Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:5]([CH:6]=O)[C:4]=1[OH:15].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:5]([CH:6]=[N:19][OH:20])[C:4]=1[OH:15]
Reactant: NO
Reactant: CC(C)(C)c1cc(C=O)c(O)c(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C=NO)c(O)c(C(F)(F)F)c1

Procedure:
0.05 moles of the aldehyde from Step A, 0.12 moles of hydroxylamine hydrochloride and sodium acetate (0.12 moles) are dissolved in a mixture of ethanol (100 ml.) and water (30 ml.). The reaction mixture is refluxed for 2 hours, cooled and water added until no more precipitate forms. The solid that separates is crystallized from ethanol to yield 3-trifluoromethyl-5-tert-butyl salicylaldehyde oxime.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)c(O)cc3OCC3CC3)ncnc12
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(O)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-hydroxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A188) and acetyl chloride the title compound is obtained as colorless solid
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])[C:5]#[N:6].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][OH:11])[C:5]#[N:6]
Reactant: N#Cc1ccc(C=O)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(CO)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
To a solution of 3-fluoro-4-formylbenzonitrile (3.6 g, 24.1 mmol) in methanol (40 mL) was added sodium borohydride (0.304 g, 8.04 mmol) slowly at room temperature. After 20 min., the reaction was complete by HPLC and LCMS. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (˜5 mL; stirred for 20 min.), and the methanol was removed under reduced pressure. The aqueous residue was diluted with dichloromethane (80 mL), washed with water (50 mL), and collected. The aqueous layer was extracted with dichloromethane (40 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 3-fluoro-4-(hydroxymethyl)benzonitrile (3.51 g, 23.2 mmol, 96% yield) as a yellow solid. The compound had an HPLC ret. time=0.720 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=152.09. 1H NMR (500 MHz, CDCl3) δ ppm 4.85 (s, 2H), 7.35 (dd, J=9.43, 1.66 Hz, 1H), 7.50 (dd, J=7.91, 1.25 Hz, 1H), and 7.65 (t, J=7.49 Hz, 1H).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:19])[CH2:16][CH2:15][CH2:14][C:13]([CH3:18])([CH3:17])[NH:12]1>O>[Cl:3][C:2]1[N:1]=[C:8]([N:12]2[C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH2:16][C:11]2([CH3:19])[CH3:10])[N:7]=[C:5]([N:12]2[C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH2:16][C:11]2([CH3:19])[CH3:10])[N:4]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Product: CC1(C)CCCC(C)(C)N1c1nc(Cl)nc(N2C(C)(C)CCCC2(C)C)n1
Reaction time: 10 h

Procedure:
18.4 g of cyanuric chloride and 113 g of 2,2,6,6-tetramethylpiperidine are heated for 10 hours at 180° and then for 10 hours at 210° in a 300 ml autoclave. The contents of the autoclave are then taken up in 500 ml of water, and the insoluble residue is filtered off by suction, washed with water and dried. The brownish residue is crystallized from ligroin. 2-Chloro-4,6-bis-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine is obtained as colorless crystals having a melting point of 188°.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24](=O)[C:25]#[CH:26])[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1.Cl.[OH:31][C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[NH:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][N:35]=[C:33]([C:32]([OH:31])([CH3:37])[CH3:36])[N:34]=3)[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Br)c2=O)c1
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Br)n1
Temperature: 75 °C
Yield: 41.9 %

Procedure:
To a solution of 5-bromo-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-6-(6-methyl-pyridin-2-ylmethoxy)-3H-pyrimidin-4-one of Step D (54 mg, 0.12 mmol) in acetonitrile (1 mL) was added 2-hydroxy-2-methylpropionamidine HCl (25 mg, 0.18 mmol) and potassium carbonate (50 mg, 0.36 mmol) and the slurry was heated at 75° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a light yellow solid (27 mg, 42% yield). MS (M, M+2): 536, 538; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.14 (s, 3H), 2.21 (s, 3H), 2.61 (s, 3H), 4.78 (s, 1H), 5.61-5.72 (m, 2H), 7.14 (d, J=7.83 Hz, 1H), 7.43 (d, J=7.44 Hz, 1H), 7.54-7.58 (m, 2H), 7.70 (s, 1H), 7.92 (s, 1H), 8.13 (d, J=7.82 Hz, 1H), 8.77 (d, J=5.09 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.N12CCCN=C1CCCCC2.[CH3:30][O:31][C:32]1[N:37]=[C:36]([CH3:38])[N:35]=[C:34]([N:39](C2C=CC=CC=2)[C:40](=O)[O-:41])[N:33]=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:15]([NH:18][C:40]([NH:39][C:34]2[N:33]=[C:32]([O:31][CH3:30])[N:37]=[C:36]([CH3:38])[N:35]=2)=[O:41])(=[O:16])=[O:17])[C:5]2[O:10][S:9](=[O:11])(=[O:12])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: CC1=Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cc(Br)cc3c2OS(=O)(=O)C(C)=C3)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A reaction mixture of 3.54 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide, 1.61 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, 2.73 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate and 35 ml of absolute dioxan is stirred for 11/2 hours at room temperature. The solvent is evaporated and the oily residue is triturated with 10 ml of 1N hydrochloric acid and 5 ml of water. The precipitate is isolated by filtration, washed with ether and dried, affording 4.84 g of N-(6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8ylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea of m.p. 196°-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][Cl:30])[CH:24]=1>>[ClH:30].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCc1cccnc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(Cc3cccnc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 3-picolylchloride hydrochloride as described for compound 105. Purified by chromatography (dichloromethane). Crystallized from diethyl ether as the hydrochloride. M.p. 192°-195° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][NH:13][CH3:14].C1COCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CNC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
Into a 20 mL scintillation vial were added 3-Bromobenzenesulfonyl chloride (0.301 g, 1.179 mmol) and anhydrous pyridine (5 mL). A 2M solution of dimethylamine in THF (1.0 mL, 2.0 mmol) was added dropwise, and the reaction mixture was stirred at rt under N2 for 5 h after which it was concentrated under vacuum. The crude residue was partitioned between EtOAc and 1M citric acid. The layers were separated, and the organic phase was washed 3× with 1M citric acid, then treated with brine, dried (Na2SO4), filtered and concentrated. Trituration with Et2O provided 3-Bromo-N,N-dimethyl-benzenesulfonamide as a white powder (0.297 g, 96%). MS: m/z 263.9/265.9 [MH+].
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:7](=[O:16])[C@H:6]1[NH2:17])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:1]([O:4][C@@H:5]1[N:8]([Si:9]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:10])[CH3:11])[C:7](=[O:16])[C@H:6]1[NH:17][C:32](=[O:33])[CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)O[C@H]1[C@H](N)C(=O)N1[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C
Yield: 90.6 %

Procedure:
To a solution of 0.387 g of (3S,4S)-4-acetoxy-3-amino-1-t-butyldimethylsilyl-2-oxoazetidine in 20 ml of THF is added 0.24 of triethylamine under ice-cooling, and then, a solution of 0.32 g of phenylacetyl chloride in THF is added dropwise. The mixture is stirred under ice-cooling for one hour, the insolubles are filtered off, and the filtrate is concentrated under reduced pressure. Purifying the residue on a silica gel column (ethyl acetate:n-hexane=1:2) yields 0.511 g of (3S,4S)-4-acetoxy-1-t-butyldimethylsilyl-3-phenylacetamido-2-oxoazetidine.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:16][O:17][C:18]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[NH:21].[Na].Cl>C(O)C>[O:13]=[C:11]1[NH:22][C:20]([C:19]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:18]=2[O:17][CH3:16])=[N:21][CH:4]=[C:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COc1ccc(C(=N)N)c(OC)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccc(OC)cc2OC)[nH]c1=O
Temperature: 0 °C
Yield: 76.2 %

Procedure:
A solution of diethyl ethoxymethylenemalonate (8.4 g., 0.0388 mole) in ethanol (20 ml.) was added dropwise to a cooled (ice-water) stirred mixture of 2,4-dimethoxybenzamidine (7.0 g., 0.0388 mole) in ethanol (50 ml.) containing sodium (0.89 g., 0.0388 g-atom). The mixture was heated under reflux for two hours. The cooled mixture was poured into ice-water and acidified with dilute hydrochloric acid. The precipitate was recrystallized from 95% ethanol to give ethyl 1,6-dihydro-6-oxo-2-(2,4-dimethoxyphenyl)pyrimidine-5 -carboxylate (9.0 g., 63.5% yield), m.p. 190°-192°.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([CH3:16])([CH3:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:3][C:4]([CH3:16])([CH3:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=[O:6]
Reactant: CSc1ccc(C(=O)C(C)(C)O[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)C(C)(C)O)cc1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of 40 mg (0.14 mmol) of 2-trimethylsilyloxy-4′-(methylthio)isobutyrophenone in 2 mL THF was added 0.2 mL of 1 M n-Bu4NF in THF. The resulting mixture was stirred for 30 min and then quenched with 10 mL of NH4OAc buffer. The product was extracted with EtOAc, dried over MgSO4 and concentrated. The residue was purified by flash chromatography, eluting with 4:1 hexane/EtOAc to give 25 mg of the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[CH:15](N)=[NH:16].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O>[N:1]1[C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[N:16][CH:15]=1
Reactant: Nc1cnccc1C(=O)O
Reactant: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Oc1ncnc2cnccc12
Temperature: 150 °C
Yield: 87.6 %

Procedure:
A mixture of 3-amino-isonicotinic acid (32)(26.24 g, 190.0 mmol) and formamidine acetate (39.56 g, 380 mmol) in dimethylacetamide (100 ml) was stirred and heated to 150° C. The reaction was maintained at this temperature with stirring for 12 hours before it was allowed to cool to 25° C. and then basified with sodium bicarbonate solution (5% aqueous) until pH 7-8 was attained. The resultant pale brown solid was removed by filtration, washed with water (20 ml) and dried in a desiccator to give the desired compound (24.50 g, 87.63%) which required no further purification. m/z (LC-MS, ESP): 148 [M+H]+, R/T=1.09 mins.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:13]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31]CCCC2C=CC([N+]([O-])=O)=CC=2)[O:14][Si:15]([CH3:21])([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.BrCCCCCCOC[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:13]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=2)[O:14][Si:15]([CH3:20])([CH3:21])[C:16]([CH3:17])([CH3:19])[CH3:18])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc(CCOCCCCCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCOCCCCc1ccc([N+](=O)[O-])cc1)c1ccc(O)c2[nH]c(=O)ccc12
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCOCCc1ccc([N+](=O)[O-])cc1)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 106, using Intermediate 53 in place of Intermediate 52. ES/MS calcd. for C31H46N3O6Si+ 584.3. Found m/z=584.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=3)[C:9]2=[O:25])=[C:4]([CH3:26])[CH:3]=1.[Cu][C:28]#[N:29]>CN(C)C=O>[C:28]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=3)[C:9]2=[O:25])=[C:4]([CH3:26])[CH:3]=1)#[N:29]
Reactant: N#C[Cu]
Reactant: COC(=O)CCc1ccc(N2CCN(c3ccc(Br)cc3C)C2=O)cc1
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(N2CCN(c3ccc(C#N)cc3C)C2=O)cc1

Procedure:
3.0 g of 1-(4-bromo-2-methyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one and 1.3 g of copper(I)cyanide were heated in 10 ml of dimethylformamide for 10 hours at a bath temperature of 175° C. The dimethylformamide was evaporated off in vacuo, the residue was digested with chloroform and filtered off. The chloroform solution was washed with water and saturated saline solution and concentrated by evaporation. The residue was purified by column chromatography (silica gel; methylene chloride/ethyl acetate=100:2)
Reaction SMILES: [CH:1]([N:3]1[C:11]2[C:6](=[C:7]([CH2:13][CH2:14][OH:15])[C:8](O)=[CH:9][CH:10]=2)[CH:5]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:4]1)=[O:2].CS(Cl)(=O)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[CH:1]([N:3]1[C:11]2[C:6](=[C:7]3[CH2:13][CH2:14][O:15][C:8]3=[CH:9][CH:10]=2)[CH:5]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:4]1)=[O:2]
Reactant: CCC(=O)NCCC1CN(C=O)c2ccc(O)c(CCO)c21
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)NCCC1CN(C=O)c2ccc3c(c21)CCO3
Reaction time: 0.33 h
Yield: 33.2 %

Procedure:
To a solution of N-[2-[1-formyl-2,3-dihydro-5-hydroxy-4-(2-hydroxyethyl)indol-3-yl]ethyl]propionamide (0.8 g, 2.61 mmol) in pyridine (10 mL) was added methansulfonyl chloride (0.2 mL, 2.61 mmol.) around -10° C. The mixture was stirred for 20 minutes while keeping the temperature -10 to 5° C. To this was added additional methansulfonyl chloride (0.1 mL, 1.3 mmol.) and the mixture was stirred for further 15 minutes at the same temperature. The mixture was diluted with ethyl acetate(10 mL). Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added slowly and the mixture was stirred for 30 minutes at room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 2N-hydrochloric acid and water, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to afford the title compound (yield 0.25 g, 33%).
Reaction SMILES: [OH:1][C:2]1([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][C:3]1=[O:13].B(F)(F)F.[CH3:23]COCC>CO>[OH:1][C:2]1([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:23])=[CH:4][C:3]1=[O:13]
Reactant: CC(C)CCC1(O)C(=O)CC(=O)c2ccccc21
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC1=CC(=O)C(O)(CCC(C)C)c2ccccc21
Temperature: 60 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
To a solution of Example 2D (0.43g, 1.7 mmol) in methanol (2 mL) heated at 60° C. was added boron trifluoride diethyl etherate (0.135 mL, 1.0 mmol). The reaction solution was stirred at 60° C. for 5 h. The solution was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic extract was concentrated in vacuo. Column chromatography on silica (2.5% methanol/dichloromethane) afforded the title compound as a white solid (0.17 g, 37.4%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.70 (dd, J=6.43, 2.39 Hz, 6H), 0.74-0.88 (m, 1H), 0.88-1.06 (m, 1H), 1.16-1.38 (m, 1H), 1.51-1.88 (m, 2H), 3.93 (s, 3H), 5.56 (s, 1H), 5.64 (s, 1H), 7.39 (t, J=7.54 Hz, 1H), 7.52 (t, J=7.54 Hz, 1H), 7.62 (d, 1H), 7.73 (d, J=7.72 Hz, 1H); MS m/z 260.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:14]([O:18][C:19](=[O:26])[NH:20][CH2:21][CH:22]1[CH2:25][NH:24][CH2:23]1)([CH3:17])([CH3:16])[CH3:15]>C(O)CCCC>[C:14]([O:18][C:19](=[O:26])[NH:20][CH2:21][CH:22]1[CH2:23][N:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:25]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Solvent: CCCCCO
Product: COc1ccc2nccc(N3CC(CNC(=O)OC(C)(C)C)C3)c2n1
Temperature: 80 °C
Yield: 42.1 %

Procedure:
A mixture of 8-bromo-2-methoxy-[1,5]naphthyridine (495 mg, 2.07 mmol, prepared as in WO 2006/032466) and tert-butyl-[(azetidin-3-yl)methyl]carbamate (405 mg, 1.05 eq) in pentanol (2 mL) was heated at 80° C. overnight. The majority of the solvent was removed in vacuo at elevated temperature (50-60° C.). The residue was triturated with ether to form the desired intermediate as beige solid (300 mg, 42%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](OCC)=[O:9]>>[OH:9][CH:8]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7]
Reactant: O=C1CCCCC1
Reactant: CCOC=O
Product: O=C1CCCCC1=CO

Procedure:
As in the previous example, 200 g (2.0 mol) of cyclohexanone was reacted with ethyl formate to give 140 g of 2-hydroxymethylenecyclohexanone, XXVIIb, bp 71°-74° C (0.6 mm). Forty grams (0.32 mol) of this substance was dissolved in 150 ml CH2Cl2. containing 30 g of pyridine and treated at -5° C with a solution of 64 g (0.34 mol) of p-toluenesulfonyl chloride and 16 g of pyridine in 150 ml CH2Cl2. The reaction was stirred overnight at this temperature. Work-up in the usual manner gave the enol tosylate XXVIIIb. This was not isolated but added directly to solution of 150 g (1.0 mol) NaI in dry acetone. After stirring overnight at room temperature this was worked up in the usual manner to give (E)-2-iodomethylenecyclohexanone, XXIXb, as a red oil. Again this was not isolated but was reduced with NaBH4 in EtOH to give crystalline dl-(E)-2-iodomethylenecyclohexanol, XXXb. Recrystallization from petroleum ether gave 40 g of white needles, mp 80° C.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1.[Cl-].[CH3:29][Zn+]>C1COCC1.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>[OH:18][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=[C:2]([CH3:29])[C:7]=3[N:8]=[C:9]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C[Zn+]
Reactant: O=C(O)c1cc(Cl)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)nc2c(-c3cccc(O)c3)nc(N3CCOCC3)nc12

Procedure:
A mixture of Example 9 (30 mg; 0.08 mmol), Pd(PPh3)4 (4.5 mg) and 2M methylzinc chloride (0.16 mL, 0.31 mmol) in THF (5 mL) was stirred at 80° C. for 16 hours then concentrated in vacuo. The residue was partitioned between EA and aq. citric acid and the two phases separated. The aqueous layer was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA/EtOH/AcOH, 90/10/1) afforded the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:18][CH3:19])=[C:7]([CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O>[Fe].CO>[NH2:15][C:13]1[CH:14]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([O:18][CH3:19])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(N)cc(C(C)(C)C)c1OC
Temperature: 25 °C
Yield: 100 %

Procedure:
Methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate (10.42 g, 39.0 mmol), iron powder (325 mesh, 10.89 g, 195 mmol), ammonium chloride (3.13 g, 58.5 mmol), water (30 mL), and methanol (150 mL) were added together. The resultant mixture was then refluxed for 1 h. The mixture was then cooled to room temperature, filtered through celite, and the celite washed with methanol. The filtrate was then concentrated under vacuum and dissolved in ethyl acetate (600 mL). The resultant solution was then washed with water and brine. The organic extract was then dried, filtered and concentrated under vacuum to yield the title compound as an oil (9.25 g, 100%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].[CH3:30][NH:31][CH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1>>[CH3:30][N:31]([CH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1)[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([N:13]2[CH2:14][C:9]3[CH2:8][N:7]([C:5](=[O:6])[C:4]4[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=4[C:2]([F:1])([F:29])[F:28])[CH2:11][C:10]=3[CH2:12]2)=[N:16][CH:17]=1
Reactant: CNCc1nccs1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Product: CN(Cc1nccs1)C(=O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 52 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (54 mg, 0.134 mmol) was reacted with methylthiazol-2-ylmethylamine analogously to example 3d. Yield: 52%, M+H+: 514.30.