Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](C3CCCCO3)[N:13]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>O1CCCC1.CO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2ncn(C3CCCCO3)n2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2nnc[nH]2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 18.8 %

Procedure:
To a 20 mL vial was added a solution of 4-{4-(4-chlorobenzyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyridine (0.2245 g, 0.635 mmol) in anhydrous tetrahydrofuran (2.000 mL) and methanol (2.000 mL). 4.0 M Hydrochloric acid in 1,4-dioxane (1.0 mL, 4.0 mmol) was added and the reaction mixture was allowed to stir at 50° C. for 18 hours. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by HPLC to afford the product (0.0423 g, 45%) as an off white solid. LC/MS (AA) ES+ 354. 1H NMR (400 MHz, d6-DMSO) δ: 14.48 (s, 1H), 8.71 (dd, J=4.4, 1.2 Hz, 2H), 7.89-7.87 (m, 2H), 7.38-7.32 (m, 4H), 4.67 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][OH:12]
Reactant: O=Cc1ccccc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccccc1Cl
Yield: 77.6 %

Procedure:
To a stirred solution of 56.2 grams (0.40 mole) of 2-chlorobenzaldehyde and 55.6 grams (0.80 mole) of hydroxylamine hydrochloride in 225 ml of ethanol and 111 ml of water was added in portions over a 15 minute period a solution of 24.0 grams (0.60 mole) of sodium hydroxide in 24 ml of water. The addition caused a solid precipitate to form. The reaction mixture was heated to boiling, and water was added until the solid dissolved. Additional water was added until the solution became cloudy. The reaction mixture was allowed to cool, and as it cooled a crystalline solid formed. The solid, collected by filtration, was dissolved in methylene chloride, and the methylene chloride solution was dried with sodium sulfate. The filtrate was concentrated under reduced pressure to remove ethanol, yielding additional solid, which was collected by filtration. This solid, too, was dissolved in methylene chloride, and the solution was dried with sodium sulfate. The two methylene chloride solutions were filtered from the sodium sulfate and the filtrates combined and concentrated under reduced pressure to give a residual solid. The solid was recrystallized from ethanol-water to give 48.3 grams of 2-chlorobenzaldoxime; mp 73.5°-75.5° C. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10].[OH:21]OS([O-])=O.[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10]
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(Cl)c2)OC1(C)C
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1ccc(OC(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 4-bromo-2-chloro-1-(difluoromethoxy)benzene (Preparation 27, 0.83 g, 3.2 mmol) in THF (16 ml) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.90 g, 3.6 mmol), Pd(dppf)Cl2 (0.12 g, 0.16 mmol), and potassium acetate (0.98 g, 9.7 mmol) under N2 and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo and the residue filtered through a silica gel cake with arbocel on top washing through with EtOAc. The filtrate was concentrated in vacuo to give a crude product of 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A solution of crude of 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 3.3 mmol) in acetone (10 ml) was added to an aqueous oxone solution (2.6 g, 3.9 mmol, 10 mL) dropwise with stirring at 0° C. for 1 hour. The reaction mixture was partitioned between water (20 ml) and EtOAc (20 ml), the combined organic phase was washed with brine, dried over sodium sulphate, filtered, and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography eluting with 0-40% EtOAc in Heptane to afford the title compound (0.53 g, 82% yield) as a pale brown oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([C:12]([CH2:17][OH:18])([CH2:15][OH:16])[CH2:13][CH3:14])[OH:11]>C(N(CC)CC)C>[C:1]([OH:8])(=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([OH:8])(=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([OH:8])(=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([C:12]([CH2:17][OH:18])([CH2:15][OH:16])[CH2:13][CH3:14])[OH:11]
Reactant: O=C(Cl)c1ccccc1
Agent: CCC(CO)(CO)CO
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1
Temperature: 100 °C
Yield: 85 %

Procedure:
While stirring, 71 parts by weight of benzoyl chloride were dripped over 30 minutes into a mixed solution of 45 parts by weight of trimethylolpropane and 101 parts by weight of triethylamine maintained at 100° C., and the resulting mixture was stirred for an additional 30 minutes. After completion of the reaction, the resulting mixture was cooled to room temperature. After collecting precipitates via filtration, washing was carried out via the addition of ethyl acetate and pure water, and the organic phase was collected via separation, followed by removal of ethyl acetate via distillation under reduced pressure, whereby 126 parts by weight (at an 85% yield) of white TMPTB crystals were prepared. The molecular weight of the resulting compound was 446.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH2:62])[C:58]([CH3:61])([CH3:60])[CH3:59])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.C(OCC)(=O)C>[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH:62][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[C:58]([CH3:60])([CH3:61])[CH3:59])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: CC(C)(C)[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@H](c2nc3cc(Cl)ccc3[nH]2)C(C)(C)C)ccc1C(=O)N1CCCC1
Yield: 21 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2,2-dimethylpropylamine in tetrahydrofuran. Yield: 21%; Rfvalue: 0.18 (silica gel; ethyl acetate); C25H29ClN4O2 (452.98); mass spectrum: (M+H)+=453/455 (chlorine isotope).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[C:45]([O:44][C:43](=[O:49])[NH:42][C@H:39]1[CH2:40][CH2:41][C@H:36]([NH:35][C:32]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:21]=2[CH3:31])=[O:33])[CH2:37][CH2:38]1)([CH3:46])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c5) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].B1([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)OCCCO1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.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>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Reactant: c1cncc(B2OCCCO2)c1
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: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)c(-c2cccnc2)c1
Yield: 68.7 %

Procedure:
A mixture of 3-bromo-4-chloronitrobenzene (5.17 g, 21.9 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (4.27 g, 26.2 mmol) in ethanol (30 ml) and toluene (30 ml) together with 2 N Na2CO3 solution (13.9 ml) was degassed with a stream of nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.3 g, 0.26 mmol) was added and the reaction was heated at reflux for over 24 h. The mixture was concentrated under reduced pressure to remove the organic solvents and water (100 ml) was added. This was extracted with ethyl acetate (200 ml) and then washed with brine (75 ml), dried (MgSO4), and concentrated under reduced pressure while dry loading onto silica. The resulting crude residue was purified by column chromatography (silica gel, 50% Et2O/CH2Cl2), to yield the title compound (3.53 g, 69%): 1H NMR (360 MHz, CDCl3) δ 7.42-7.48 (1H, m), 7.70 (1H, d, J 8.7 Hz), 7.81 (1H, dt, J 8.0, 1.8 Hz), 8.17-8.27 (2H, m), 8.68-8.77 (2H, m).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:13]=1[CH2:12][C:11]1[CH:10]=[C:9](O)[C:8]([OH:15])=[CH:7][C:6]=1[CH2:5]2.[C:16]([O-:19])([O-])=O.[K+].[K+].O.[CH3:23]N(C=O)C>[Cl-].C1([N+](C)(C)C)C=CC=CC=1>[CH3:23][O:15][C:8]1[C:9]([O:19][CH3:16])=[CH:10][C:11]2[CH2:12][C:13]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH2:5][C:6]=2[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc2c(cc1O)Cn1ccnc1C2
Reactant: CN(C)C=O
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: COc1cc2c(cc1OC)Cn1ccnc1C2
Yield: 8.4 %

Procedure:
A mixture of 5,10-dihydro-imidazo[1,2-b]isoquinoline-7,8-diol, obtained according to the procedure described in Ex.No. A8c, (0.155 mol), phenyltrimethylammonium chloride (0.31 mol) and K2CO3 (0.68 mol) in DMF (400 ml) was stirred at 90° C. for 20 hours, cooled, poured out into H2O and filtered over dicalite. The filtrate was separated into its layers. The organic layer was washed with H2O, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0 to 97/3). The pure fractions were collected and the solvent was evaporated, yielding 3 g of 5,10-dihydro-7,8-dimethoxyimidazo[1,2-b]isoquinoline (8.4%) (interm. 22).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:30]([NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])=[O:31])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: COc1ccccc1N=C=O
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 258°-260° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:28][C:29](O)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:28][C:29]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1CCCCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1CCCCCCC1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Triethylamine 0.24 ml was added in a methylene chloride 10 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo (3.2.1]octane hydrochloride 0.28 g, and stirred at 0° C. for 30 min. Cyclooctyl acetic acid 0.25 g and WSC 0.40 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 21 hours. The reaction mixture was washed wits saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-cyclooctylacetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THP 15 ml solution of lithium aluminum hydride 0.12 g and refluxed for 1 hour. The reaction mixture was cooled, then added water and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform: acetone=10:1) to obtain the product. Yield: 0.26 g (Yield 61%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7](=[O:22])[C:8]4[C:18]([OH:19])=[CH:17][C:16]([O:20]C)=[CH:15][C:9]=4[O:10][C:11]=3[O:12][C:13]=2[CH:14]=1.N1C(=O)CC[C@H]1C(O)=O.Cl>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7](=[O:22])[C:8]4[C:18]([OH:19])=[CH:17][C:16]([OH:20])=[CH:15][C:9]=4[O:10][C:11]=3[O:12][C:13]=2[CH:14]=1
Reactant: COc1cc(O)c2c(=O)c3c(oc2c1)oc1cc(O)ccc13
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Product: O=c1c2c(O)cc(O)cc2oc2oc3cc(O)ccc3c12
Temperature: 190 °C
Yield: 43.2 %

Procedure:
A mixture consisting of 10 (0.17 g) and 7g Pyr-HCl was heated to 190° C. for 45 min. The reaction was allowed to cool and then partitioned between water and EtOAc. The EtOAc was dried over MgSO4, filtered, concentrated and chromatographed on silica gel (EtOAc/hexanes; 3:7) to give the product as a white solid (0.07 g): Mp 318-322 (dec); 1H NMR (DMSO-d6) δ 12.90 (s, 1H), 10.97 (br s, 1H), 9.99 (br s, 1H), 7.72 (d, 1H, J=8.4 Hz), 7.11 (d, 1H, J=2.1 Hz), 6.93 (dd, 1H, J=8.4 Hz, 2.1 Hz), 6.56 (d, 1H, J=2.1 Hz), 6.30 (d, 1H, J=2.1 Hz); MS FI (neg) 283 (M−H)−.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f2) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:20]3[CH2:24][CH2:23][NH:22][C:21]3=[O:25])[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: O=C1NCCN1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)CN3CCNC3=O)CC2)ccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), imidazolidin-2-one (64 mg, 0.73 mmol, 1.10 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.4 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-imidazolidin-2-one (22): HPLC retention time, 1.33 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 352.8, found, 353.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](Cl)[N:11]=1)[C:5]([O:7]C)=[O:6].[CH3:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:14]([CH3:13])[S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: CNS(C)(=O)=O
Product: CN(c1cc(C(=O)O)cc(Cl)n1)S(C)(=O)=O

Procedure:
Prepared from Methyl 2,6-dichloroisonicotinate and methyl(methylsulfonyl)amine as described in the preparation of intermediate 4.2c.1, steps A and B.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[C:9]=2[C:8](=[O:17])[N:7]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[C:6]1=[O:25].[Cl-].[NH4+]>O1CCCC1.CCOCC>[OH:24][C:22]([CH3:1])([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:7]1[C:8](=[O:17])[C:9]2[N:10]([CH2:14][CH2:15][CH3:16])[CH:11]=[N:12][C:13]=2[N:5]([CH3:4])[C:6]1=[O:25]
Reactant: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
22.4 g (0.3 mol) of methylmagnesium chloride in the form of a 20% strength solution in tetrahydrofuran are added dropwise with vigorous stirring at room temperature to a suspension of 61.3 g (0.2 mol) of 3-methyl-1-(5-oxohexyl)-7-propylxanthine in 2 l of anhydrous ether, the internal temperature rising to approximately 30° C. The mixture is then warmed with stirring and under reflux for 2 hours, treated with saturated aqueous ammonium chloride solution to decompose the alkoxide formed, and the organic phase is separated off and washed twice with 500 ml of water each time. The collected water phases are extracted thoroughly with dichloromethane again. The dichloromethane extract is combined with the ethereal phase, dried over sodium sulfate, filtered and evaporated under reduced pressure, 59.0 g of crude product (91.5% of theory) being obtained, which is purified by recrystallization from diisopropyl ether.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11](=[O:14])([O-])[O-].[Ca+2].Cl[CH2:17][CH:18]([OH:21])[CH2:19]Cl>O>[OH:1][CH2:2][CH2:3][N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:17][CH:18]([OH:21])[CH2:19][N:4]([CH2:3][CH2:11][OH:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCCNc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: OC(CCl)CCl
Agent: [Ca+2]
Solvent: O
Product: OCCN(CC(O)CN(CCO)c1ccccc1)c1ccccc1

Procedure:
The mixture consisting of 2 moles (274.4 g) of N-β-hydroxyethylaniline, 140 g of calcium carbonate and 1.2 moles (154.8 g) of 1,3-dichloro-2-propanol in 1 liter of water is heated for 6 hours under water reflux.
Reaction SMILES: O[CH:2]=[C:3]1[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[CH2:6][C:5]([CH3:13])([CH3:12])[CH2:4]1.Cl.[NH2:15]O>C(O)C.O>[CH3:12][C:5]1([CH3:13])[CH2:4][C:3]2[CH:2]=[N:15][O:9][C:8]=2[C:7]([CH3:11])([CH3:10])[CH2:6]1
Reactant: CC1(C)CC(=CO)C(=O)C(C)(C)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(C)Cc2cnoc2C(C)(C)C1
Temperature: 110 °C
Yield: 88.3 %

Procedure:
Under a nitrogen atmosphere and with stirring, a solution of 16 (140 mg, 0.77 mmol) in ethanol (19.1 mL) was added to a solution of hydroxylamine hydrochloride (7.98 mmol, 555 mg, 10.4 eq) in water (980 μL) at room temperature. The mixture was heated to 110° C. and stirred at reflux for 1 hour. After heating, the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with methylene chloride/ethyl ether (1:2, 3×10 mL). The organic layers were then combined and washed with saturated aqueous sodium bicarbonate solution (1×12 mL) and brine (2×12 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 17 as a yellow oil (122 mg, 0.68 mmol, 89%). The material was used in the next reaction without further purification: 1H NMR (CDCl3) δ 8.00 (1H, s), 2.24 (2H, s), 1.60 (2H, s), 1.34 (6H, s), 1.03 (6H, s); 13C NMR (CDCl3) δ 173.2, 150.0, 110.4, 52.4, 34.4, 32.6, 32.4, 29.7, 29.3. MS: No molecular ion peak is observed by ESI+ and EI methods.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].CS(O[CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C.CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]=[C:27]([O:31][CH2:37][CH2:38][NH:39][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2cccc(OCCNC(=O)OC(C)(C)C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 82.5 °C
Yield: 32.6 %

Procedure:
To a solution of N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 17, Step A; 50 mg, 0.121 mmol) and 2-(tert-butoxycarbonylamino)ethyl methanesulfonate (71 mg, 0.297 mmol) in N,N-dimethylacetamide (2 mL) was added cesium carbonate (79.0 mg, 0.242 mmol). The mixture was heated to 80-85° C. for 90 minutes. After allowing to cool the mixture was diluted with ethyl acetate and methanol, filtered and concentrated under a stream of nitrogen. The material was purified using preparative thin layer chromatography on silica, eluting with 5% methanol and 1% triethylamine in ethyl acetate to give the product 21.9 mg (33%).