O)c(C(=O)Oc2ccccc2)c1

Procedure:
A mixture of 2-acetoxy-5-(4'-fluoro-2'-methoxyphenyl)-benzoic acid (0.1 mole), phosphorous oxychloride (0.1 mole), and phenol (0.12 mole), is heated at 75° C. until no more hydrogen chloride is evolved. The product, phenyl-2-acetoxy-5-(4'-fluoro-2'-methoxyphenyl)-benzoate, is isolated by partitioning the reaction mixture between benzene and dilute sodium bicarbonate solution, and subjecting the benzene solution to chromatography on silica gel.