Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[N:9]1[C:15](=[O:30])[C@@H:16]([C@@H:21]([C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[OH:22])[CH2:17][CH2:18][C:19]#[CH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])(=O)=O>ClCCl>[CH2:1]([C@H:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[N:9]1[C:15](=[O:30])[C@@H:16]([C@H:21]([O:22][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:17][CH2:18][C:19]#[CH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCC[C@@H](C(=O)N1C(=O)OCC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(Cl)nc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C#CCC[C@@H](C(=O)N1C(=O)OCC[C@@H]1Cc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a stirred solution of 29.7 g (71.9 mmol) of (4S)-4-benzyl-3-{(2R)-2-[(S)-(6-chloropyridin-3-yl)(hydroxy)methyl]hex-5-ynoyl}-1,3-oxazinan-2-one from Step B above and 15.0 mL (126 mmol) of 2,6-lutidine in 300 mL of anhydrous dichloromethane at 0° C. under an atmosphere of nitrogen was added 22 mL (94 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate at a rate slow enough to keep the internal temperature below 3° C. The reaction mixture was stirred for 16 h at 0° C. then evaporated in vacuo to remove all volatiles. The residue was diluted with 400 mL of water and extracted with diethyl ether (3×300 mL). The combined organics were washed sequentially with a 0.5 M aqueous hydrochloric acid solution (100 mL), water (100 mL) brine (100 mL) then dried over magnesium sulfate. After filtration and evaporation in vacuo the residue was purified by silica gel chromatography eluting with a 5-8% ethyl acetate in hexanes gradient to afford the title compound as a colorless foam (37 g, 97%). LC-MS: m/z (ES) 527.3 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](=O)[CH2:6]Br)[CH3:2].[S:10]([N:20]1[C:28]2[C:23](=[N:24][C:25]([NH2:29])=[CH:26][N:27]=2)[CH:22]=[CH:21]1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].O1CCOCC1>CC#N>[S:10]([N:20]1[C:28]2[N:27]=[CH:26][C:25]3[N:24]([CH:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])[N:29]=3)[C:23]=2[CH:22]=[CH:21]1)([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N)cnc32)cc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1COCCO1
Solvent: CC#N
Product: CCOC(=O)c1cn2c(cnc3c2ccn3S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 72 h
Yield: 75.5 %

Procedure:
3-Bromo-2-oxo-propionic acid ethyl ester (0.090 mL, 0.72 mmol) was added to a mixture of 5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-amine (0.180 g, 0.624 mmol, prepared using E from Example #3 Step E and HCl) and 1,4-dioxane (3.5 mL) under nitrogen. After about 3 days, the volatiles were removed under reduced pressure. The residue was slurried in Et2O (5 mL) and then filtered to afford a tan powder. The solid was slurried in MeCN (3.50 mL) under nitrogen. PFPAA (0.40 mL, 2.1 mmol) was added. After about 30 min, the volatiles were removed under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with saturated aqueous NaHCO3/water (2:1, 20 mL). The aqueous layer was extracted with DCM (20 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 20-100% EtOAc/heptane to afford ethyl 3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-7-carboxylate (0.181 g, 75%): LC/MS (Table 1, Method n) Rt=0.70 min; MS m/z: 385 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([C:13]#[N:14])[CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[Cl:1][CH:2]([C:13]#[N:14])[CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:17])=[O:7]
Reactant: N#CC(Cl)Cc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#CC(Cl)Cc1ccccc1C(=O)Cl

Procedure:
209.5 parts of 2-(2-chloro-2-cyanoethyl) benzoic acid are made into a paste in 220 parts of toluene and 125 parts of thionyl chloride and the mixture is refluxed until the acid completely dissolves. Then the surplus thionyl chloride and toluene are eliminated under reduced pressure. 2-(2-chloro-2-cyanoethyl) benzoyl chloride is obtained which is liquid at normal temperature.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:38]=[C:37]([Cl:39])[C:23]([CH2:24][CH:25]2[CH2:29][CH2:28][N:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:26]2=[O:36])=[C:22]([Cl:40])[CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:38]=[C:37]([Cl:39])[C:23]([CH2:24][CH:25]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[C:26]3=[O:36])=[C:22]([Cl:40])[CH:21]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Yield: 58 %

Procedure:
Place 3-Chloro-2-methyl-benzenesulfonyl chloride (160 mg, 0.70 mmol) in CH2Cl2 (10 mL) and cool to 0° C. Slowly add pyridine (0.06 mL, 0.70 mmol) and stir for 15 minutes. Add 3-(4-Amino-2,6-dichloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (Example 183), 200 mg, 0.59 mmol) and stir for 12 hours. Quench with 1N HCl and extract with dichloromethane. Wash the extract with NaHCO3, brine. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (10-80% ethyl acetate in hexanes) to afford 181 mg (58%) of the title compound: Mass spectrum (apci) m/z=529.05 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].I.CS[C:18]1[NH:19][CH2:20][C:21](=[O:23])[N:22]=1.C(N(CC)CC)C>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]2[NH:19][CH2:20][C:21](=[O:23])[N:22]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC1=NC(=O)CN1
Agent: I
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(CSCCNC2=NC(=O)CN2)o1

Procedure:
2-(5-Dimethylaminomethylfuran-2-ylmethylthio)ethylamine (4.00 g), 2-methylthio-imidazolin-4-one hydroiodide (9.63 g) and triethylamine (7.27 g) were refluxed in ethanol (50 ml) for 6 hours.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][CH:6]([C:8]1[N:9](C2CCCCO2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:13]=[C:12]([Cl:23])[N:11]=2)[CH3:7])=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>CO>[Br:1][CH2:2][C:3]([NH:5][CH:6]([C:8]1[NH:9][C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)[N:13]=[C:12]([Cl:23])[N:11]=2)[CH3:7])=[O:4]
Reactant: CC(NC(=O)CBr)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(NC(=O)CBr)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
2-Bromo-N-{1-[2-chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethyl}-acetamide (crude from step 5, 385 mg) was dissolved in methanol (15 mL) and p-toluenesulfonic acid monohydrate (35 mg) was added. The mixture was stirred at RT for 16 h. Water was added, aqueous sodium bicarbonate was added to give pH 7 and the precipitate was filtered off, washed with water and dried (in vacuo, 50° C.) to give 2-Bromo-N-[1-(2-chloro-6-morpholin-4-yl-9H-purin-8-yl)-ethyl]-acetamide (207 mg, 76%). The aqueous filtrate was extracted three times with ethyl acetate. The organic layer was separated and dried (Na2SO4), then concentrated in vacuo to afford a further crop of less pure 2-Bromo-N-[1-(2-chloro-6-morpholin-4-yl-9H-purin-8-yl)-ethyl]-acetamide (39 mg). LCMS RT=2.57 min, [M+H]+=403/405/407
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[I:22]I>C(Cl)Cl>[I:22][C:11]1[S:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:12]=1
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Reactant: II
Solvent: ClCCl
Product: COc1ccc(-c2cc(I)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)thiophene (5.92 g, 20 mmole) in 70 ml methylene chloride was cooled in an ice bath and treated in portions with iodine (5.6 g, 20 mmole) and red mercuric oxide (4.32 g, 20 mmole). The reaction mixture was stirred at room temperature for 4 hours and then treated with additional portions of iodine (2.8 g, 10 mmole) and mercuric oxide (2.16 g, 10 mmole). After 2 hours additional, the reaction mixture was filtered through a celite pad.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.Cl.[NH2:41][C@@H:42]([CH2:48][CH3:49])[C:43]([N:45]([CH3:47])[CH3:46])=[O:44].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:39]=[CH:38][C:34]([C:35]([NH:41][C@H:42]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH2:48][CH3:49])=[O:37])=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:20][CH2:21]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1
Reactant: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Reactant: CC[C@H](N)C(=O)N(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CC[C@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (14 μL, 0.080 mmol) was added to a mixture of 4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoic acid (11 mg, 0.026 mmol), (2S)-2-amino-N,N-dimethylbutanamide hydrochloride (5.8 mg, 0.034 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14 mg, 0.032 mmol) in DMF (0.4 mL). The mixture was stirred at RT overnight. The residue was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=527.0
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]([NH:10][C:11]([C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[C:14]=1[OH:22])=[O:12])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1.[I-].[K+]>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:23])[C:7]([CH3:9])([NH:10][C:11]([C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[C:14]=1[O:22][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:36][CH:37]=1)=[O:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc2sccc2c1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc2sccc2c1OCc1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
80 mg 2-[(4-Hydroxy-benzo[b]thiophene-5-carbonyl)-amino]-2-methyl-propionic acid tert-butyl ester, 90 mg cesium carbonate, 55 mg of 1-bromomethyl-4-trifluoromethyl-benzene and 8 mg potassium iodide were dissolved in 1 ml of N,N-dimethylformamide and stirred for 1 h at 60° C. 10 ml of ethyl acetate and 10 ml of brine were added to the reaction. The organic layer was separated and washed again with 10 ml of brine. It was then dried over sodium sulphate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate) to afford 113 mg of 2-methyl-2-{[4-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-5-carbonyl]-amino}-propionic acid tert-butyl ester
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[N:54]([C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[C:60]#[N:61])=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:55]([NH:54][C:57]2[CH:64]=[CH:63][CH:62]=[C:59]([C:60]#[N:61])[CH:58]=2)=[O:56])[CH2:48]1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(NC(=O)N2CC[C@@H](CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)c1
Yield: 77 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 3-isocyanatobenzonitrile as the starting materials in 77% yield. LCMS for C31H29ClN9O2 (M+H)+: m/z=594.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([NH:23][CH2:24][CH2:25]P(=O)(O)O)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.NC1C=[CH:44][C:34]([CH2:35][P:36](=[O:43])([O:40]CC)[O:37]CC)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([NH:23][C:24]2[CH:25]=[CH:44][C:34]([CH2:35][P:36](=[O:37])([OH:43])[OH:40])=[CH:33][CH:32]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCP(=O)(O)O)c2)C1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Nc3ccc(CP(=O)(O)O)cc3)c2)C1

Procedure:
Compound 3 was prepared in an analogous manner to that of Compound 1 using diethyl 4-aminobenzylphosphonate (Intermediate 3.2) as the amine. 1H-NMR (300 MHz, CD3OD, ppm): 7.89 (d, J=7.8 Hz, 1H), 7.61˜7.66 (m, 1H), 7.52˜7.54 (m, 2H), 7.21˜7.20 (m, 2H), 7.11 (s, 1H), 6.95 (d, J=8.1 Hz, 2H), 6.73 (s, 1H), 4.51˜4.59 (m, 3H), 3.33 (s, 1H), 3.03˜2.89 (m, 6H). MS (ES, m/z): 541 [M+H]+.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:4]=1.[O:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1>>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([NH:10][C:5]2[N:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[N:4]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: OC1CCOCC1
Agent: [Na]
Product: COc1cc(Nc2nc(C)cc(OC3CCOCC3)n2)ccc1-n1cnc(C)c1
Temperature: 100 °C
Yield: 11 %

Procedure:
Sodium (10 mg, 0.45 mmol) was dissolved under stirring and heating (100° C. for 3 hours) under an atmosphere of nitrogen in tetrahydro-4H-pyran-4-ol (0.99 mL). (4-Chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (99 mg, 0.3 mmol) was added and the suspension was heated to 100° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound as a white solid (13 mg, 11%). MS ISP (m/e): 396.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.65 (s, 1H), 7.62 (s, 1H), 7.17 (d, 1H), 7.15 (s, 1H), 7.13 (d, 1H), 6.87 (s, 1H), 6.12 (s, 1H), 5.30 (m, 1H), 3.98 (m, 2H), 3.86 (s, 3H), 3.62 (m, 2H), 2.36 (s, 3H), 2.31 (s, 3H), 2.04 (m, 2H), 1.84 (m, 2H).
Reaction SMILES: OCCONC(C1N(C2CC2)C2C=CN=CC=2C=1NC1C=CC(I)=CC=1F)=O.C([O:31][CH2:32][CH2:33][O:34][NH:35][C:36]([C:38]1[N:46]([CH:47]2[CH2:49][CH2:48]2)[C:45]2[CH:44]=[CH:43][N:42]=[CH:41][C:40]=2[C:39]=1[NH:50][C:51]1[CH:56]=[CH:55][C:54]([S:57][CH3:58])=[CH:53][C:52]=1[F:59])=[O:37])=C>>[OH:31][CH2:32][CH2:33][O:34][NH:35][C:36]([C:38]1[N:46]([CH:47]2[CH2:49][CH2:48]2)[C:45]2[CH:44]=[CH:43][N:42]=[CH:41][C:40]=2[C:39]=1[NH:50][C:51]1[CH:56]=[CH:55][C:54]([S:57][CH3:58])=[CH:53][C:52]=1[F:59])=[O:37]
Reactant: C=COCCONC(=O)c1c(Nc2ccc(SC)cc2F)c2cnccc2n1C1CC1
Agent: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Product: CSc1ccc(Nc2c(C(=O)NOCCO)n(C3CC3)c3ccncc23)c(F)c1

Procedure:
This compound was prepared in an analogous fashion to 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-hydroxy-ethoxy)-amide, using 1-cyclopropyl-3-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide as the starting material. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.54 (s, 1H), 8.32 (d, J=5.9 Hz, 1H), 7.70-7.41 (m, 3H), 7.20 (dd, J=8.50 Hz, 1H), 6.26 (t, J=9.6 Hz, 1H), 4.78 (br s, 1H), 3.87 (dd, J=6.31 Hz, 2H), 3.70-3.39 (m, 3H), 1.27 (br s, 1H), 1.18-1.03 (m, 2H), 0.90-0.67 (m, 2H); LC-MS (method D): [M+H]+=417.0, RT=1.61 min.
Reaction SMILES: C([O:3][C:4]([C:6]1([N:15]([CH3:28])[C:16]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:28][N:15]([C:16]([C:18]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1)=[O:17])[C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1
Reactant: CCOC(=O)C1(N(C)C(=O)c2cccc3c2CCCC3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C(=O)c1cccc2c1CCCC2)C1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
The mixture of 2-[methyl-(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (120) (226 mg, 0.60 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜3. The precipitate is filtered to give a pure product (121) as a pale orange solid (150 mg, 72%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1.I[CH2:32][CH:33]=[CH2:34]>C1COCC1>[CH2:34]([C:14]1([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12][N:11]([C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:16][CH2:15]1)[CH:33]=[CH2:32]
Reactant: C=CCI
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCN(C(=O)OCc2ccccc2)CC1
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
Lithium bis(trimethylsilyl)amide (LiHMDS) in THF (1.0 M, 45 mL) was added to a solution of 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (10.0 g, 0.0360 mol) at −78° C. The reaction mixture was slowly warmed to −50° C. and kept at this temperature for 10 min, and then re-cooled to −78° C. 3-Iodo-1-propene (4.95 mL, 0.0541 mol) was added slowly. After the addition, the mixture was allowed to warm slowly to room temperature and kept at room temperature for 3 hours. The mixture was carefully quenched (the pH was adjusted to 4) with 1N HCl solution, and ethyl acetate (200 mL) was added. The organic layer was separated and washed with water, NaHCO3 (7.5%), brine, dried over MgSO4, and filtered. The filtrate was concentrated. The residue was purified by flash chromatography with 20% ethyl acetate in hexane to give 1-benzyl 4-methyl 4-allylpiperidine-1,4-dicarboxylate (10.4 g, 90.9%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:16]([OH:18])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.[NH2:19][C@H:20]([CH2:25][OH:26])[CH2:21][CH:22]([CH3:24])[CH3:23]>>[OH:26][CH2:25][C@@H:20]([NH:19][C:16]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[N:8]=1)=[O:18])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C[C@H](N)CO
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)F)n1
Product: CC(C)C[C@@H](CO)NC(=O)c1ccc(C2CC2)c(OCC(F)(F)F)n1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and L-leucinol (CAN 17016-87-4) as starting materials, MS (EI): m/e=361.3 [M+H]+.
Reaction SMILES: C([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:21][C:22]([O:24][C@@H:25]2[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[O:23])[CH:15]=1)(=O)C1C=CC=CC=1.O.[OH-].[Li+]>CO.O>[N:27]12[CH2:28][CH2:29][CH:30]([CH2:31][CH2:32]1)[C@@H:25]([O:24][C:22](=[O:23])[NH:21][CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:12][CH2:11][CH2:10][OH:9])[CH:15]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:26]2
Reactant: O=C(NC(c1ccccc1)c1cccc(OCCCOC(=O)c2ccccc2)c1)O[C@H]1CN2CCC1CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NC(c1ccccc1)c1cccc(OCCCO)c1)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a stirred solution of 3-(3-(phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)propyl benzoate (0.370 g, 0.72 mmol) in methanol (3.6 mL), was added a solution of lithium hydroxide monohydrate (0.060 g, 1.44 mmol) in water (1.2 mL). The reaction mixture was stirred at room temperature for 1 hour. Further lithium hydroxide monohydrate (0.060 g, 1.44 mmol) was added, and the reaction stirred at room temperature for a further 16 hours. The reaction mixture was heated at 40° C. for 3.5 hours and allowed to cool. The solvent was evaporate at reduced pressure, and the residue partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate (×2). The combined organic extracts were washed with 10% aqueous potassium carbonate (×2), saturated brine, and dried with anhydrous sodium sulfate. The mixture was filtered and the solvent evaporated at reduced pressure to afford the title compound (0.275 g, 93%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:9])[N:5]([CH3:8])[C:6]=1[CH3:7].BrC1N(C)C(C)=C(Br)N=1.C([Li])CCC.CI.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][N:37]3[C:40]([C:43]4[CH:44]=[C:45]([NH:49][C:50]([NH:52][CH2:53][C:54]([F:57])([F:56])[F:55])=[O:51])[CH:46]=[CH:47][CH:48]=4)=[CH:41][N:42]=[C:36]3[CH:35]=2)O1>>[F:57][C:54]([F:56])([F:55])[CH2:53][NH:52][C:50]([NH:49][C:45]1[CH:46]=[CH:47][CH:48]=[C:43]([C:40]2[N:37]3[CH:38]=[CH:39][C:34]([C:2]4[N:3]=[C:4]([CH3:9])[N:5]([CH3:8])[C:6]=4[CH3:7])=[CH:35][C:36]3=[N:42][CH:41]=2)[CH:44]=1)=[O:51]
Reactant: Cc1nc(Br)c(C)n1C
Reactant: CC1(C)OB(c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)OC1(C)C
Agent: Cc1c(Br)nc(Br)n1C
Agent: [Li]CCCC
Solvent: CI
Product: Cc1nc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)c(C)n1C

Procedure:
4-Bromo-1,2,5-trimethyl-1H-imidazole may be prepared from 2,4-dibromo-1,5-dimethyl-1H-imidazole by treatment with n-butyl lithium and methyl iodide as described in J. Org. Chem., 1994, 59, 5524. This may be coupled with 1-[3-(7-boronic acid-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea or 1-{3-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea according to procedure E3.