Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[C:19]([O:21]C)=O.CC(C)([O-])C.[K+]>O1CCCC1>[O:21]=[C:19]1[CH:7]2[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11][N:6]2[CH2:5][CH:4]1[C:3]([O:2][CH3:1])=[O:23]
Reactant: COC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1CN2CCN(C(=O)OC(C)(C)C)CC2C1=O
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-tert-butyl 3-methyl 4-(3-methoxy-3-oxopropyl)piperazine-1,3-dicarboxylate (Example 100A, 180 g, 0.545 mol) in tetrahydrofuran (1.3 L) was added potassium t-butoxide (98 g, 0.872 mol) with stirring at 0-5° C. under N2 atmosphere portion-wise over a period of 30 minutes. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction was then quenched with saturated aqueous ammonium chloride solution (500 mL) and extracted with ethyl acetate (1 L). The organic layer was separated, washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.28-2.35 (m, 2H), 2.65-2.83 (m, 1H), 2.83-3.12 (m, 3H), 3.43 (t, 1H, J=8.4 Hz), 3.61 (t, 1H, J=8.4 Hz), 3.78 (s, 3H), 3.98-4.20 (bs, 1H), 4.20-4.45 (bs, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:21])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCCCC3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (100 mg) and piperidine (22.7 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(piperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (81.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14](OC)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH:14]=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl trans-4-(4-chlorophenyl)cyclohexanecarboxylate (compound of formula (VIIa)) (50.5 g, 200 mmol) in tetrahydrofuran (400 mL) at 0° C. under argon was added a 1M solution of lithium aluminium hydride in tetrahydrofuran (100 mL, 100 mmol) and the reaction mixture stirred for 30 minutes. The reaction mixture was cooled to 0° C. and 1M aqueous hydrochloric acid (500 mL, 500 mmol) was added and the mixture stirred for 5 minutes. The aqueous was separated and extracted with ethyl acetate (250 mL) then the combined organics were washed twice with water (2×125 mL). The resulting organics were concentrated under vacuum to a volume of 150 mL. The residue was diluted with ethyl acetate (250 mL) and the mixture concentrated under vacuum to a volume of 150 mL. The residue was diluted with ethyl acetate (250 mL) and the mixture concentrated under vacuum to a volume of 150 mL. The residue was diluted with ethyl acetate (250 mL) and the mixture concentrated under vacuum to a volume of 150 mL. To the resulting stirred mixture, at ambient temperature under argon, was added dimethyl sulfoxide (100 mL) and triethylamine (112 mL, 804 mmol). The mixture was cooled to 0° C. then pyridine sulphur trioxide complex (64 g, 402 mmol) was added in 4 equal portions and the reaction mixture stirred between 0 and 20° C. for 2 hours. Ethyl acetate (400 mL) was added, the mixture cooled to 0° C. with stirring and then 1M aqueous hydrochloric acid (400 mL, 400 mmol) was added. The resulting mixture was stirred at ambient temperature for 5 minutes then the organic layer was separated, diluted by the addition of ethyl acetate (500 mL) and washed with water (250 mL). The resulting organics were concentrated under vacuum to a volume of 200 mL, the residue diluted by the addition of ethyl acetate (500 mL) and then concentrated to a volume of 200 mL. The resulting mixture containing the title compound was used in the next step without analysis or purification.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16]O)[CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:40][C:41]([NH:43][S:44]([NH2:47])(=[O:46])=[O:45])=[O:42])[CH:38]=[CH2:39].C(OC(N=NC(OCC)=O)=O)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16][N:43]([S:44](=[O:45])(=[O:46])[NH2:47])[C:41]([O:40][CH2:37][CH:38]=[CH2:39])=[O:42])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CO
Reactant: C=CCOC(=O)NS(N)(=O)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CN(C(=O)OCC=C)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-allyloxycarbonylpyrrolidine-2-methanol (8.02 g: ca. 30 mmole) in ethyl acetate (83 ml) under ice cooling, triphenylphosphine (9.44 g: 13.6 mmole), N-allyloxycarbonylsulfamide (3.12 g: 15.9 mmole), and azodicarboxylic acid diethylester (5.67 ml: 36 mmole) are successively added. The mixture is stirred under ice cooling for 55 minutes and at room temperature for 4 hours. The reaction mixture is dissolved in toluene (60 ml), concentrated, diluted with toluene (60 ml), filtered to remove separating crystals, and the filtrate is concentrated. The residue is purified by silica gel chromatography to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(N-sulfamoyl-N-allyloxycarbonylamino)methylpyrrolidine (6.74 g). Yield: 55%. Colorless oil.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[CH2:18]([N:20]1[C:24]2=[N:25][C:26]3[C:31]([C:32]([NH:33][CH2:34][CH:35]4[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]4)=[C:23]2[CH:22]=[N:21]1)=[CH:30][C:29]([O:42][CH3:43])=[CH:28][CH:27]=3)[CH3:19].C(N(CC)CC)C.CS(O)(=O)=O>C(Cl)Cl.CC(O)C.CCOCC.O>[CH2:18]([N:20]1[C:24]2=[N:25][C:26]3[C:31]([C:32]([NH:33][CH2:34][CH:35]4[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]4)=[C:23]2[CH:22]=[N:21]1)=[CH:30][C:29]([O:42][CH3:43])=[CH:28][CH:27]=3)[CH3:19]
Reactant: CCn1ncc2c(NCC3CCC(O)CC3)c3cc(OC)ccc3nc21
Agent: CS(=O)(=O)O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1ncc2c(NCC3CCC(=O)CC3)c3cc(OC)ccc3nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of CH2Cl2 (35 ml) and trifluoroacetic anhydride (3.6 ml, 0.0224 mol) at -78° C. is added CH2Cl2 (5 ml) and DMSO (3.22 ml, 0.0454 mol). The reaction mixture is stirred for 1 hour, then a solution of 1-ethyl-6-methoxy-N-(4-hydroxycyclohexylmethyl)-1H-pyrazolo-[3,4-b]quinolin-4-amine (1.8 g, 0.0051 mol) in CH2Cl2 (30 ml) is added, and the reaction mixture is slowly warmed to 0° C. with stirring overnight. The reaction mixture is cooled to -78° C. and triethylamine (11 ml, 0.075 mol) is added. The reaction mixture is warmed to room temperature, stirred for 5 hours and then poured into water. The mixture is extracted with CH2Cl2 and the CH2Cl2 extracts are combined, washed with water, dried over MgSO4 and evaporated. The residue is purified by column chromatography on silica gel eluting with ethyl acetate to afford the product as the free base. The free base is dissolved in 2-propanol and methanesulfonic acid is added. The volume is reduced to about 5 ml, ether is added and the precipitated salt is collected by filtration and recrystallized from 2-propanol/ether to afford 1 g of 1-ethyl-6-methoxy-N-[4-oxocyclohexylmethyl]-1H-pyrazolo[3,4-b]quinolin-4-amine. CH3SO3H. 1/2 H2O.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([OH:23])[C:21]2[CH:25]=[CH:26][C:18]([Br:17])=[CH:19][CH:20]=2)[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(=C(O)c2ccc(Br)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared analogously to Example 10(a) from 1-acetyl-5-nitro-2-indolinone and 4-bromo-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hunig's base (20° C., overnight) and evaporation in vacuo. A sample of the crude product obtained was purified by column chromatography on silica gel with CH2Cl2 /MeOH (20:1) as eluant.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17](OC)=[O:18])[CH2:3][CH:4]=[CH2:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C@H:2]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:17][OH:18])[CH2:3][CH:4]=[CH2:5]
Reactant: C=CC[C@H](C)Oc1c(C(=O)OC)ccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1c(CO)ccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a mixture of (S)-methyl 1-(pent-4-en-2-yloxy)-2-naphthoate (300 mg, 1.110 mmol) in THF (10 mL) was added 1 N LAH (2.220 mL, 2.220 mmol) and the reaction was stirred at rt for 1 h. It was then quenched with NH4Cl and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate (S)-(1-(pent-4-en-2-yloxy)naphthalen-2-yl)methanol (200 mg, 0.825 mmol, 74.4% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.19-8.08 (m, 1H), 7.90-7.80 (m, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.58-7.45 (m, 3H), 5.96 (ddt, J=17.1, 10.1, 7.2 Hz, 1H), 5.25-5.11 (m, 2H), 4.93 (qd, J=12.6, 5.9 Hz, 2H), 4.54-4.34 (m, 1H), 2.65 (qd, J=6.8, 5.5 Hz, 1H), 2.59-2.48 (m, 1H), 2.18 (t, J=6.0 Hz, 1H), 1.31 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.[CH3:25]CO.[ClH:28]>>[CH2:1]([O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[NH2:7])[CH3:25].[ClH:28]
Reactant: CCO
Reactant: COC(=O)[C@H](O)CN(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CCOC(=O)[C@H](O)CN(N)Cc1ccc(Br)cc1

Procedure:
A solution of (R)-3-[N-(4-bromobenzyl)-N′-t-butoxycarbonylhydrazino]-2-hydroxypropionic acid methyl ester (25 g, 62 mmol) in EtOH/HCl (1M, 310 mL, 0.3 mol) was stirred overnight until the reaction was complete. The mixture was then concentrated and the residue was washed with EtOAc (120 mL) and filtered. The solids were collected to yield the title compound as a white solid HCl salt (15 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[CH:25]=[N:24][C:23]4[NH:22][CH2:21][CH2:20][O:19][C:18]=4[CH:17]=3)=[O:15])[C@H:11]([C:26]([F:29])([F:28])[F:27])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:31]12[CH2:37][C@H:34]([NH:35][CH2:36]1)[CH2:33][O:32]2>>[O:19]1[CH2:20][CH2:21][NH:22][C:23]2[N:24]=[CH:25][C:16]([C:14](=[O:15])[CH2:13][N:12]3[C:4]4=[N:3][C:2]([N:35]5[CH2:36][C@@H:31]6[CH2:37][C@H:34]5[CH2:33][O:32]6)=[CH:7][C:6](=[O:8])[N:5]4[CH2:9][CH2:10][C@H:11]3[C:26]([F:28])([F:27])[F:29])=[CH:17][C:18]1=2
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1cnc2c(c1)OCCN2
Agent: Cl
Product: O=C(CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F)c1cnc2c(c1)OCCN2

Procedure:
110 mg (0.25 mmol) of (8S)-2-chloro-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 41.64 mg (0.31 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by passing through an RP18 reverse-phase column (eluent: from 100% H2O to 100% CH3CN over 30 minutes), 30 mg of (8S)-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: C([NH:4]/[N:5]=[CH:6]/[C:7]1[N:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:8]=1[C:9](OCC)=[O:10])(=O)C.[OH-].[Na+]>O1CCOCC1>[Cl:18][C:14]1[C:8]2[C:9](=[O:10])[NH:4][N:5]=[CH:6][C:7]=2[N:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c(Cl)ccnc1/C=N/NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1[nH]ncc2nccc(Cl)c12
Temperature: 145 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
(E)-ethyl 2-((2-acetylhydrazono)methyl)-4-chloronicotinate (2850 mg, 10.57 mmol) in 15 mL of dioxane was mixed with aq. NaOH (42.3 mg, 1.06 mmol, 2 M). The reaction mixture was stirred in a microwave for 60 min at 145° C. After cooling to room temperature, the solid was filtered off. The solid was dissolved in methanol and the residue was filtered off. The filtrate was concentrated and triturated with EA to give 1.4 g (73.0%) of the title compound as orange brown solid.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([C:11]#[CH:12])[CH2:4][CH2:5][C:6]([O:8]CC)=[O:7]>Cl>[ClH:1].[NH2:2][CH:3]([C:11]#[CH:12])[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: C#CC(N)CCC(=O)OCC
Agent: Cl
Product: C#CC(N)CCC(=O)O

Procedure:
A solution of 0.4 g of 1 in 2 ml of concentrated hydrochloric acid was stirred at room temperature for one hour. The water was evaporated. Toluene was added to the residue and distilled to remove residual water by azeotropic distillation. The residue was dried under reduced pressure to give 2, as a hygroscopic solid.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:25])[C@@H:8]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C>C(O)(C)C.O=[Pt]=O>[CH:1]1([O:6][C:7](=[O:25])[C@@H:8]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC1CCCC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCC(O)CC1)C(=O)OC1CCCC1
Reaction time: 16 h
Yield: 76.4 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acid cyclopentyl ester (Scheme 12) (2.35 g, 9.5 mmol) in isopropanol (40 ml) was placed in a glass insert (120 ml volume). PtO2 (0.47 g, 2.1 mmol) was added to the glass insert which was placed in a hydrogenation bomb. Acetic acid (3 ml) was placed in a glass vial in the bomb next to the glass insert. The bomb was sealed and the reaction stirred for 16 h under an atmosphere of hydrogen (5 bar pressure). The reaction mixture was filtered through celite and washed with isopropanol. The solvent was removed in vacuo and azeotroped with THF to remove excess isopropanol to furnish the 2.58 g (quantitative yield) of the desired product.
Reaction SMILES: [C:1]1([CH:7]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH2:27][C:28](=[CH:32][C:33]([O:35]C)=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=2[Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.COC1C=CC(C(C)CN(CCCOC2CC(=CC(O)=O)C=CC=2)CC2C=CC=C(C(F)(F)F)C=2Cl)=CC=1>>[ClH:21].[C:1]1([CH:7]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH2:27][C:28](=[CH:32][C:33]([OH:35])=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[C:12]=2[Cl:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(CC(C)C)c2ccccc2)C1
Agent: COc1ccc(C(C)CN(CCCOC2=CC=CC(=CC(=O)O)C2)Cc2cccc(C(F)(F)F)c2Cl)cc1
Agent: Cl
Product: CC(C)CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Yield: 74 %

Procedure:
The titled compound was prepared from N-(2-phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in 74% yield in the same manner as the preparation of N-(2-[4-Methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine, hydrochloride in Example 188f. MS (ESI) 562 (MH+)
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[C:23]([N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:22]3[N:42]=[CH:43][CH:44]=[C:21]3[N:20]=2)[CH2:15][CH2:14]1)=[O:12]>C(#N)C>[CH3:9][O:10][C:11]([CH:13]1[CH2:14][CH2:15][CH:16]([C:19]2[CH:24]=[C:23]([N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[N:22]3[N:42]=[CH:43][C:44]([I:1])=[C:21]3[N:20]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: COC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
N-Iodosuccinimide (811 mg, 3.6 mmol) was added into a solution of 4-{7-[bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexanecarboxylic acid methyl ester (Int-7e, 1.75 g, 3.27 mmol) in acetonitrile (25 mL). The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified via silica gel chromatography (0% to 30% ethyl acetate in hexanes gradient) to yield the title compound (1.79 g, 82.8% yield) at clear oil. LC-MS: 703 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:11]=[C:4]2[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:11]=[C:4]2[N:3]=1
Reactant: Cc1ccccc1-c1cc2nc(Cl)cc(Cl)n2n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Cc1ccccc1-c1cc2nc(Cl)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
There was dissolved, in 1,4-dioxane (2 mL), 5,7-dichloro-2-(2-methyl-phenyl)-pyrazolo[1,5-a]pyrimidine (74.4 mg, 0.267 mM), then morpholine (46.6 μL, 0.534 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, the resulting residue was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to give the title compound (75.3 mg, yield: 86%).
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([CH2:22][N:23]3[C:27]4=[N:28][CH:29]=[C:30]([F:32])[CH:31]=[C:26]4[N:25]=[CH:24]3)[CH:19]=[CH:18][C:16]=2[N:17]=1)(=O)=O.[CH3:33][S-:34].[Na+]>CN(C=O)C>[F:32][C:30]1[CH:31]=[C:26]2[N:25]=[CH:24][N:23]([CH2:22][C:20]3[CH:19]=[CH:18][C:16]4[N:17]=[C:13]([NH:12][C@@H:7]5[CH2:8][CH2:9][CH2:10][CH2:11][C@H:6]5[S:34][CH3:33])[S:14][C:15]=4[CH:21]=3)[C:27]2=[N:28][CH:29]=1
Reactant: CS(=O)(=O)O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.8 %

Procedure:
A mixture of (1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl methanesulfonate (100 mg, 0.2 mmol) and sodium thiomethoxide (74 mg, 1.0 mmol) in DMF (1.0 mL) was stirred at rt for 2 h. The mixture was purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-((1R,2R)-2-(methylthio)cyclohexyl)benzo[d]thiazol-2-amine (5 mg, 4%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.41 (t, J=1.8 Hz, 1H), 8.04-8.11 (m, 2H), 7.67 (s, 1H), 7.30 (m, 1H), 7.23 (m, 1H), 5.48 (s, 2H), 3.72 (m, 1H), 2.56 (m, 1H), 1.99-2.08 (m, 5H), 1.63-1.71 (m, 2H), 1.41-1.51 (m, 1H), 1.21-1.36 (m, 3H); LCMS (ESI) m/z 428 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].Cl[C:13]1[C:14]2[C:21]([C:22]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)=[O:23])=[CH:20][NH:19][C:15]=2[N:16]=[CH:17][N:18]=1>>[C:24]1([C:22]([C:21]2[C:14]3[C:13]([NH:1][C:2]4[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=4)[C:5]([NH:7][CH3:8])=[O:6])=[N:18][CH:17]=[N:16][C:15]=3[NH:19][CH:20]=2)=[O:23])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(c1cccc2ccccc12)c1c[nH]c2ncnc(Cl)c12
Reactant: CNC(=O)c1cccc(N)c1
Product: CNC(=O)c1cccc(Nc2ncnc3[nH]cc(C(=O)c4cccc5ccccc45)c23)c1

Procedure:
3-((5-(1-Naphthoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-methylbenzamide was synthesized using 3-amino-N-methylbenzamide and (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(naphthalen-1-yl)methanone according to the general procedure A. A yellow solid was obtained. M.p.>300° C.; 400 MHz 1HNMR (DMSO-d6) δ 11.53 (s, 1H), 8.48-8.44 (m, 2H), 8.24-8.20 (m, 2H), 8.14 (d, J=8.0 Hz, 1H), 8.06-8.03 (m, 2H), 7.80-7.78 (m, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.64-7.53 (m, 3H), 7.50-7.44 (m, 2H), 2.77 (d, J=4.4 Hz, 3H); LCMS [M+H] 422.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][O:32][CH3:33])[C:23](=[O:26])[CH2:24]Cl>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:24]=1[C:23](=[O:26])[C:22]1[CH:27]=[CH:28][C:29]([O:30][CH2:31][O:32][CH3:33])=[C:20]([O:19][CH2:18][O:17][CH3:16])[CH:21]=1
Reactant: COCOc1ccc(C(=O)CCl)cc1OCOC
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2ccc(OCOC)c(OCOC)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and [3,4-bis(methoxymethyloxy)]phenacyl chloride (step 1). 1H-NMR (CDCl3) δ: 8.25 (1H, d, J=1.8 Hz), 7.61 (1H, d, J=2.2 Hz), 7.52 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=8.4, 1.8 Hz), 7.29 (1H, dd, J=8.4, 1.8 Hz), 7.18 (1H, d, J=8.4 Hz), 5.72 (2H, br s), 5.29 (2H, s), 5.25 (2H, s), 3.86 (2H, q, J=7.3 Hz), 3.52 (6H, s), 0.91 (3H, t, J=7.3 Hz).