Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][C:17]#[N:18].C(N(CC)CC)C>O1CCCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:12][CH2:16][C:17]#[N:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: N#CCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCNc1ccc(Oc2ccccc2)cc1
Temperature: 85 °C
Yield: 44.8 %

Procedure:
A mixture of 4-phenoxyaniline (7.0 g, 37.8 mmol), bromoacetonitrile (4.5 g, 37.8 mmol) and triethylamine (4.2 g, 41.6 mmol) in tetrahydrofuran (50 mL) was heated at 85° C. for 5.25 hours then cooled and another portion of bromoacetonitrile (6.5 g, 5.46 mmol) was added. The mixture was heated at 85° C. for 18 hours then cooled and concentrated under reduced pressure. The residue was partitioned between dichloromethane (50 mL) and water (50 mL). The aqueous layer was extracted with dichloromethane (30 mL) then the combined organic solutions were extracted with 5 N aqueous sodium hydroxide (30 mL), dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel using dichloromethane/ethyl acetate (98:2) as an eluent to provide 3.8 g (45%) of the title compound as a dark brown solid: 1H NMR (DMSO-d6, 400 MHz) δ 7.32 (t, 2H), 7.03 (t, 1H), 6.87–6.94 (m, 4H), 6.76 (d, 2H), 6.26 (bs, 2H), 4.25 (s, 2H);RP-HPLC (Hypersil HS-C18, 5 μm, 100 A, 4.6×250 mm; 25%–100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 18.4 min.; MS: MH+ 225.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([NH:13]C(=O)OCC3C=CC=CC=3)[C:11]([CH3:12])=[C:5]2[C:4]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)#[N:2].Cl>CO.[Pd]>[NH2:13][C:10]1[C:11]([CH3:12])=[C:5]2[C:4]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:29][CH:30]=3)=[C:3]([C:1]#[N:2])[CH:8]=[N:7][N:6]2[CH:9]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
To a solution of compound 11A (40 mg, 0.082 mmol) in MeOH (4 mL) was added Pd/C (12 mg), and the reaction mixture was stirred under hydrogen (1 atm) for 30 minutes, after which time HCl (4M in dioxane, 0.1 mL) was added. The reaction mixture was filtered and the filtrate concentrated in vacuo to provide 32 mg of compound 11B as an orange solid (quantitative yield as HCl salt). HPLC: 100% at 2.90 min (retention time) (YMC S5 ODS column, 4.6×50 mm eluting with 10-90% McOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). MS (ES): m/z 356.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25](OCC)=[O:26])=[O:7])=[CH:4][CH:3]=1.[NH2:32][CH2:33][CH2:34][OH:35]>CN1C(=O)CCC1.CCOC(C)=O>[OH:35][CH2:34][CH2:33][NH:32][C:25]([C:10]1[N:11]=[C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[S:13][C:9]=1[NH:8][C:6](=[O:7])[C:5]1[CH:30]=[CH:31][C:2]([NH:11][CH2:10][CH2:25][OH:26])=[CH:3][CH:4]=1)=[O:26]
Reactant: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(F)cc1
Reactant: NCCO
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(Nc1sc(Nc2ccc3ccccc3c2)nc1C(=O)NCCO)c1ccc(NCCO)cc1
Yield: 47.5 %

Procedure:
A solution of Ethyl 5-(4-fluorobenzamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxylate (25 mg, 0.06 mmol) and 2-aminoethanol (0.024 mL, 0.40 mmol) in NMP (0.5 mL) was treated using a microwave synthesizer for 70 min (Biotage, 150° C.). The reaction mixture was diluted with EtOAc. The organic layer was washed with H2O, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluted with 2.5% MeOH in DCM to give 7 mg (25% yield) of the titled compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:19])([F:18])[F:17])[O:13]2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[Cl:25]Cl>CCOC(C)=O.C(Cl)Cl>[Cl:25][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[C:3]([CH3:5])([CH3:4])[CH2:2][OH:1])[O:13][CH:12]([C:16]([F:18])([F:19])[F:17])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10]2
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)CO)cc2OC1C(F)(F)F
Reactant: ClCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)CO)cc2OC1C(F)(F)F

Procedure:
A single treatment of ethyl 7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (5.4 g 16 mmoles) with Cl2 was performed as described in Example 115 Step 2. Chromatography of the residue using a gradient of 0-10% EtOAc—DCM as eluent gave the title compound, 3.7 g, as a nearly colorless oil.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[N:19]=[C:18]3[CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH:45]5[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]5)=[CH:39][CH:38]=4)=[CH:33][CH:32]=3)[CH:12]=2)[S:6]1(=[O:52])=[O:51])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH:45]1([CH2:44][O:43][C:40]2[CH:39]=[CH:38][C:37]([C:34]3[CH:33]=[CH:32][C:31]([CH2:30][C:18]4[N:17]([C:13]5[CH:12]=[C:11]([C:7]6[S:6](=[O:51])(=[O:52])[NH:5][C:9](=[O:10])[CH:8]=6)[CH:16]=[CH:15][CH:14]=5)[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=5[Cl:29])[N:19]=4)=[CH:36][CH:35]=3)=[CH:42][CH:41]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: CC(C)(C)N1C(=O)C=C(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCC5CCCCC5)cc4)cc3)c2)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=C(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCC5CCCCC5)cc4)cc3)c2)S(=O)(=O)N1

Procedure:
2-tert-Butyl-5-{3-[2-(4′-cyclohexylmethoxy-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-isothiazol-3-one-1,1-dioxide (4 mg, 0.005 mmol) was treated with TFA following general procedure to give 5-{3-[2-(4′-cyclohexylmethoxy-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-isothiazol-3-one-1,1-dioxide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([CH2:10][O:11][N:12]=[C:13]([C:37]2[N:38]=[C:39]([NH:42]C=O)[S:40][CH:41]=2)[C:14]([NH:16][CH:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]4[N:30]([CH3:31])[N:29]=[N:28][N:27]=4)[CH2:22][S:23][C@H:18]23)=[O:15])=[O:9])[CH:2]=1.Cl>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([CH2:10][O:11][N:12]=[C:13]([C:37]2[N:38]=[C:39]([NH2:42])[S:40][CH:41]=2)[C:14]([NH:16][CH:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]4[N:30]([CH3:31])[N:29]=[N:28][N:27]=4)[CH2:22][S:23][C@H:18]23)=[O:15])=[O:9])[CH:2]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3cccnc3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3cccnc3)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 23.2 %

Procedure:
To a suspension of 7-[2-{N-(3-pyridyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.7 g.) in methanol (40 ml.) was added conc. hydrochloric acid (1.09 ml.) with stirring at room temperature followed by stirring for 2 hours at the same temperature. The reaction mixture was separated by decantation into two groups, that is, a methanol layer and viscous precipitates. The methanol layer was treated with activated charcoal and concentrated and then the residue was dissolved in water. After the solution was adjusted to pH 3 to 4 with an aqueous solution of sodium bicarbonate, the precipitates are collected by filtration to give a powder of the title compound (0.6 g.). On the other hand, the viscous precipitates were dissolved in a mixture of methanol conc. hydrochloric acid and water and the solution was stirred for an hour at room temperature, treated with activated charcoal and then concentrated. The residue was dissolved in water and thereto was added an aqueous solution of sodium bicarbonate under cooling whereby the pH was adjusted to 3 to 4. The precipitates were collected by filtration to give a powder of the title compound (1.0 g.). Total Total yield: 1.6 g. mp. 180° to 210° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](Cl)=[CH:4][C:5]([F:8])([F:7])[F:6].[OH-].[K+]>C(O)C.[Ni]>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)CCC(F)(F)F
Yield: 46.7 %

Procedure:
40 g (0.2 mol) of 1,1,1,4,4,4-hexafluoro-2-chloro-2-butene were hydrogenated in 300 ml of ethanol in the presence of 12 g of potassium hydroxide and 24 g of Raney nickel in the pressure range of from 20 to 40 bar and at a temperature from 20 to 100° C. The solid components were filtered off, the solvent was extracted with water, and the organic phase was separated and purified by distillation to give 15.5 g (47% of theory) of 1,1,1,4,4,4-hexafluorobutane. The boiling point was 25 to 27° C. at 1013 mbar.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=2)[C:12](O)=[O:13])=[CH:6][CH:5]=1.[CH2:33]([NH2:35])[CH3:34]>>[CH2:33]([NH:35][C:12](=[O:13])[CH:11]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:32])([F:31])[F:1])=[CH:9][CH:8]=1)[CH3:34]
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCC(F)(F)F)cc1
Reactant: CCN
Product: CCNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 3-[4-(trifluoromethoxy)phenyl]-2-{[4-(3,3,3-trifluoropropoxy)benzoyl]amino}propanoic acid (139 mg) prepared in Example 70 (70a) and ethylamine (30 μL, 70% aqueous solution) to give 106 mg of the title compound (white powder).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:20][CH2:21][O:22][CH3:23])[S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1Cl)(=[O:8])=[O:7].[H-].[Na+].[OH2:26]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:20][CH2:21][O:22][CH3:23])[S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1[OH:26])(=[O:8])=[O:7]
Reactant: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 55 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N,N-di-(2-methoxyethyl)-2,6-dichloro-3-nitrobenzenesulfonamide (800 mg, 2.07 mmol), 60% NaH (248 mg, 6.21 mmol) and water (45 μL, 2.48 mmol) were reacted to form the desired product (420 mg, 55%). EI-MS (m/z) 366.89, 368.81 (M−).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:15][C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([O:37][C@@H:38]([C@H:40]3[CH2:44][NH:43][C:42](=[O:45])[CH2:41]3)[CH3:39])[C:20]=12.C(N(CC)CC)C>ClCCl>[C:1]([N:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:23]3[N:22]=[C:21]([O:37][C@@H:38]([C@H:40]4[CH2:44][NH:43][C:42](=[O:45])[CH2:41]4)[CH3:39])[C:20]4[N:19]([N:18]=[CH:17][C:16]=4[CH3:15])[CH:24]=3)=[CH:26][CH:27]=2)[CH2:36][CH2:35]1)(=[O:3])[CH3:2]
Reactant: Cc1cnn2cc(-c3ccc(N4CCNCC4)cc3)nc(O[C@H](C)[C@H]3CNC(=O)C3)c12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(-c3cn4ncc(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1
Reaction time: 2 h
Yield: 79.3 %

Procedure:
Acetic anhydride (3.1 μL, 0.03 mmol) was added to a solution of (R)-4-((R)-1-(3-methyl-6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.56 (14.6 mg, 0.03 mmol) and triethylamine (0.03 mL, 0.21 mmol) in dichloromethane (1.5 mL) at room temperature. After two hours, reaction mixture was directly loaded onto silica gel and purified (0-10% methanol/dichloromethane) to yield (R)-4-((R)-1-((6-(4-(4-acetylpiperazin-1-yl)phenyl)-3-methylpyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.57 (11 mg).
Reaction SMILES: O.O.Cl.[F:4][C:5]([F:27])([F:26])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[C:11]2[NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=O.[NH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH3:36])[CH2:30]1.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>S(Cl)(Cl)=O.C(Cl)(Cl)Cl.O>[CH2:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:29]([NH:28][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[NH:16][C:11]2[C:10]3[C:15](=[C:6]([C:5]([F:26])([F:27])[F:4])[CH:7]=[CH:8][CH:9]=3)[N:14]=[CH:13][CH:12]=2)[CH2:30]1)[CH3:36]
Reactant: CCN1CCCC(N)C1
Reactant: O=C(O)c1ccccc1Nc1ccnc2c(C(F)(F)F)cccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCN1CCCC(NC(=O)c2ccccc2Nc2ccnc3c(C(F)(F)F)cccc23)C1
Reaction time: 1 h
Yield: 62.6 %

Procedure:
11.5 Grams (0.0285 Mole) of 2-(8-trifluoromethyl-4-quinolylamino)benzoic acid hydrochloride dihydrate were refluxed in 80 milliliters of thionyl chloride for half an hour. A yellow solid precipitated. The thionyl chloride was evaporated off. The resulting acid chloride hydrochloride was added in portions with stirring to a cooled mixture of 3.84 grams (0.03 moles) of 3-amino-1-ethylpiperidine in 100 milliliters of chloroform and 31.8 grams (0.3 mole) of sodium carbonate in 100 milliliters of water. The mixture was stirred for one hour and allowed to stand overnight. The chloroform layer was separated and dried and the chloroform evaporated to give a nearly colourless solid. Trituration with ether gave a colourless solid which was recrystallized from methanol to give 7.9 grams (63% yield) of title compound, melting point 212° to 213° C.
Reaction SMILES: [CH2:1]([NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[CH2:1]([N:5]1[C:17](=[O:18])[C:16]([OH:22])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6]1(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCCNS(=O)(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
N-Butyl-1-phenylmethanesulfonamide (2.0 g, 8.80 mmol) was dissolved in dry DMF (113 mL) under an atmosphere of nitrogen. Diethyl oxalate (1.44 g, 9.83 mmol) was added and the reaction mixture was cooled to 0° C. using an ice-bath. Potassium tert-butoxide (1.25 g, 11.14 mmol) was added in one portion and the reaction mixture was stirred for 5 mins at 0° C., followed by 19 h at rt. The mixture was cooled in an ice-bath and HCl (2M) was carefully added to give a pH˜1 of the mixture. Most of the solvents were evaporated and the residue was partitioned between HCl (2M) and EtOAc. The combined organic layers were washed with water several times, dried with MgSO4 and evaporated to dryness. The residue was purified using preparative HPLC (ACE C8, 0.1M NH4OAc/MeCN, gradient) to give the title compound (0.96 g, 39%); 1H NMR (400 MHz, DMSO-d6): δ 7.88-7.83 (m, 2H), 7.22-7.29 (m, 3H), 7.14 (bs, 1H), 6.98-7.15 (m, 2H), 3.48 (t, 2H), 1.59-1.67 (m, 2H), 1.27-1.37 (m, 2H), 0.88 (t, 3H); 13C NMR (100 MHz, DMSO-d6): δ 163.1, 158.4, 132.3, 128.7, 124.2, 123.2, 37.8, 30.9, 20.2, 14.1; Mass Spectrum: M−H′ 280.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][C:3]=1[C:30]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33].[CH:40]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:40]1([NH:45][C:2]2[N:7]3[N:8]=[C:9]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:12]=4)=[C:6]3[CH:5]=[CH:4][C:3]=2[C:30]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Reactant: NC1CCCC1
Product: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1
Temperature: 80 °C
Yield: 96.1 %

Procedure:
A mixture of 4-[7-chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (2.37 g, 4.28 mmol) and cyclopentylamine (10 mL, 100 mmol) was heated in a sealed tube at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and excess cyclopentylamine was removed in vacuo. The crude solid was triturated in water. The solids were collected on a filter to provide N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-7-amine (2.48 g, 96%). Rf 0.42 (4:1 hexanes:ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1H), 7.75 (d, 1H), 7.68–7.60 (m, 3H), 7.12 (t, 2H), 6.36–6.31 (m, 2H), 5.30 (m, 1H), 5.07 (d, 1H), 4.53 (m, 1H), 3.45 (q, 6H), 2.12–1.95 (m, 4H), 1.80–1.45 (m, 12H), 1.25 (t, 9H); MS m/z 603 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:12]([F:13])=[C:11]([F:14])[C:7]([C:8](Cl)=[O:9])=[C:6]([F:15])[C:5]=1[F:16].[CH2:17]([OH:19])[CH3:18]>>[CH3:1][O:2][CH2:3][C:4]1[C:12]([F:13])=[C:11]([F:14])[C:7]([C:8]([O:19][CH2:17][CH3:18])=[O:9])=[C:6]([F:15])[C:5]=1[F:16]
Reactant: COCc1c(F)c(F)c(C(=O)Cl)c(F)c1F
Reactant: CCO
Product: CCOC(=O)c1c(F)c(F)c(COC)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The acid chloride from stage 1 (1.00 g) was dissolved in dry ethanol (5 cm3) and, when the initial exothermic reaction had subsided, the solution was stirred for a further 3 hours at the ambient temperature. The excess ethanol was evaporated under reduced pressure to yield ethyl 4-(methoxymethyl)-2,3,5,6-tetrafluorobenzoate (0.90 g) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:7]1[S:11][C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)[C:4]([NH2:6])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:6][CH2:4][CH:3]([C:7]1[S:11][C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)[CH2:2][OH:1]
Reactant: NC(=O)C(CO)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(CO)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1
Temperature: 50 °C

Procedure:
To a solution of compound 74.1 (0.08 mmol) in THF (1.0 mL) is added LAH (0.24 mL of 1.0 M solution in THF) and the reaction mixture is heated at 50° C. for 4 hours. The reaction is quenched with the dropwise addition of saturated NH4Cl, the volatiles are removed under reduced pressure and then extracted with EtOAc. The combined organic layers are filtered and concentrated to provide 1-[5-(2-amino-1-hydroxymethyl-ethyl)-thiazol-2-yl]-3-(3-trifluoromethyl-phenyl)-urea (compound 74.2) of sufficient purity for use in the next step.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:22]12[CH2:29][O:28][C:25]([C:30]3[CH:35]=[CH:34][C:33]([C:36]#[C:37][Si](C)(C)C)=[CH:32][CH:31]=3)([O:26][CH2:27]1)[O:24][CH:23]2[C:42]([F:45])([F:44])[F:43])[CH2:20][CH3:21]>O1CCCC1>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:25]23[O:28][CH2:29][C:22]([CH2:19][CH2:20][CH3:21])([CH2:27][O:26]2)[CH:23]([C:42]([F:44])([F:45])[F:43])[O:24]3)=[CH:35][CH:34]=1)#[CH:37]
Reactant: CCCC12COC(c3ccc(C#C[Si](C)(C)C)cc3)(OC1)OC2C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C23OCC(CCC)(CO2)C(C(F)(F)F)O3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrabutylammonium fluoride solution (0.84 ml., 1M solution in tetrahydrofuran) was added to a stirred solution of 4-n-propyl-3-trifluoromethyl-1-[4-(2-trimethylsilylethynyl)phenyl]-2,6,7-trioxabicyclo[2,2,2]octane (0.28 g.) in dry tetrahydrofuran (5 mls). The mixture was stirred for 30 minutes at room temperature. The solvent was removed in vacuo and the residue was dissolved in dry diethyl ether. The ethereal solution was washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was recrystallised from hexane. 1-(4-Ethynylphenyl)-4-n-propyl-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane was obtained as a pale yellow solid (70 mg.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH:15]=O)[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17])[CH3:2].[CH3:19][NH:20][CH3:21].C(O)(=O)C.[BH3-]C#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH2:15][N:20]([CH3:21])[CH3:19])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)Cc1c(C)oc2ccc(C=O)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(C)oc2ccc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of (5-formyl-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (1.00 g, 4.06 mmol) in anhydrous ethanol (25 mL) is added a 5 M solution of dimethylamine in ethanol (4.1 mL). The resulting reaction mixture is stirred for 18 h at room temperature. Acetic acid (1.4 mL) and NaBH3CN (279 mg, 4.22 mmol) are added and the resulting reaction mixture is heated at 50° C. for 4 h. After cooling to room temperature the solvents are removed by rotary evaporation. The residue is taken up in water, basified (pH=8) with a saturated aqueous NaHCO3 solution and extracted twice with EtOAc. The combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. The crude product is purified by flash column chromatography (silica gel, gradient of dichloromethane/methanol 10:0 to 9:1) to afford the title compound as a colorless oil (744 mg, 2.70 mmol, 67%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.39 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.58 (s, 2H), 3.50 (s, 2H), 2.41 (s, 3H), 2.25 (s, 6H), 1.23 (t, J=7.1 Hz, 3H). MS (ES+): 276 (M(C16H21NO3)+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(C(C)C)cc1
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3oc(C)c(-c4ccc(C(C)C)cc4)c3c2C)cc1
Yield: 49 %

Procedure:
By using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 49%. Amorphous.