Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]1([NH:35]C(=O)OC(C)(C)C)[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[C:24]([O:31][CH:32]([CH3:34])[CH3:33])[CH:25]=[CH:26][CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[ClH:43].O1CCOCC1.C(OCC)C>C(Cl)Cl>[ClH:43].[ClH:43].[CH3:1][C@:2]1([NH2:35])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[C:24]([O:31][CH:32]([CH3:33])[CH3:34])[CH:25]=[CH:26][CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:10])([F:11])[F:9])[CH2:3]1
Reactant: CC(C)Oc1cccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)Oc1cccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(N)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a stirred solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(8-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (1.30 g, 2.22 mmol) in DCM (20 mL) was added 4N HCl in dioxane (5.56 mL, 22.2 mmol). The reaction mixture was stirred at ambient temperature for 3 hours. Diethyl ether (100 mL) was added to the reaction mixture. The suspension was stirred for 10 min. The solid was collected by filtration to give (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(8-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine dihydrochloride (1.20 g, 97%). MS APCI (+) m/z 485 (M+1) detected. Specific rotation: [α]20D=−2.14° (c=0.97, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].Br[CH2:15][CH:16]([OH:20])[CH2:17][CH2:18]Br.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]2[CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]2)[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: OC(CBr)CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(N2CCC(O)C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
3-Methoxy-5-(trifluoromethyl)aniline (15.0 g) and 1,4-dibromobutan-2-ol (18.3 g) were stirred at 100° C. for 3 hr. After cooling to room temperature, to the reaction mixture was added saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-50:50) to give the title compound (9.57 g, yield 47%) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:18])([CH3:17])[C@@H:4]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:19][C:20]([F:41])([F:40])[C:21]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26][CH2:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:41][C:20]([F:19])([F:40])[C:21]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][CH:27](/[CH:30]=[C:10]2/[C:6]([NH:5][C@H:4]([C:12]([N:14]([CH3:15])[CH3:16])=[O:13])[C:3]([O:2][CH3:1])([CH3:18])[CH3:17])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:26][CH2:25]1
Reactant: COC(C)(C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: COC(C)(C)[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a solution of 3-methoxy-N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-valinamide (460 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (628 mg) in 2-propanol (15 mL) was added piperidinium acetate (269 mg) at room temperature. The reaction mixture was stirred at 60° C. for 3 hr, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (380 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][N+:5]=1[O-])([OH:3])=[O:2]>C(O)(=O)C.[Pd]>[C:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][N:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccnc(C(=O)O)c1
Reaction time: 2 h

Procedure:
A solution of 2-carboxy-4-nitropyridine N-oxide (0.5 g, 27 mmol) (E. Prafft et al., J. Prakt. Chem. 1961, 13, 58) in acetic acid (20 ml) was hydrogenated under pressure (70 psi) in the presence of Pd/C. (10%) (0.25 g) at ambient temperature for 2 hours. The catalyst was removed by filtration, and the filtrate evaporated to give 2-carboxy-4-aminopyridine as an off-white solid which was dried in a dessicator (300 mg, 80%).
Reaction SMILES: [CH:1]1([CH2:9][OH:10])[CH2:6][CH2:5][CH:4](CO)[CH2:3][CH2:2]1.C1(=O)[O:17][CH2:16]CCCC1>>[C:1]1([CH2:9][OH:10])([CH2:16][OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCCCO1
Reactant: OCC1CCC(CO)CC1
Product: OCC1(CO)CCCCC1

Procedure:
Using a procedure similar to that for Experiment 1, various ratios of 1,4-cyclohexanedimethanol were reacted with ε-caprolactone. Table 1 gives the ratio of moles to viscosity and amount of unreacted cyclohexanedimethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][C:14]=1[N+:27]([O-:29])=[O:28]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:15][C:14]=2[N+:27]([O-:29])=[O:28])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(c2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
24.5 ml (168 mmol) of 1-ethoxycarbonylpiperazine are added to a solution of 15.0 g (56 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 50 ml of dimethyl formamide and the solution is stirred at a reaction temperature of 100° C. for 3 hours. When the reaction mixture is cold, it is poured out on 300 ml of ice water with vigorous stirring. The precipitated solid is suction filtered, washed with a small quantity of ethanol and diethyl ether and recrystallized from 500 ml of ethanol. 16.7 g (76%) of orange yellow crystals, m.p. 140° to 142° C., are obtained.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:15][C:14](=[O:16])[CH:13]=[CH:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:31]([O:34][CH2:35][CH3:36])(=[O:33])C.C(Cl)(Cl)Cl>O1CCOC1>[C:1]([O:9][CH2:10][C@H:11]1[O:15][C:14](=[O:16])[CH2:13][C@@H:12]1[CH:31]1[O:34][CH2:35][CH2:36][O:33]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C[C@@H](COC(=O)c2ccccc2)O1
Reactant: CCOC(C)=O
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCO1
Product: O=C1C[C@H](C2OCCO2)[C@@H](COC(=O)c2ccccc2)O1
Yield: 80 %

Procedure:
A solution containing 180 mg (0.825 mmol) compound (2e) and 22.5 mg (0.123 mmol) benzophenone in 110 mL [1,3]-dioxolane was irradiated at 20° C. for 7 hours according to the general procedure. Column chromatography (silica gel 40 g, ethyl acetate in hexanes 40%) gave compound (3e) (193 mg. 80%) as a colorless solid, Rf=0.29, [α]25D 35.2°, c 1.2, CHCl3, IR (neat) 2360, 2342, 1779, 1721, 1272, 1118 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 2.53 (d, 1H J=11.6 Hz), 2.62-2.73 (m, 2H), 3.83 (mc, 2H), 3.94 (mc, 2H), 4.37 (dd, 1H, J=5.1 Hz, J=12.3 Hz), 4.53 (dd, 1H, J=2.9 Hz, J=12.3 Hz), 4.74 (ddd, 1H, J=2.9 Hz, J=5.1 Hz, J=6.9 Hz), 4.88 (d, 1H, J=3.4 Hz), 7.37 (dd, 2H, J=7.7 Hz, J=7.9 Hz), 7.49 (dd, 1H, J=1.0 Hz, J=7.7 Hz), 7.92 (dd, 2H, J=1.0 Hz, J=7.9 Hz). 13C-NMR (100.6 MHz, CDCl3, Dept) δ: 29.77 (−), 40.06 (+), 65.37 (−), 65.50 (−), 65.99 (−), 77.56 (+), 103.14 (+), 128.51 (+), 129.31 (quat), 129.57 (+), 133.30 (+), 166.00 (quat) 175.62 (quat). C15H16O6; Exact Mass: 292.09; Mol. Wt.: 292.28; C, 61.64, H, 5.52, O, 32.84.
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18](Cl)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:35][CH:36]=2)O1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:1]([N:4]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18]([C:31]3[CH:36]=[N:35][C:34]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[CH:33][CH:32]=3)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2cc(Cl)ccc21
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2cc(F)c(-c3ccc(N4CCOCC4)nc3)nc2C=Cc2cc(Cl)ccc21
Yield: 64.5 %

Procedure:
The title compound (21.6 mg, 64.3%) was prepared from 9C (24.4 mg, 0.072 mmol) and 5A (22 mg, 0.072 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.649 min; LCMS Found: (M+H)+=465.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:21]([Cl:22])=[CH:20][C:17]([CH2:18]Br)=[CH:16][C:15]=3[Cl:23])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].[C-:24]#[N:25].[Na+].C1(C)C=CC=CC=1>CN(C=O)C.O>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:21]([Cl:22])=[CH:20][C:17]([CH2:18][C:24]#[N:25])=[CH:16][C:15]=3[Cl:23])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(CBr)cc3Cl)cc12
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(CC#N)cc3Cl)cc12

Procedure:
Analogously to the procedure of Example VIII, 1.0 g (2.42 mmol) of benzyl bromide from Example XVIII is reacted with 0.15 g (3.03 mmol) of sodium cyanide in DMF/H2O (10:1) at 50° C. in 60 min. After isolation of the crude product (distilling off DMF and quenching with ethyl acetate/water), chromatography is carried out on silica gel 60 by means of toluene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1C(=O)N([Br:17])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC#N>[Br:17][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([CH3:9])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(N)cccc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(N)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of 3-chloro-2-methylaniline (30 g, 0.212 mol) in CH3CN (300 mL) was added NBS (45.2 g, 0.254 mol) in portions at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, saturated Na2S2O3 (500 mL) was added slowly into the reaction mixture at 10° C. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was washed with petroleum ether to afford the title compound (30 g), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.24 (d, 1H), 6.48 (d, 1H), 3.70 (br, 2H), 2.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30]>C(#N)C>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:7]([NH:6][C:4](=[O:5])[C:3]1[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:2]=1[Cl:1])=[O:8]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: Nc1ccccc1-c1nc2ccccc2[nH]1
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1ccccc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 142 mg of 2-(1H-benzimidazol-2-yl)phenylamine in 8 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered off with suction and dried under reduced pressure.
Reaction SMILES: C(=[NH:14])(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:16]1[CH:17]=[CH:18][C:19]([C:22]2([C:33]#[N:34])[CH2:27][CH2:26][N:25]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[CH2:24][CH2:23]2)=[N:20][CH:21]=1.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH2:14][C:16]1[CH:17]=[CH:18][C:19]([C:22]2([C:33]#[N:34])[CH2:27][CH2:26][N:25]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[CH2:24][CH2:23]2)=[N:20][CH:21]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(O)CN1CCC(C#N)(c2ccc(Br)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(O)CN1CCC(C#N)(c2ccc(N)cn2)CC1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 81.1 %

Procedure:
Benzophenonimine (2.22 g) was added to a suspension of 4-(5-bromopyridin-2-yl)-1-(2-hydroxy-2-methylpropyl)piperidine-4-carbonitrile (3.95 g), palladium (II) acetate (328 mg), racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl (909 mg) and sodium tert-butoxide (1.68 g) in toluene (29 ml), and stirred at 120° C. for 2.5 hours. The reaction solution was left stand, a mixture of concentrated hydrochloric acid (2 ml) and water (6 ml) were added at 60-80° C. and stirred at room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with basic silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (2.6 g) as a pale yellow solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:19][CH2:18]3)=[O:16])[CH:11]=2)[N:6]1[CH2:31][CH2:32]C#N)([CH3:4])([CH3:3])[CH3:2].[Cl:35]CC=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:19][CH2:18]3)=[O:16])[CH:11]=2)[N:6]1[CH2:31][CH2:32][Cl:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CCCl
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2N1CCC#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2N1CCCl
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
To a solution of N-(2-tert-butyl-1-(2-cyanoethyl)indolin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (71 mg, 0.17 mmol) in anhydrous dichloromethane (1 mL) was added chloroacetaldehyde (53 μL, 0.41 mmol) at room temperature under N2. After 20 min of stirring, NaBH(OAc)3(90 mg, 0.42 mmol) was added in two portions. The reaction mixture was stirred overnight at room temperature. The product was purified by column chromatography on silica gel (2-15% ethyl acetate/hexanes) providing N-(2-tert-butyl-1-(2-chloroethyl)indolin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxamide (51 mg, 63%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][C@@H:10]([CH3:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([CH2:7]O)[S:5][CH:6]=1.CS(Cl)(=O)=O.C1COCC1.N12CCCN=C1CCCCC2>O>[Br:1][C:2]1[C:3]2[O:9][C@@H:10]([CH3:20])[CH2:11][N:12]([C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[CH2:7][C:4]=2[S:5][CH:6]=1
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)Oc1c(Br)csc1CO
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of tert-butyl [(2S)-2-{[4-bromo-2-(hydroxymethyl)thiophen-3-yl]oxy}propyl]carbamate (1.83 g), methanesulfonyl chloride (0.58 ml,) and THF (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.65 ml,), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution (30 mL) of the residue in DMF was added sodium hydride (60% in oil, 0.4 g) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→20% ethyl acetate/hexane) to give the title compound (1.17 g, 67%) as a colorless oil.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][CH3:17])[CH:10]=1)=O)(C)(C)C.[ClH:18]>O1CCOCC1>[ClH:18].[F:15][C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][C:11]=1[O:16][CH3:17]
Reactant: COc1cc(NC(=O)OC(C)(C)C)ccc1F
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(N)ccc1F

Procedure:
(tert-Butoxy)-N-(4-fluoro-3-methoxyphenyl)carboxamide (0.98 g, 4.06 mmol) (from Example 34c supra) was treated with 4 N hydrochloric acid in dioxane (20 mL) (Aldrich) overnight at room temperature. The resulting precipitate was collected by filtration and washed with dry ether to give 4-fluoro-3-methoxyphenylamine hydrochloric acid salt as a white, crystalline, solid. (Yield 512 mg, 71%).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:5]1=[O:35])[CH2:2][CH3:3].Br[CH2:37][C:38]#[C:39][C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][N:25]([CH2:37][C:38]#[C:39][C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)[CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:5]1=[O:35])[CH2:2][CH3:3]
Reactant: Cc1ccc(C#CCBr)cc1
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(COCC[Si](C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4ccc(C)cc4)c3)n2COCC[Si](C)(C)C)n(COCC[Si](C)(C)C)c1=O
Temperature: 52.5 °C
Yield: 30 %

Procedure:
A mixture of 1-propyl-8-(1H-pyrazol-4-yl)-3,7-bis-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (prepared as per literature procedure US20080194593) (0.1 g, 0.18 mmol), 1-(3-bromo-prop-1-ynyl)-4-methyl-benzene (prepared according to example E1) (0.039 g, 0.18 mmol), potassium carbonate (0.051 g, 0.37 mmol), and acetone (10 ml) were heated at 50-55° C. for 16 hours. Reaction mixture was cooled to 20-25° C. and filtered off. The filtrate was evaporated and residue was purified by preparative TLC to afford 1-propyl-8-[1-(3-p-tolyl-prop-2-ynyl)-1H-pyrazol-4-yl]-3,7-bis-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.035 g, 28%) as a brown sticky mass.
Reaction SMILES: CS(O[C@:6]1([CH3:18])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=O)=O.[C-:19]#[N:20].[Na+]>CN(C=O)C>[C:19]([CH2:18][C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])#[N:20]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)OS(C)(=O)=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CC#N
Temperature: 60 °C
Yield: 26.8 %

Procedure:
To a solution of (R)-2-methanesulfonyloxy-methyl-pyrrolidine-1-carboxylic acid, tert-butyl ester (D3) (90 g, 0.32 mol) in DMF (1200 ml) was added sodium cyanide (24 g, 0.49 mol). Heated to 60° C. overnight. Reaction mixture was concentrated and partitioned between water and ether. The organic phase was dried and concentrated to give the title compound (18 g, 30%) (M-Boc) 110.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:42])[CH2:23][NH:24][C:25](=[O:41])[CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][C:31]([NH:34][C:35]([O:37][CH2:38][CH2:39]Cl)=[O:36])=[CH:30][CH:29]=4)[CH3:21])[C:14]=3[Cl:43])[C:5]2=[N:4][C:3]=1[CH3:44].C[O-].[Na+].O>CO>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:42])[CH2:23][NH:24][C:25](=[O:41])[CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:39][CH2:38][O:37][C:35]5=[O:36])=[CH:30][CH:29]=4)[CH3:21])[C:14]=3[Cl:43])[C:5]2=[N:4][C:3]=1[CH3:44]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)OCCCl)cc4)c3Cl)cccn2c1Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N5CCOC5=O)cc4)c3Cl)cccn2c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-[N-[4-(2-chloroethoxycarbonylamino)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (128 mg) in methanol was added dropwise sodium methanolate (28% in methanol, 37 mg) under nitrogen in ice-water bath and the mixture was stirred for 1 hour at same temperature and then at ambient temperature for 2 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography(ethyl acetate) to give 3-bromo-8-[2,6-dichloro-3-[N-[4-(2-oxo-3-oxazolidinyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (77 mg) as an amorphous powder.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]2[CH:14]=1)[CH2:2][C:3]#[CH:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][F:23])[N:17]=1>>[Cl:13][C:12]1[C:7]2[N:8]([CH:14]=[C:5]([CH2:1][CH2:2][C:3]#[C:4][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][F:23])[N:17]=3)[N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#CCCc1cn2cccc(Cl)c2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCc2cn3cccc(Cl)c3n2)n1
Yield: 54.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine (500 mg, 2.44 mmol, Example 255(B)) and 2-bromo-6-(fluoromethyl)pyridine (487 mg, 2.57 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 420 mg (1.34 mmol, 55%) of 8-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine as a slightly yellow solid (M.P.=73-74.5° C.).