Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1](N(C)C)(N(C)C)N(C)C.C(Br)(Br)(F)F.[C:16]([O:20][C:21]([C@@H:23]([N:26]1[C:30](=[O:31])[CH2:29][CH:28]([CH:32]=[O:33])[CH2:27]1)[CH2:24][CH3:25])=[O:22])([CH3:19])([CH3:18])[CH3:17].[PH4+].P(CCCC)(CCCC)CCCC.C(F)(Cl)(Cl)Cl>C1COCC1.CCO.CCCCCC>[C:16]([O:20][C:21]([C@@H:23]([N:26]1[C:30](=[O:31])[CH2:29][CH:28]([CH:32]=[O:33])[CH2:27]1)[CH2:24][CH3:25])=[O:22])([CH3:19])([CH3:17])[CH3:18].[PH3:1]
Reactant: CN(C)P(N(C)C)N(C)C
Agent: CCCCP(CCCC)CCCC
Agent: CC[C@@H](C(=O)OC(C)(C)C)N1CC(C=O)CC1=O
Agent: FC(F)(Br)Br
Solvent: FC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: P
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The synthesis of the two diastereoisomers of (2S)-2-(2-oxo-4-(2,2-difluorovinyl)-1-pyrrolidinyl)butanoic acid 2,2-(dimethyl)ethyl ester 399 is representative. In a three necked flask under argon, (Me2N)3P (89.8 g, 0.55 mol.) is added to a solution of CF2Br2 (58 g, 0.25 mol.) in THF (280 ml) at −78° C. (appearance of a white precipitate) and warmed to room temperature. A solution of the aldehyde 396 as a 1/1 mixture of diastereoisomers (35.2 g, 0.138 mol.) in THF is added dropwise to the preformed phosphonium salt. After 1 h, the reaction mixture is filtered through celite and concentrated in vacuo. The reaction mixture is diluted with hexane, washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the crude olefin which is purified by column chromatography on silicagel (CH2Cl2/MNeOH 99/01 (v/v)) to afford 34.6 g of a 1/1 diastereoisomeric mixture of (2S)-2-(2-oxo-4-(2,2-difluorovinyl)-1-pyrrolidinyl)butanoic acid 2.2-(dimethyl)ethyl ester 399 (87%): 1H NMR (250 MHz, (CD3)2SO): 0.81-0.91 (m, 3H), 1.44 (s, 9H), 1.50-1.75 (m, 1H), 1.80-1.95 (m, 1H), 2.30-2.40 (m, 2H partially overlapped with solvent), 3.00-3.35 (m, 2H), 3.45-3.55 (m, 1H), 4.20-4.40 (m, 1H), 4.60 (ddd, 1H for one diastereoisomer), 4.75 (ddd, 1H for another diastereoisomer). 6.2.4. By Olefination with (nBu)3P/CCl3F Alternatively to §6.2.3., halovinyl derivatives can be obtained by Wittig olefination of the 1-[(1S)-1-(tertbutoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxaldehyde 396 in the presence of a phosphine and an halogenomethane. For example of 2-(2-oxo-4-(2-(Z)-fluorovinyl)-1-pyrrolidinyl)butanoic acid 2,2-(dimethyl)ethyl ester is obtained from aldehyde 396 by successive reaction with CFCl3 and n-Bu3P followed by dephosphorylation of the intermediate vinylic phosphonium by NaOH. 6.2.5. Synthesis of the 4-cyano-pyrrolidone Alternatively, 4-cyano-pyrrolidone derivatives are obtained by reacting 1-[(1S)-1-(tertbutoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxaldehyde 396 with hydroxylamine followed by SeO2. 6.3. Amination of the 2.2-dimethyl-ethyl Ester 63.1. Deprotection with Trifluoroacetic Acid and Aminolysis The synthesis of the two diastereoisomers of (2S)-2-(2-oxo-4-(2,2-difluorovinyl)-1-pyrrolidinyl)butanamide 213 and 222 is representative:
Reaction SMILES: [OH:1][C@H:2]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([CH3:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:30]1([NH:33][C:18](=[O:19])[CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C@@H:3]([CH3:21])[C@H:2]([OH:1])[CH2:22][CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:10][CH:9]=3)=[CH:16][CH:15]=2)[CH2:32][CH2:31]1
Reactant: NC1CC1
Reactant: C[C@H](Oc1ccc(-c2ccc(CC(=O)O)cc2)cc1)[C@H](O)CCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(-c2ccc(CC(=O)NC3CC3)cc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
Prepared according to the method described in Example 66. (1S,2R)-[4′-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy)-biphenyl-4-yl]acetic acid (Example 55, 0.07 g), cyclopropylamine (0.011 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.038 g) and 1-hydroxybenzotriazole (0.027 g) were dissolved in dimethylformamide (2 ml) and stirred for 16 hours at room temperature. The dimethylformamide was removed by vacuum distillation, the residue was dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.063 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:17][C:6]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[CH:3]=[N:4][CH:5]=1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2ccncc2)CC1
Yield: 17.9 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088 mmol), pyridin-4-yl boronic acid (12 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (5 mg, 18%), LC-MS (ESI, 3.5 min) Rt 1.10 min, m/z 317 (100%, [M+H]+); m/z (ESI) C16H18ClN4O requires 317.1164 found [M+H]+ 317.1160
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=[C:11]2I)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH:30]=[C:31]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]3[N:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Cl)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 90 °C

Procedure:
7-Benzenesulfonyl-4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (4.05 g, 9.65 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.985 g, 9.65 mmol), potassium carbonate (2.935 g, 21.25 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (678 mg, 0.96 mmol) were combined in dioxane/water (85 mL:21 mL) and heated to 90° C. for 2 h. After cooling the reaction mixture was extracted with ethyl acetate (3×50 mL), the organic layers were combined and washed with aqueous sodium bicarbonate, brine and finally water. The organic layer was dried over anhydrous magnesium sulphate, filtered and pre-absorbed onto silica in vacuo. Purification on silica gel by gradient elution with isohexane:ethyl acetate (6:1) finishing with isohexane:ethyl acetate (4:1) yielded a yellow solid. 1H NMR (d6-DMSO, 400 MHz) 8.8(1H, s), 8.0 (2H, d), 7.8(1H,m), 7.6(2H,m), 6.8(1H, s), 6.0(1H, s), 4.1(2H, br. s), 3.6(2H,m), 2.5(2H, br. s), and 1.5(9H, s); LC/MS: m/z 474 [M+H]+, Rt=4.42 min
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](#[N:9])[CH3:8].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:14]#[N:15]>>[NH2:15][C:14]([C:13]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:11]([Cl:10])[CH:12]=1)=[CH:8][C:7]#[N:9]
Reactant: CC#N
Reactant: N#Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: N#CC=C(N)c1ccc(Cl)c(Cl)c1

Procedure:
Using a similar procedure to that of Preparation IX-2, but using 1.5 equivalents of potassium t-butoxide and 1.5 equivalents of acetonitrile per 1 equivalent of 3,4-dichlorobenzonitrile, there is obtained 3-amino-3-(3,4-dichlorophenyl)acrylonitrile.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[CH:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:40]([O:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:43])[CH:41]=[CH2:42].C(=O)([O-])O.[Na+].O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[CH:16][C:15](/[CH:42]=[CH:41]/[C:40]([O:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:43])=[CH:14][CH:13]=2)=[O:39])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CC(=O)OCCCC
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)/C=C/c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3)c2c1
Temperature: 100 °C
Yield: 24.2 %

Procedure:
A suspension of tert-butyl[4-(4-chlorophenyl)-2-isobutyl-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate (Example 186 (1)) (2.06 g, 3.5 mmol), butyl acrylate (0.76 ml, 5.3 mmol), sodium hydrogencarbonate (0.45 g, 5.3 mmol), tetrabutylammonium chloride (0.11 g, 0.4 mmol) and palladium acetate (0.09 g, 0.4 mmol) in N,N-dimethylformamide (20 ml) was stirred with heating at 100° C. under an argon atmosphere for 48 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give butyl (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate (0.48 g, 23.8%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:25]([N:29]=[C:30]=[O:31])[CH2:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[CH2:25]([NH:29][C:30]([NH:21][C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:23]=[CH:24][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:14][CH:15]=1)[CH3:22])=[O:31])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN=C=O
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(N)=O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)NC(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
2-(4-((3-Chloro-5-(trifluoromethyl)-2-pyridyl)-oxy)phenoxy)propanamide (2.24 grams (g), 0.006 mole) was dissolved in dry toluene (50 ml). Butyl isocyanate (1.8 g, 0.018 mole) was then added and the mixture refluxed 13 hours. At the end of this time most of the toluene was removed by distillation under reduced pressure and the residue taken up in hot heptane and treated with decolorizing carbon. After filtration and cooling the product was deposited in the form of fine white crystals, m.p. 126°-127° C.; Yield 2.1 g; 73.6%.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[CH2:23]([N:30]1[C:40]([CH3:42])([CH3:41])[CH2:39][O:38][C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([N:30]1[C:40]([CH3:42])([CH3:41])[CH2:39][O:38][C:32]2([CH2:33][CH2:34][N:35]([C:9]([C:8]3[CH:12]=[CH:13][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([CH3:14])[CH:7]=3)=[O:11])[CH2:36][CH2:37]2)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Reactant: CC1(C)COC2(CCNCC2)CN1Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)C(C)(C)CO3)ccc1OC(C)C
Reaction time: 0.08 h
Yield: 70.3 %

Procedure:
A solution of 4-isopropoxy-3-methylbenzoic acid (31.0 mg, 0.161 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (61.3 mg, 0.161 mmol) in acetonitrile was treated with triethylamine (67 μL, 0.48 mmol) and stirred for 5 min. 8-Benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride (56.0 mg, 0.161 mmol) was added and the reaction mixture stirred for 3 h. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified by chromatography (0-80% of ethyl acetate/hexanes) to provide (8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (51.0 mg, 70%) as colorless oil. ESI-MS m/z calc. 450.6. found 451.3 (M+1)+; Retention time: 1.54 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.N1[CH2:16][CH2:15][CH2:14][CH2:13]1.C1(=O)CCC1>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:13]1([CH2:16][CH2:15][CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: C1CCNC1
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: O=C1CCC1
Solvent: O
Solvent: CO
Product: O=C1CC2(CCC2)Oc2ccc(Cl)cc21
Yield: 96.5 %

Procedure:
To a stirred solution of 5′-chloro-2′-hydroxy acetophenone (5.0 g, 29.308 mmol) in methanol (50 ml) was added pyrrolidine (4.16 g, 58.616 mmol) followed by cyclobutanone (4.1 g, 58.616 mmol) at room temperature. The reaction mixture was heated to reflux under nitrogen for 14 h. The solvent was evaporated under reduced pressure and the residue obtained was diluted with water (100 ml) and the mixture was acidified to pH 4.0. The mixture was extracted with chloroform (3×100 ml). The combined organic extracts were washed with water (100 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The residue obtained after evaporation of the solvent was purified by silica gel column chromatography using 15% ethyl acetate in petroleum ether to give 6.3 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.69-1.88 (m, 5H), 1.96-2.04 (m, 1H), 2.88 (s, 2H), 6.91 (d, J=9.0 Hz, 1H), 7.38 (d, J=6.6 Hz, 1H), 7.76 (s, 1H).
Reaction SMILES: N[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:19])[C:16]=3[F:18])[C:11]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]2[CH:33]2[CH2:35][CH2:34]2)[CH:6]=[N:5]1.C([O-])([O-])=O.[Cs+].[Cs+].BrCC[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C=O)C>[C:49]([O:48][C:46](=[O:47])[CH2:45][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:19])[C:16]=3[F:18])[C:11]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]2[CH:33]2[CH2:35][CH2:34]2)[CH:6]=[N:5]1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCN)c3)c3c(F)c(Cl)ccc23)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCCC(=O)OC(C)(C)C)c3)c3c(F)c(Cl)ccc23)c1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a stirred solution of indole 1 (Example 11, Step 3; 200 mg, 0.42 mmol) in DMF (5 mL) under inert atmosphere were added Cs2CO3 (206 mg, 0.63 mmol) and tert-butyl 4-bromobutanoate (141 mg, 0.63 mmol) at RT and stirred for 16 h. The mixture was diluted with ice cold water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. This was purified (silica gel chromatography; 20% EtOAc/hexanes) to afford compound 2 (180 mg, 70%) as a pale brown oil. 1H NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 7.64 (s, 1H), 7.63-7.60 (m, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.10-7.06 (m, 1H), 6.93 (t, J=8.0 Hz, 1H), 6.77 (t, J=7.6 Hz, 1H), 4.41 (q, 2H), 4.28 (t, J=6.8 Hz, 2H), 2.28-2.19 (m, 4H), 1.74-1.66 (m, 1H), 1.46 (s, 9H), 1.41 (t, J=7.2 Hz, 3H), 1.06-1.02 (m, 2H), 0.89-0.84 (m, 2H); LC-MS (ESI): m/z 618.6 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].CCN(CC)CC.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([Si:26]([CH3:28])([CH3:27])[O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14])([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc2c(cc1O)C(=O)CCC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)C(=O)CCC2
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a well-stirred solution of 7-Hydroxy-6-methoxy-1-tetralone (80.0 mg, 0.42 mmol) in CH2Cl2, was added Et3N (47 mg, 0.46 mmol), followed by DMAP (5.1 mg, 0.042 mmol) and TBSCl (69 mg, 0.46 mmol) at 0° C. under dry nitogen. After 2 h (at rt), the mixture was partitioned between CH2Cl2 and water. The organic layer was dried over anhydrous sodium sulfate, and after filtration, the organic layer was concentrated in vacuo to provide a yellow oil. 7-[(tertButyldimethylsilyl)oxy]-6-methoxy-1-tetralone (122 mg, 0.40 mmol, 95%) was obtained following purification by column chromatography. 1H-NMR (CDCl3, 300 MHz) 0.15 (s, 6H), 0.99 (s, 9H),2.11 (m, 2H), 2.58 (t, J=6.1 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 3.86 (s, 3H), 6.63 (s, 1H), 7.56 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Reactant: CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.7 %

Procedure:
To a solution of 4-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide (0.109 g 0.25 mmol) in chloroform (10 ml) was added diisopropylethylamine (Aldrich) (100 μl), 4-dimethylaminopyridine (0.02 g 0.16 mmol) and valeryl chloride (Aldrich) (0.072 g 0.6 mmol) and the reaction was stirred at room temperature for 20 hr. It was washed with M Na2CO3 (5 ml), water (5 ml) and dried (MgSO4). Removal of solvent gave a solid which was purified by SPE chromatography. Elution with cyclohexane:ethyl acetate (2:1) gave the title compound as a white solid (0.075 g 58%).
Reaction SMILES: CC(O)C.C(N(CC)CC)C.[CH2:12]([O:14][C:15]([CH:17]([NH2:27])[C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[CH:19]=1)=[O:16])[CH3:13].Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Cl:39])[CH:37]=2)[N:32]=[CH:31][N:30]=1>O>[CH2:12]([O:14][C:15]([CH:17]([NH:27][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Cl:39])[CH:37]=2)[N:32]=[CH:31][N:30]=1)[C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[CH:19]=1)=[O:16])[CH3:13]
Reactant: Clc1ccc2ncnc(Cl)c2c1
Reactant: CCOC(=O)C(N)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Yield: 85.5 %

Procedure:
30 ml of 2-propanol, 1.07 g of triethylamine and 1.01 g of α-ethoxycarbonyl-3,4-methylenedioxybenzylamine were added to 704 mg of 4,6-dichloroquinazoline. The obtained mixture was refluxed for 4 hours, followed by the addition of water. The obtained mixture was extracted with chloroform thrice. The chloroform layers were combined, dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The residue was recrystallized (from ethanol/ethyl acetate/hexane) to give 1.167 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.Br.Br[CH2:19][CH2:20][NH2:21].C(N(CC)CC)C>CN(C=O)C.O.C1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[O:6][CH2:19][CH2:20][N:21]=1
Reactant: NCCBr
Reactant: O=C(O)c1ccccc1F
Agent: Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Fc1ccccc1C1=NCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.5 %

Procedure:
A mixture of 2-fluorobenzoic acid (4.5 g, 32.14 mmol), oxalyl chloride (4.1 mL, 48.2 mL), DMF (2 drops) and methylene chloride (40 mL) was heated 2 hours at reflux. The reaction mixture was allowed to cool to 25° C., then stirred approximately 12 hours and concentrated. The residue was slowly added to a suspension of 2-bromoethylamine hydrobromide (5.7 g, 28 mmol), triethylamine (21 mL, 160 mmol) and benzene (200 mL). The mixture was heated 12 hours at reflux, allowed to cool to 25° C., stirred an additional 12 hours and diluted with water. The aqueous layer was separated and extracted with methylene chloride (2×50 mL). The combined extracts were dried (MgSO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (5:1) to give 2-fluoro-1-(4,5-dihydrooxazol-2-yl)benzene (1.96 g, 11.9 mmol).
Reaction SMILES: C(OC1C=C[N:12]([C:15]2[CH:20]=CC(O)=[CH:17][CH:16]=2)[C:11](=O)C=1)C1C=CC=CC=1.[CH2:23]([OH:25])[CH3:24]>>[OH:25][CH2:23][C:24]1[CH:17]=[CH:16][C:15]([CH3:20])=[N:12][CH:11]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Reactant: CCO
Product: Cc1ccc(CO)cn1

Procedure:
Step (5) of Example 1 was repeated except that 4-benzyloxy-1-(4-hydroxyphenyl)-1H-pyridin-2-one and 2-dimethylamino)ethanol were replaced with the compound as obtained in above Step (1) and 5-hydroxymethyl-2-methylpyridine, to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH2:41][CH2:40]1>>[F:26][C:25]([F:28])([F:27])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([O:31][CH3:30])=[C:33]([N:39]5[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH2:41][CH2:40]5)[CH:34]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:29]
Reactant: COc1ccc(N)cc1N1CCN(CCS(C)(=O)=O)CC1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Product: COc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)C(F)(F)F)c4)nn4ccccc34)n2)cc1N1CCN(CCS(C)(=O)=O)CC1
Yield: 42 %

Procedure:
The compound was synthesized from N-{3-[3-(2-chloro-4-pyrimidinyl)-pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (see Example 1, Step C) and 4-(methyloxy)-3-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline to afford a yellow solid in 42% yield. ES-LC/MS m/z 695 [M+H]+.