Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C(#[N:21])C>>[CH:1]1([NH3+:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:10][C:9](=[O:11])[C@@H:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:12]
Reactant: C1=COCCC1
Reactant: O=C(O)[C@H](O)Cc1ccccc1
Reactant: CC#N
Product: O=C(OC1CCCCO1)[C@H](O)Cc1ccccc1
Product: [NH3+]C1CCCCC1

Procedure:
6.64 g (40 mmole) of 3-phenyl-D-lactic acid and 3.7 g (44 mmole) of dihydropyran are reacted in acetonitrile according to the method of Obrecht and Heimgartner [Helv. Chim. Acta 67, 526 (1984)]. The reaction mixture is evaporated at 20-25 millibar from a water bath at about 40° C. The residue is dissolved in 20 ml of dichloromethane, washed with water, dried over sodium sulfate and repeatedly evaporated. The obtained O-tetrahydropyranyl-3-phenyl-D-lactic acid is dissolved in diethyl ether and converted into cyclohexylammonium salt. The crystals are filtered off, washed with diethyl ether and dried at reduced pressure.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][C:11]([CH3:20])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13](Cl)=[C:8]2[N:7]=[CH:6]1)CCC.ClC1[C:27]([C:28](OCC)=[O:29])=[C:26]([CH3:33])N=C2N(C)C=NC=12>>[CH2:28]([O:29][C:13]1[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:20])[N:10]=[C:9]2[N:5]([CH3:1])[CH:6]=[N:7][C:8]=12)[CH2:27][CH2:26][CH3:33]
Reactant: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl
Reactant: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21
Product: CCCCOc1c(C(=O)OCC)c(C)nc2c1ncn2C
Yield: 61 %

Procedure:
By replacing 3-butyl-7-chloro-5-methyl-3H-imidazo[4,5-b]-pyridine-6-carboxylic acid, ethyl ester in Example 5 with 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester of Example 2 c, 7-butoxy-3,5-dimethyl-3H-imidazo[ 4,5-b]pyridine-6-carboxylic acid, ethyl ester is formed. Yield 61%, b.p. 180°-190° /0.01.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][OH:18])=[O:14].ClC(Cl)(Cl)C(=N)O[CH2:34][CH:35]=[CH2:36].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][O:18][CH2:36][CH:35]=[CH2:34])=[O:14]
Reactant: COC(=O)[C@H](CO)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCOC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluoromethanesulfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95°-97° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14].[H][H].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.O>[CH2:17]([N:9]1[C:8]2[C:7](=[O:13])[NH:6][C:5](=[O:14])[N:4]([CH3:3])[C:12]=2[N:11]=[CH:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
16.8 g (0.7 mol) of sodium hydride were introduced in portions with stirring into a suspension of 99.6 g (0.6 mol) of 3-methylxanthine in 1.5 l of dimethylformamide. After evolution of hydrogen had ended, the mixture was heated to 100° C., treated dropwise with 76 g (0.6 mol) of benzyl chloride and heated at 120° C. for a further 6 hours. The reaction mixture was cooled and cautiously poured into 3 l of water. The solid was filtered off with suction and washed with water, the filter residue was taken up in ethanol and the solution was stirred at room temperature for one hour. The crystallizate was filtered, washed with ethanol and dried under reduced pressure.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[CH3:16].[C:18]([OH:23])(=[O:22])[C:19]([CH3:21])=O>>[CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:9]=1[N:10]=[C:15]([CH3:16])[CH:21]=[C:19]2[C:18]([OH:23])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(=O)O
Reactant: Nc1ccccc1Cc1ccccc1
Reactant: CC=O
Product: Cc1cc(C(=O)O)c2cccc(Cc3ccccc3)c2n1

Procedure:
The compound is prepared from 2-benzylaniline, acetaldehyde and pyruvic acid using the method of Irving, Clifton, J. Chem. Soc. (1959) 288.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:3]=1.C([Li])CCC.CN(C)[CH:28]=[O:29]>O1CCCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:8]([C:4]2[N:3]=[C:2]([CH:28]=[O:29])[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=1
Reactant: CN(C)C=O
Reactant: CN(C)CCC(c1ccc(Cl)cc1)c1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)CCC(c1ccc(Cl)cc1)c1cccc(C=O)n1
Reaction time: 0.08 h

Procedure:
To a cold (-70°) solution of 2-bromo-6-(1-(4-chlorophenyl)-3-dimethylaminopropyl)pyridine (1.44 g) under nitrogen in dry tetrahydrofuran (50 mL) was added with stirring a solution of n-butyllithium (2.4 mL, 1.7M in hexane). After an additional 5 min at -70°, dry dimethylformamide (1.5 mL) was added dropwise during 2 min. The solution was allowed to warm and then quenched with water (5 mL). The solvents were removed under reduced pressure and the residue was dissolved in methylene chloride (50 mL). This solution was extracted with water (3×25 mL), dried (Na2SO4), and concentrated to give crude 6-(1-(4-chlorophenyl)-3-dimethylaminopropyl)2-pyridine carboxaldehyde (formyl proton δ 10.05, 60 MHz, CDCl3) which was chromatographed on reverse phase (C18, Waters Prep 500, 60:40/acetonitrile:water, K1 =6.3 (C18 ; 70:30/acetonitrile:water).
Reaction SMILES: C(O)(=O)C.CCN(CC)CC.[C:12]([C@@H:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:13].[N-:30]=[N+:31]=[N-:32].[Na+]>C1(C)C=CC=CC=1>[C:16]1([CH2:15][C@H:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[C:12]2[NH:32][N:31]=[N:30][N:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C#N)Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nnn[nH]1
Temperature: 100 °C
Yield: 84.3 %

Procedure:
To a solution of acetic acid (93 μL, 1.62 mmol) in PhMe (2.0 mL) was added Et3N (226 μL, 1.624 mmol). (S)-tert-Butyl (1-cyano-2-phenylethyl)carbamate (100 mg, 0.41 mmol) was then added to the mixture followed by NaN3 (106 mg, 1.62 mmol). The resulting reaction mixture was heated at 100° C. for 2 h and then filtered, rinsing with EtOAc. The filtrate was concentrated in vacuo and purified using preparative HPLC to give the title compound (100 mg, 85%) as a white solid after lyophilization. 1H NMR (CDCl3) δ 7.37-7.20 (m, 3H), 7.12 (d, J=6.6 Hz, 2H), 5.56 (br s, 1H), 5.30 (d, J=6.2 Hz, 1H), 3.35 (d, J=6.4 Hz, 2H), 1.51-1.17 (m, 9H); MS (ESI+) m/z 290.2 (M+H)+.
Reaction SMILES: [Br:1]Br.[Br:3][CH:4]([F:35])[C:5]([F:34])([F:33])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([CH3:32])=[C:15]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[N:19]=3)[S:16][CH:17]=2)=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:1][C:17]1[S:16][C:15]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[N:19]=2)=[C:14]([CH3:32])[C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]([F:34])([F:33])[CH:4]([Br:3])[F:35])=[CH:12][CH:11]=1
Reactant: BrBr
Reactant: Cc1c(-c2ccc(OC(F)(F)C(F)Br)cc2)csc1-c1nc(-c2c(F)cccc2Cl)nn1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)sc(Br)c1-c1ccc(OC(F)(F)C(F)Br)cc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 68.8 %

Procedure:
Bromine (0.03 g, 0.2 mmol) in acetic acid (0.5 mL) was added dropwise to a solution of 5-{4-[4-(2-bromo-1,1,2-trifluoroethoxy)phenyl]-3-methylthien-2-yl}-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (0.1 g, 0.2 mmol) in acetic acid (1 mL) at 0° C. The reaction was allowed to warm to 25° C. and stirred for 50 h. The reaction mixture was made basic with saturated aq NaHCO3 (30 mL) and extracted with ether (3×30 mL). The combined ether extracts were washed with brine, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure to give crude product. Column chromatography gave the product as a clear oil (88 mg, 77%): 1H NMR (CDCl3) δ 2.19 (s, 3H), 4.06 (s, 3H), 6.58 (dt, 1H, J=47.6, 5.1, 4.0, 4.4 Hz), 7.08-7.14 (m, 1H), 7.29-7.40 (m, 6H), EI/MS 636 m/e (M+H).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O[CH2:13][C@@H:14]1[CH2:18][N:17]([C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][C:25](=[O:28])[NH:24][C:23]=3[CH:29]=2)[C:16](=[O:30])[CH2:15]1.[N-:31]=[N+:32]=[N-:33].[Na+].O>N1C=CC=CC=1.ClCCl>[N:31]([CH2:13][C@@H:14]1[CH2:18][N:17]([C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][C:25](=[O:28])[NH:24][C:23]=3[CH:29]=2)[C:16](=[O:30])[CH2:15]1)=[N+:32]=[N-:33]
Reactant: O=C1COc2ccc(N3C[C@@H](CO)CC3=O)cc2N1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reaction time: 24 h
Yield: 65.3 %

Procedure:
p-Toluenesulfonyl chloride (611 mg, 3.20 mmol) was added at room temperature to a solution of 6-[(4S)-4-(hydroxymethyl)-2-oxopyrrolidin-1-yl]-2H-1,4-benzoxazin-3(4H)-one (420 mg, 1.60 mmol) in pyridine (5 ml) and the mixture was stirred for 24 hours. The reaction solution was concentrated under reduced pressure and the obtained resultant was dissolved in dichloromethane and washed with 1N hydrochloric acid. The aqueous layer was extracted with dichloromethane and the organic layer was washed sequentially with water and a saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The obtained brown solid was dissolved in N,N-dimethylformamide (5 mL), sodium azide (208 mg, 3.20 mmol) was added thereto and the mixture was stirred at 80° C. for 2 hours. After adding water, the reaction solution was poured into a mixture of dichloromethane and a saturated sodium hydrogen carbonate aqueous solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. Dichloromethane was added to the obtained residue to prepare a slurry and the solid was collected by filtration to yield 300 mg of the title compound in the form of a light yellow solid. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (dichloromethane/methanol) to yield 132 mg of the title compound in the form of a light yellow solid. Total yield 432 mg (94%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C(Cl)(=O)C.[Na+].[I-:15]>C(#N)C>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([I:15])=[N:3][CH:4]=1
Reactant: [I-]
Reactant: Cc1cc(Br)cnc1Br
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Cc1cc(Br)cnc1I
Yield: 94.8 %

Procedure:
To a stirred solution of 2,5-dibromo-3-methyl-pyridine (20.0 g, 79.7 mmol, 1 eq) in acetonitrile (120 mL) was added acetyl chloride (8.5 mL, 119.5 mmol, 1.5 eq) followed by addition of NaI (47.8 gm, 319 mmol, 4 eq) at room temperature. Resulting reaction mixture was refluxed for 16 hours. After complete consumption of starting material, reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (3×200 mL). Organic layer was washed with aqueous sodium bicarbonate (2×300 mL), brine (300 mL) and dried over sodium sulfate. Organic layer was concentrated under reduced pressure to afford brown oil (35.5 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 5% EtOAc in hexane to get title compound as brown oil (22.5 g, 94.78%). 1H NMR (400 MHz, CDCl3) δ: 2.36 (s, 3H), 7.56 (d, J=2.4 Hz, 1H), 8.24 (d, J=2.28 Hz, 1H). LC-MS (m/z): 297.9 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:12][C:11]=1[Cl:34].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)COP([O-])(O)=O)C2=CC=1C.[Na+]>ClCCl.C(N(CC)CC)C.CCOC(C)=O>[Cl:34][C:11]1[CH:12]=[C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(Cl)c1)C2
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)COP(=O)([O-])O)c2cc1C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)cc1Cl
Reaction time: 18 h
Yield: 40 %

Procedure:
Isobutyryl chloride (46 mg, 0.4 mmol) was added to a solution of (4-aminomethyl-3-chloro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E106.2 (161 mg, 0.4 mmol) in dichloromethane (10 ml) and triethylamine (to pH9) at room temperature. The mixture was stirred for 18 h, diluted with EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (75 mg, 40%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[NH:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3]1.C=O.[CH:13](O)=O>O>[CH3:13][N:3]1[C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[NH:6][C:2]1([CH3:10])[CH3:1]
Reactant: CC1(C)NC(=O)C(C)(C)N1
Reactant: O=CO
Agent: C=O
Solvent: O
Product: CN1C(C)(C)NC(=O)C1(C)C
Temperature: 30 °C

Procedure:
A 500 ml. resin kettle, equipped with a mechanical stirrer, reflux condenser, thermometer in thermowell, and an addition funnel, was charged with 122.9 g. (0.8642 moles) of 2,2,5,5-tetramethylimidazolidin-4-one, 74.8 g. (0.8642 moles) of 37% formalin solution, and 200 ml. of water. This mixture was stirred without heating as 44.2 g. (0.8642 moles) of 90% formic acid was added over the course of 20 minutes, with the mixture warming up to 30° C. and becoming a solution in this time.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][N:30](C(OC(C)(C)C)=O)[CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[NH:29]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=23)[CH:31]=[N:30]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
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: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A mixture of 4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (1.63 g, 4.98 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.61 g, 5.48 mmol, Aldrich: Cat. #632732), tetrakis(triphenylphosphine)palladium(0) (288 mg, 0.249 mmol) and sodium carbonate (1.58 g, 14.9 mmol) in 1,4-dioxane (16.0 mL) and water (8.0 mL) was stirred at 110° C. for 2 hours. After cooling, the mixture was diluted with ethyl acetate, and washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was treated with ether, filtered and washed with ether to afford the desired product (1.08 g, 69%) which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=315.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:46][C:47]([NH2:50])([CH3:49])[CH3:48]>CN(C=O)C.C(OCC)(=O)C>[C:47]([NH:50][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:19]=1)=[O:23])([CH3:49])([CH3:48])[CH3:46]
Reactant: CC(C)(C)N
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Yield: 112.7 %

Procedure:
To a stirred suspension of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (111 mg, 242 μmol) in DMF (4 mL) was added EDC (107 mg, 557 μmol), HOBT (107 mg, 557 μmol) and 2-methylpropan-2-amine (78.6 mg, 0.113 mL, 1.08 mmol) at 20° C. After 3 h the reaction mixture was diluted with ethyl acetate and washed with 10% citric acid solution. The organic layer was then washed with saturated sodium bicarbonate and brine then dried (sodium sulfate), filtered and concentrated in vacuo to give the crude N-tert-butyl-2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg) as a light brown oil. This was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.S(OC)(O[CH3:13])(=O)=O>>[CH3:13][S:7][CH2:6][C:5]1[O:8][C:2]([CH3:1])=[CH:3][CH:4]=1.[CH3:1][C:2]1[O:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Agent: Cc1ccc(CS)o1
Product: CSCc1ccc(C)o1

Procedure:
a. 5-Methylfurfuryl methyl sulfide was prepared by reacting 5-methylfurfuryl-mercaptan with dimethyl sulfate in alkaline solution according to known methods. 5-Methylfurfurylmercaptan was obtained from the corresponding alcohol by the method described in Org. Syn. 35, 67 (1955). The product is a colorless liquid boiling at 71°-72° C./11 mm. Hg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:39][O:40][CH2:41][CH2:42]O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CCOC(C)=O.C1C=CC=CC=1>[CH3:39][O:40][CH2:41][CH2:42][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2
Reactant: COCCO
Reactant: CC(C)(C)OC(=O)Cc1ccc2ncc(O)cc2c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COCCOc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Temperature: 0 °C
Yield: 0.3 %

Procedure:
A flask was charged with tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (581.04 mg, 2.241 mmol) and triphenylphosphine (1.175 g, 4.482 mmol) then sealed with a septum and an placed under N2. Benzene (10 mL) was added, followed by 2-methoxyethanol (0.8838 ml, 11.20 mmol). The heterogeneous solution was cooled to 0° C., and di-tert-butyl azodicarboxylate (1.032 g, 4.482 mmol) was added as a solid in a single portion. The solution was allowed to warm to rt and maintained 20 h. The solution was then partitioned between saturated aqueous. NH4Cl, and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL), and the combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by MPLC (Teledine Isco combiFlash Companion), 80 g SiO2, solvent system: 90:10 hexanes:EtOAc gradient to 50:50 hexanes:EtOAc to give tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate (585. 2 mg, 82% yield). LRMS (ESI) m/z calcd for C18H24NO4 (M+H) 318.2. found 318.3.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22]4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: c1ccc2[nH]ccc2c1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccc4ccccc43)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 77, with Intermediate B instead of Intermediate C and with indole instead of 2-phenyl-1H-imidazole. LCMS: 376.2 m/z (M+H)+; ret. Time: 9.10 min (Analytical Method A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:25][CH2:24][CH2:23][C@@:10]2([C:14](=[O:15])[N:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH2:9]1.CI.[C:33](=O)([O-])[O-].[K+].[K+].CC(C)=O>>[F:1][C:2]1[CH:3]=[C:4]([N:26]([CH3:33])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:25][CH2:24][CH2:23][C@@:10]2([C:14](=[O:15])[N:13]([C@H:16]3[CH2:17][CH2:18][C@H:19]([OH:22])[CH2:20][CH2:21]3)[CH2:12][CH2:11]2)[CH2:9]1
Reactant: CS(=O)(=O)Nc1ccc(N2CCC[C@]3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(c1ccc(N2CCC[C@]3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)c(F)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-{3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}methanesulfonamide (20 mg, 0.00006 mol, example 312), methyl iodide (4.1 μL, 0.000066 mol), and potassium carbonate (10 mg, in excess) in acetone (2 mL, 0.03 mol) was stirred at rt for 2 h and then heated to 40° C. for 2 h. The reaction mixture was allowed to cool to rt and was purified by prep-HPLC to afford the desired product. LC-MS: 454.2 (M+H)+.