Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH2:9][N:10]([CH2:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1)[C:11](=[O:19])[CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH2:26]([N:29]([CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH:33]=O)[CH2:27][CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH2:35]([N:29]([CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31][CH2:32][CH2:33][N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][C:11]([N:10]([CH2:20][C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)[CH2:9][C:5]2[NH:4][CH:8]=[CH:7][N:6]=2)=[O:19])[CH2:14][CH2:15]1)[CH2:36][CH3:37]
Reactant: O=C(CC1CCNCC1)N(Cc1ncc[nH]1)Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN1CCC(CC(=O)N(Cc2ncc[nH]2)Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The compound 45 and 4-(dipropylamino)butanal (55.6 mg) were added and a 10% acetic acid-anhydrous dimethyl formamide solution (3 mL) was stirred under an argon atmosphere for 5 minutes. To the reaction solution, sodium triacetoxyborohydride (103 mg) was added, followed by stirring at room temperature for 15 hours. To the reaction solution, an aqueous 2N sodium hydroxide solution (10 mL) was added and the aqueous layer was extracted three times with ethyl acetate. The organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain the title compound (86.4 mg) having the following physical properties.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:46])[NH:13][CH:14]([C:40](=[O:45])N(OC)C)[CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)([CH3:10])([CH3:9])[CH3:8].CC(=O)OCC.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[C:7]([O:11][C:12](=[O:46])[NH:13][CH:14]([CH:40]=[O:45])[CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:20]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: CON(C)C(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 84.1 %

Procedure:
A suspension of lithium aluminum hydride (263 mg, 6.92 mmol) in THF (20 mL) was added slowly to [1-(methoxy-methyl-carbamoyl)-2-(1-trityl-1H-imidazol-4-yl)-ethyl]-carbamic acid tert-butyl ester (3.4 g, 6.3 mmol) in THF (75 mL) at −20° C. The reaction was complete (silica gel, EA, Rf 0.48) in 15 minutes. Saturated sodium potassium tartrate (10 mL) was added, and the solvent removed. Water was added and the residue extracted with Et2O. The Et2O was washed with brine, dried and filtered. Removal of the solvent gave the title compound (2.552 g, 84%). ESMS 482 (M+H+) 1H NMR ( ) 13C NMR ( )
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:28])([CH3:27])[CH2:11][C:12](=[O:26])[C:13]([NH:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)=[O:14])[C:4]=2[O:3][CH2:2]1.[F:29][C:30]([Si](C)(C)C)([F:32])[F:31].C(=O)([O-])[O-].[Cs+].[Cs+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:28])([CH3:27])[CH2:11][C:12]([OH:26])([C:30]([F:32])([F:31])[F:29])[C:13]([NH:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)=[O:14])[C:4]=2[O:3][CH2:2]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(CC(=O)C(=O)Nc1cccc2ncccc12)c1cccc2c1OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CC(O)(C(=O)Nc1cccc2ncccc12)C(F)(F)F)c1cccc2c1OCO2
Reaction time: 2 h

Procedure:
22 mg of 4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide and 0.04 ml of trifluoromethyltrimethylsilane in 1 ml of DMF are mixed at 0° C. with 11 mg of cesium carbonate. After 2 hours, a spatula-tip full of tetrabutylammonium fluoride is added, and after another 20 minutes, the reaction is added to water. It is extracted 3 times with ethyl acetate, washed with water and brine, dried, and the solvent is removed in a vacuum. The remaining oil is separated by chromatography on silica gel. 11 mg of 4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide is obtained as a solid. Flash point: 164-167° C.
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([O:14]CC)(=O)[CH2:7][C:8]([O:10]CC)=O.Cl.[CH:18]1([C:24](=[NH:26])[NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH:18]1([C:24]2[N:26]=[C:6]([OH:14])[CH:7]=[C:8]([OH:10])[N:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: N=C(N)C1CCCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(O)nc(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A solution of sodium ethoxide in ethanol [previously prepared by dissolving sodium (2.12 g, 92.2 mmol) in ethanol (200 mL)] was treated with diethyl malonate (6.1 mL, 40.2 mmol) with stirring at ambient temperature. A solution of cyclohexanecarboximidamide hydrochloride (5 g, 31 mmol) in ethanol (100 mL) was then added dropwise with stirring at room temperature. On completion of addition the reaction mixture was heated at reflux for 8 h and allowed to stand overnight. The reaction mixture was concentrated in vacuo, water added and the pH adjusted to pH 7-8 using 2N HCl. The resulting solid formed was filtered and washed with diethyl ether to give the title compound as a solid (5.53 g, 93%). MS (ES+) m/e=195. 1H NMR: (DMSO) 1.09-1.81 (10H, m), 2.40-2.53 (1H, m), 5.09 (1H, s), 11.61 (2H, brs).
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH:24][CH3:25])[CH2:18][CH2:17]2)=[CH:14][CH:13]=[CH:12][N:11]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:9][C:10]1[C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:25])[S:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[CH2:18][CH2:17]2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNCCN1CCN(c2cccnc2Cl)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCN(c2cccnc2Cl)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
Add triethylamine (0.850 mL, 6.103 mmol) to a stirring solution of {2-[4-(2-chloro-pyridin-3-yl)-piperazin-1-yl]-ethyl}-methyl-amine hydrochloride salt (2.000 g, 6.103 mmol) in dichloromethane (10 mL). Stir at room temperature for 5 min. Add 4-fluoro-benzenesulfonyl chloride (0.356 g, 1.831 mmol) at room temperature. Stir at room temperature for 18 hr. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate the phases and extract the aqueous phase with dichloromethane. Combine the organic phases, dry over sodium sulfate, filter, and concentrate. Purify the resulting material by silica gel chromatography eluting with hexanes:acetone 1:1 to afford the title preparation (0.525 g, 83% yield). MS ES: m/z=413 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)O)CC4)nc23)c1
Product: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)N5CCOCC5)CC4)nc23)c1

Procedure:
Prepared from compound 46 of Example 1 by reaction with N,N'-carbonyldiimidazole and morpholine.
Reaction SMILES: [C:1]1([S:7][CH:8]=[CH:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[S:18][C:17]([S:19][CH3:20])=[N:16][CH:15]=1>C(#N)C.C(N(CC)CC)C>[CH3:20][S:19][C:17]1[S:18][C:14]([NH:13][C:10](=[O:12])[CH:9]=[CH:8][S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][N:16]=1
Reactant: CSc1ncc(N)s1
Reactant: O=C(O)C=CSc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1ncc(NC(=O)C=CSc2ccccc2)s1
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a solution of 3-(phenylthio)acrylic acid (3.69 g) in acetonitrile (50 mL) were added a solution of 5-amino-2-(methylthio)thiazole (3.00 g) in acetonitrile (10 mL) and triethylamine (2.80 mL) under ice-cooling. The mixture was stirred at the same temperature for 2 hours and then at room temperature for 3 hours, and then concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (50 mL), which was extracted with ethyl acetate (100 mL) twice. The organic layers were combined, washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain N-[2-(methylthio)thiazol-5-yl]-3-(phenylthio)acrylamide (1.90 g) as a dark yellow crystal.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].F[C:13]1[C:14]([N+:29]([O-:31])=[O:30])=[C:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[CH:16]=[CH:17][CH:18]=1.[NH4+].[Cl-]>CS(C)=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:14]=1[N+:29]([O-:31])=[O:30])[C:3]([O:10][CH3:11])=[O:9]
Reactant: O=[N+]([O-])c1cccc(Nc2cccc(F)c2[N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1cccc(Nc2cccc([N+](=O)[O-])c2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 0.26 g, 11 mmol) in DMSO (30 ml) is added dimethyl malonate (1.43 g, 11 mmol) slowly. The reaction is stirred at room temperature for 1 hour. After that, a solution of (3-fluoro-2-nitro-phenyl)-(3-nitro-phenyl)-amine (1.0 g, 3.6 mmol) in DMSO (5 ml) is added. The reaction is brought to 80° C. and stirred for 20 hours. It is poured into saturated NH4Cl and extracted with ethyl acetate (30 ml×3). The organic layers are combined, washed with water, brine and dried with Na2SO4. The desired compound is obtained after purification of the residue by flash column chromatography (silica gel, eluted by hexa-nes-ethyl acetate): LC-MS: 390.0 (MH+),
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][OH:29].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:29][CH2:28][C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: OCc1ccc2ccccc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2ccc3ccccc3c2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-naphthalenemethanol and DBU in DME. ES-MS m/e (%): 365 (M+Na+, 100), 343 (M+H+, 40).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:2].[CH3:9][OH:10]>F[B-](F)(F)F.C[N+](C)(C)C>[CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:10][CH3:9])=[O:2]
Reactant: CO
Reactant: O=CN1CCCCC1
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: COC1CCCCN1C=O
Reaction time: 0.25 h
Yield: 95 %

Procedure:
In the cell and device as described in Example 2 a mixture of 480 g of 1-formylpiperidine, 1,360 g of methanol and 6.80 g of tetramethylammonium tetrafluoroborate was electrolyzed for 34 hours and 15 minutes at 1 A (corresponding to 240 Ahr), 98 volts and 25° C. By distillative work up, 577 g of 1-formyl-2-methoxypiperidine could be isolated from the clear electrolyte, corresponding to a current efficiency of 90.2% of the theory.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][NH:43][C@@H:44]([CH3:51])[CH2:45][N:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1>C(Cl)Cl.C1COCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:43]([C@@H:44]([CH3:51])[CH2:45][N:46]2[CH2:49][CH:48]([OH:50])[CH2:47]2)[CH3:42])=[O:17])=[CH:18][CH:19]=1
Reactant: CN[C@@H](C)CN1CC(O)C1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 15.8 %

Procedure:
DIPEA (0.200 mL, 1.15 mmol) was added to a stirred suspension of 4-chlorobenzoic acid (0.06 g, 0.38 mmol) and TBTU (0.123 g, 0.38 mmol) in DCM (2 mL) at rt. The suspension was stirred for 5 min before it was cooled on an ice-bath. A solution of (S)-1-(2-(methylamino)propyl)azetidin-3-ol (Compound M11) (0.06 g, 0.42 mmol) in THF (1.5 mL) was added over 10 min. The ice-bath was removed and the reaction was stirred at rt over night. DCM (3 mL) was added and the mixture was washed with NaHCO3 (8% aq., 3 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and NaOH (aq., 2M) was added. The resulting mixture was stirred at rt for 3 h, then concentrated under reduced pressure. DCM (5 mL) and NaHCO3, (aq., 8%, 5 mL) was added. The organic phase was collected and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC to give the title compound (17 mg, 16%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.99-1.12, 2.18-2.23, 2.33-2.79, 3.15-3.56, 4.03-4.18, 4.44-4.54, 5.16-5.28, 7.32-7.55. Some signals overlap with solvent. HRMS (M+H)+: calculated 283.1213. found 283.1219.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][CH:11]([C:13]2[CH:14]=[C:15]([C:30]([O:32]C)=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][C:18]3=[O:29])[CH3:12])[CH:7]=[CH:8][CH:9]=1.C1COCC1>CO>[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][CH:11]([C:13]2[CH:14]=[C:15]([C:30]([OH:32])=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:19][C:18]3=[O:29])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(C(C)Nc2cccc(Cl)c2F)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Sodium hydroxide (0.217 mL, 0.43 mmol) was added to a stirred solution of methyl 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (200 mg, 0.43 mmol) dissolved in MeOH (2 mL). The resulting solution was stirred at room temperature for 16 hrs. THF was added and the resulting solution was stirred at 50° C. for 8 hrs. The pH was adjusted to 3 with HC12N, the solvent was removed under vacuum and the residue diluted with H2O. The solid was collected by filtration, washed with water and dried to give 8-(1-(3-chloro-2-fluorophenylamino) ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (171 mg, 88%) as a white solid. Mass Spectrum: M+H+ 447.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[N:14]#[C:15]Br>C(Cl)Cl.O>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:15]#[N:14])[CH2:2][CH2:3]1
Reactant: OCC1CCNCC1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CN1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-piperidinemethanol (140 g, 1.22 mol) in CH2Cl2 (1 L) was treated with a slurry of NaHCO3 (205 g, 2.44 mol) in water (1.4 L) at 0° C. The mixture was stirred at 0° C. for 15 min, and then charged with a solution of cyanogen bromide in CH2Cl2, (1.34 mol) at 0° C. The reaction mixture was stirred and allowed to warm to ambient temperature, and stirred overnight. The aqueous layer was separated and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was combined with other batches made similarly and purified by chromatography on a silica gel column to give 300 g of 4-(hydroxymethyl)-1-piperidinecarbonitrile.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)[C:5]([F:24])=[CH:4][N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][O:31][CH2:32][CH2:33][O:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[F:24][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:39][C:38]2[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][O:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:41][CH:40]=2)=[N:3][CH:4]=1
Reactant: COCCOCOCCOc1ccc(N)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(Nc2nc(Cl)ncc2F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COCCOCOCCOc1ccc(Nc2ncc(F)c(Nc3cccc(N(C)C(=O)OC(C)(C)C)c3)n2)cc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 57.5 %

Procedure:
In a 25 ml 3-Neck RBF, tert-butyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)(methyl)carbamate (0.88 g), 4-(2-((2-methoxyethoxy)methoxy)ethoxy)aniline (0.901 g), Cs2CO3 (1.21 g) and Xantphose (0.144 g) were added in degassed 1,4-dioxane (10 mL) and the reaction mixture was degassed under argon for 30 minutes. Palladium(II)acetate (0.055 g) was added to reaction mixture and again it was degassed for 30 minutes. The reaction mixture was heated to 80° C. and stirred for 3.5 h. The reaction was monitored on TLC using CHCl3:methanol (9.5:0.5) as mobile phase. After completion of the reaction, reaction mixture was allowed to cool at room temperature. The reaction mixture was poured into water and product was extracted with ethyl acetate (3×25 ml). Ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by using Combiflash chromatography. Product was eluted with 2% methanol in CHCl3 to give 0.8 g of tert-butyl (3-((5-fluoro-2-((4-(2-((2-methoxyethoxy)methoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)(methyl)carbamate. M+1=557.9.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:25])[CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[O:26]1CCCC1.O.[OH-].[Li+].OO>O>[C:19]1([C@H:15]([CH2:16][CH:17]=[CH2:18])[C:14]([OH:25])=[O:26])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C1CCOC1
Reactant: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C=CC[C@H](C(=O)O)c1ccccc1
Reaction time: 3 h

Procedure:
Combine (S)-4-benzyl-3-(2-phenylpent-4-enoyl)-2-oxazolidinone (3.35 g, 10 mol), tetrahydrofuran (80 mL), and water (20 mL). Cool in an ice bath. Add lithium hydroxide hydrate (0.84 g, 20 mmol) and an aqueous solution of hydrogen peroxide (4 mL, 30%, 46.4 mmol). After 3 hours, concentrate the reaction mixture to about half volume, dilute the concentrated reaction mixture with an aqueous 1 M sodium hydroxide solution and extract twice with diethyl ether. Cool the aqueous layer in an ice bath, acidify with an aqueous 3 M hydrochloric acid solution, and extract twice with dichloromethane. Extract the combined organic layers with a saturated aqueous sodium thiosulfate solution, dry over MgSO4, filter, and evaporate in vacuo to give (S)-2-phenylpent-4-enoic acid: Rf =0.48 (silica gel, 5% methanol/dichloromethane).
Reaction SMILES: [F:1][C:2]([F:20])([CH2:17][CH2:18][CH3:19])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.Cl.[NH2:22][C:23]1([C:26]#[N:27])[CH2:25][CH2:24]1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(C(C)C)CC)(C)C>>[C:26]([C:23]1([NH:22][C:5]([C@@H:4]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH2:3][C:2]([F:1])([F:20])[CH2:17][CH2:18][CH3:19])=[O:7])[CH2:25][CH2:24]1)#[N:27]
Reactant: N#CC1(N)CC1
Reactant: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)NC1(C#N)CC1

Procedure:
Prepared by reacting (S)-4,4-Difluoro-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid and 1-Amino-cyclopropanecarbonitrile hydrochloride, using TOTU as the coupling agent and diisopropyl ethylamine as the base.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.CI.[C:20](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4]([N:5]([CH3:20])[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)=[N:3]1
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21
Reaction time: 8 h
Yield: 101.8 %

Procedure:
A mixture of 2.0 g (0.0087 mole) 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one, 1.1 ml (0.0174 mole) methyl iodide, anhydrous potassium carbonate (1 gram) and acetone (100 ml) was heated under reflux, with stirring, overnight. After refluxing had continued 21 hours an additional 1 ml of methyl iodide was added and solids removed from the mixture by suction filtration. The filtrate was evaporated under reduced pressure and the resulting residue dissolved in ethyl acetate, washed with water, then with brine and dried over MgSO4, filtered and solvent stripped off to give B 1.8 g of crude product. Purification by high pressure liquid chromatography gave a solid, mp 79°-82° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27]>>[CH:26]([S:29]([N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:6][CH2:7]1)(=[O:31])=[O:30])([CH3:28])[CH3:27]
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Product: CC(C)S(=O)(=O)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and isopropylsulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 10.08 (1H, s), 8.41 (1H, d), 8.01 (1H, d), 7.95 (1H, s), 7.86 (1H, dd), 5.35 (2H, s), 4.75 (1H, m), 3.69 (2H, m), 3.31 (1H, m), 3.13 (2H, m), 2.17 (2H, m), 1.97 (2H, m), 1.20 (6H, d).