Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:12][CH2:13][CH2:14][CH2:15][C:16]1[O:21][C:20](=[O:22])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N:17]=1>>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:22])=[O:21]
Reactant: O=c1oc(CCCCl)nc2ccccc12
Reactant: CCCCCCCCCCN
Product: CCCCCCCCCCNC(=O)c1ccccc1NC(=O)CCCCl
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
n-Decylamine (0.45 ml) was added to 2-(3-chloropropyl)-4H-3,I-benzoxazine-4-one (0.50 g). After being stirred for 45 minutes at 40° C., the reaction mixture was purified by silica gel column chromatography (silica gel 50 g, chloroform), thereby yielding 0.59 g of the aimed compound as light-yellow solid.
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH4+:18].[OH-]>CS(C)=O.CCOC(C)=O>[NH2:18][C:2]([CH3:1])([CH2:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [NH4+]
Reactant: CCOC(=O)/C(C)=C/C(=O)c1ccc(C)cc1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(N)CC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a solution of Intermediate 102A (1.067 g, 4.59 mmol) in DMSO (20 mL) under argon was added NH4OH (18.04 mL, 271 mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with water (40 mL) and brine (20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give a yellow oil. The oil was purified by silica gel chromatography (120 g silica gel) to provide the desired product (0.632 g, 55%) as a clear oil. LCMS Anal. Calc'd for C14H19NO3 249.14, found [M+H] 250.1. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=8.25 Hz, 2H), 7.24 (d, J=7.98 Hz, 2H), 4.14 (dd, J=7.15, 2.75 Hz, 2H), 3.65 (d, J=17.61 Hz, 1H), 3.20 (d, J=17.61 Hz, 1H), 2.40 (s, 3H), 2.18-2.27 (m, 2H), 1.39 (s, 3H), 1.19 (t, J=7.01 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1COCC1>[Si:14]([O:7][CH2:6][CH2:5][C:2]([CH3:8])([CH3:1])[CH2:3][OH:4])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(CO)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(CO)CCO[Si](C)(C)C(C)(C)C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To a solution of the product from Example 9A (0.80 g, 6.8 mmol) and imidazole (0.462 g) in THF (8.0 mL) at room temperature was added tert-butyldimethylsilyl chloride (1.02 g), and the solution was stirred for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with 33% hexanes in chloroform and ending with 25% ethyl acetate in chloroform, to give the title compound (1.153 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:19])[F:20]
Reactant: CCOC(=O)c1ccc(-c2ccc(F)c(C(F)(F)F)c2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(F)c(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
Ethyl 5-[4-fluoro-3-(trifluoromethyl)phenyl]furan-2-carboxylate (136 mg, 0.45 mmol.) and LiOH (25 mg, 0.59 mmol) were diluted with THF/H2O=1:1 (3 mL), and then stirred for 1 hrs at room temperature. The mixture was acidified with 1N HCl, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield the crude title compound as a white solid (91 mg, 73%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:37][CH:38]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Product: CC(C)(CC(=O)NC1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2)C1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-butanamide (Example 51, Step A) and 4'-bromomethyl-1,1'-biphenyl-2-nitrile (Example 69, Step C) by the procedure described in Example 1, Step K. FAB-MS: calculated for C37H36N4O4 600; found 601 (M+H,100%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([OH:21])=[C:15]2[CH:14]=[N:13]1.[CH3:22][NH:23][CH3:24]>CS(C)=O>[CH3:22][N:23]([CH3:24])[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([OH:21])=[C:15]2[CH:14]=[N:13]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(O)ncnc32)c(F)c1
Reactant: CNC
Solvent: CS(C)=O
Product: CN(C)c1cc(S(C)(=O)=O)ccc1-n1ncc2c(O)ncnc21
Temperature: 120 °C
Yield: 89.3 %

Procedure:
1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (0.520 g, 1.68 mmol) was dissolved in DMSO (3 mL) and dimethylamine (2M solution in THF) (4 mL, 150 mmol) was added. The mixture was heated at 120° C. for 15 h. The solvent was removed under reduced pressure and the crude was purified by HPLC, yielding 1-(2-dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol as an off-white solid (0.500 g, 89%). Exact mass calculated for C14H15N5O3S 333.09, found 334.4 (MH+, 100%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C:11]1([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: OC1(C(F)(F)F)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OC1(C(F)(F)F)CCNCC1

Procedure:
A suspension of 6.48 g (25.00 mmol) of 1-benzyl-4-trifluoromethylpiperidin-4-ol and 810 mg Pd/C (10%) in 100 mL of MeOH was hydrogenated at RT and 3 bar hydrogen pressure for 17 hours. The catalyst was filtered off and the filtrate evaporated down in vacuo. Yield: 4.22 g (quant. yield); C6H10F3NO (M=169.145); calc.: molpeak (M+H)+: 170; found: molpeak (M+H)+: 17; Rf value: 0.00 (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:23]([OH:24])[C@@H:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:21]([CH2:33][O:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[O:20][C@H:10]1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>C1(C)C=CC=CC=1>[C:47]([O:24][C@H:23]1[C@@H:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:21]([CH2:33][O:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[O:20][C@@H:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](OC(C)=O)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 17 (10 mg, 18.0 μmol) was dissolved by addition of pyridine (1 mL). Acetic anhydride (0.5 mL) was added to the solution, and the mixture was stirred at the room temperature for 2 hours. The solvent was subjected to azeotropy with toluene, and the residue was purified with Sephadex LH-20 (CHCl3:MeOH=1:2) to obtain Compound 18 (11 mg, qu.).
Reaction SMILES: [CH:1]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]3C(OC(=O)[C:11]=3[CH:10]=2)=O)=[O:8])=[CH:5][C:4]2C(OC(=O)[C:3]=2[CH:2]=1)=O.C(O)C>CN1CCCC1=O>[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:6]1[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: O=C(c1ccc2c(c1)C(=O)OC2=O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CN1CCCC1=O
Solvent: CCO
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
32.21 Gram of 3,3',4,4'-benzophenonetetracarboxylic dianhydride in 69.1 g of N-methyl-2-pyrrolidone was heated to 80° C., and 9.21 g of ethanol was added and reacted at 100° C. for 2 hr to form a solution of benzophenone-tetracarboxylic ester. To this solution was added 20.01 g of 4,4'-diaminodiphenyl ether and reacted at 80° C. for 3 hr. The thus obtained solution of poly(amic acid) ester oligomer was found to have a viscosity of 2 poises at 25° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][C:25]([C:26]([F:29])([F:28])[F:27])=[C:20]3[NH:19][C:18]2=[O:30])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:32][CH3:33].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][C:25]([C:26]([F:29])([F:28])[F:27])=[C:20]3[N:19]([CH2:32][CH3:33])[C:18]2=[O:30])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCI
Reactant: O=c1[nH]c2c(C(F)(F)F)ccnc2n1-c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of NaH (40.9 mg), 3-[4-(benzyloxy)phenyl]-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (197 mg) in DMF (dry) (3 mL) was added iodoethane (0.082 mL), and the mixture was stirred at room temperature for 3 h. To the mixture was added sat. NaHCO3 aq. and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (197 mg).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:15]=1>N1C=CC=CC=1>[C:1]([O:8][CH:9]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCC(O)/C=C/C=C/c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Solvent: c1ccncc1
Product: CCCCCCCCC(/C=C/C=C/c1cccc(CO[Si](C)(C)C(C)(C)C)c1)OC(C)=O
Temperature: 23 °C
Reaction time: 15 h

Procedure:
For acetylation, 31 ml of acetic anhydride is added to a solution of 11 g of the above-produced alcohol in 120 ml of pyridine and stirred for 15 hours at 23° C. Then, it is concentrated by evaporation in a vacuum with adding toluene and the residue is chromatographed on silica gel. With hexane/0-3% ethyl acetate, 8.9 g of the title compound is obtained as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]([F:11])([F:10])[F:9])=[N:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].OS(O)(=O)=O>>[C:12]([C:5]1[C:4]([C:8]([F:10])([F:9])[F:11])=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(F)(F)F)nn1C
Agent: O=S(=O)(O)O
Product: CC(=O)c1c(C(F)(F)F)nn(C)c1C
Yield: 21.7 %

Procedure:
22.6 g (0.138 mol) of 1,5-dimethyl-3-trifluoromethyl-1H-pyrazole are added dropwise at 0° C. to a solution of 156 ml (1.65 mol) of acetic anhydride and 0.5 ml of conc. H2SO4. The reaction mixture is stirred under reflux for approx. 8 days. After each 24 h of reaction time, 0.5 ml of H2SO4 each time is added to the reaction mixture. On completion of the reaction, excess acetic anhydride is distilled off under reduced pressure, the residue is taken up in 500 ml of CH2Cl2 and the organic phase is washed 3 times with 300 ml of water each time. The organic phase is dried over MgSO4 and concentrated by rotary evaporation. Distillation of the oily residue results in 6.20 g (0.030 mol; 21.8%) of 4-acetyl-1,5-dimethyl-3-trifluoromethyl-1H-pyrazole (b.p.: 142° C./0.4 mbar).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][OH:20].O>CN(C=O)C>[OH:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: OCCCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCCCO)c1
Yield: 96.2 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (366 mg, 3 mmol) in anhydrous DMF (7 ml), under nitrogen atmosphere, K2CO3 (829 mg, 6 mmol), and, after 10 minutes, 3-bromo-1-propanol (500 mg, 3.6 mmol) were added. The mixture was heated to reflux for 2 hours, then water was added and the product was extracted with CH2Cl2. The organic layers were washed with water and with NaCl saturated solution, dried on Na2SO4. After evaporation of the solvent the crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate 2/1); 520 mg (yield 95%) of title product were obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[N:27]=[C:26]([CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=1>CCCCO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:29][CH2:28][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:21])[N:27]=2)[N:10]=1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1cccc(CN)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(CNc2nc(F)nc3[nH]cnc23)n1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.4 g, 2.3 mmol) in n-BuOH (50 ml) under an argon atmosphere at 0° C., was added DIEA (2.5 ml, 14.7 mmol) followed by (6-methylpyridin-2-yl)methanamine (0.36 g, 2.95 mmol). The reaction mixture was stirred at this temperature for 1 h and then allowed to return to room temperature and stirred for 4 h, it was still seen incomplete, hence heated the reaction to 100° C. and left at that temperature for 8 h. The solvent was evaporated in vacuo and the residue was purified by gradient flash column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→90:10), to afford the product as a white solid; Yield: 0.35 g (60%). δH (CDCl3, 500 MHz) 2.44 (3 H, s, CH3), 4.83-4.54 (3 H, m, NH and NHCH2), 7.1-7.05 (2 H, m, ArH), 7.61-7.55 (1 H, m, ArH), 8.13-8.09 (1 H, m, ArH), 8.61 (1 H, s, br, NH); δC (CDCl3, 500 MHz) 159.41 (C), 158.78 (C), 158.53 (C), 157.19 (C), 155.38 (C), 147.69 (CH), 137.03 (C), 136.93 (CH), 121.34 (CH), 117.76 (CH), 117.31 (C), 46.47 (CH2), 23.9 (CH3); m/z 259.2 (M+H)
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C@H:5]1[O:15][CH3:16])=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C@H:5]1[O:15][CH3:16]
Reactant: CCOC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](OC)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CC[C@@H](N)[C@H](OC)C1
Yield: 97.4 %

Procedure:
A mixture of 15.6 parts of ethyl trans-4-azido-3-methoxy-1-piperidinecarboxylate and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated in vacuo, yielding 13.8 parts (97.4%) of ethyl trans-4-amino-3-methoxy-1-piperidinecarboxylate as a residue (interm. 5).
Reaction SMILES: [C:1]([CH:3]=[CH:4][NH:5][NH:6][C:7]([NH2:9])=[O:8])#[N:2].C(N(CC)CC)C>C(O)C>[NH2:2][C:1]1[N:6]([C:7]([NH2:9])=[O:8])[N:5]=[CH:4][CH:3]=1
Reactant: N#CC=CNNC(N)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)n1nccc1N
Yield: 80 %

Procedure:
A solution of 5.0 g of the product of Example 13 in 50 ml of ethyl alcohol containing 3.0 ml of triethylamine is heated at reflux for 4 hours then concentrated in vacuo to a residue which is stirred with cold water. The resulting solid is filtered, washed with additional cold water and dried to give 4.0 g of the desired product as a yellow crystalline solid. M+H=127.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:21])([CH3:20])[C:11](=[O:19])[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6](=[O:22])[C:5]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:29]COCC>CN(C)C=O>[CH3:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:20])([CH3:21])[C:11](=[O:19])[C:12]([CH3:29])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6](=[O:22])[C:5]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(C)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reaction time: 16 h

Procedure:
Sodium hydride (67 mg of 60%) was added to a stirred solution of ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2,4-dimethyl-3-oxo-pentanoate (0.4 g) in N,N-dimethylformamide at 0° C. lodomethane (0.1 ml) was added and stirring continued for 16 hours. Ether was added and the organic phase washed (brine), dried (magnesium sulphate), evaporated and the residue purified by column chromatography eluting with ethyl acetate/hexane (1:2) to give ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2,2,4-trimethyl-3-oxo-pentanoate (Compound 197, 0.3 g), NMR 1.21(3H, t), 1.47(6H, s), 1.52(6H, s), 1.92(3H, s), 4.13(2H, q), 5.16(2H, s), 7.2-7.4(5H, m).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:18]([NH:19][NH2:20])=[CH:17][C:15](=[O:16])[N:14]([CH2:21][CH2:22][CH2:23][CH3:24])[C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=S.CO>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:18]2[NH:19][N:20]=[C:25]([NH:26][CH3:27])[C:17]=2[C:15](=[O:16])[N:14]([CH2:21][CH2:22][CH2:23][CH3:24])[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=S
Reactant: CCCCn1c(=O)cc(NN)n(CCOCc2ccccc2)c1=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(CCOCc2ccccc2)c1=O
Yield: 40 %

Procedure:
A solution of 1-(2-benzyloxyethyl)-3-butyl-6-hydrazinouracil (2.1 g, 6.3 mM) and methyl isothiocyanate (1.36 ml, 20 mM) in DMF (20 ml) was stirred at 120° C. for 20 hours. To the solution was added 50% methanol (20 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol/water gave pale yellow crystals (0.94 g, 40%), m.p. 214°-216° C.
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)([OH:18])[C@:5]([CH3:26])([OH:25])[CH2:4]2)[CH3:2].Cl[CH2:28][C:29]#[N:30]>>[CH2:1]([C@@:3]12[CH2:4][C@:5]([OH:25])([CH3:26])[C@:6]([OH:18])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:7][C@H:8]1[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([O:17][CH2:28][C:29]#[N:30])[CH:14]=[CH:15][C:16]2=1)[CH3:2]
Reactant: N#CCCl
Reactant: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccn3)C[C@H]1CCc1cc(O)ccc12
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccn3)C[C@H]1CCc1cc(OCC#N)ccc12

Procedure:
The title compound was prepared from the compound of Example 102 according to the procedure of Example 57, running the reaction at room temperature overnight and using chloroacetonitrile as the alkylating agent. Mass spectrum (m/e) 393 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.[N:20]#[C:21][NH2:22].[Na]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:21]([NH:22][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1)#[N:20]
Reactant: N#CN
Reactant: CCCOc1ccc(-c2ccc(Cl)nn2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc(NC#N)nn2)cc1OC

Procedure:
1.8 g 3-chloro-6-(3-methoxy-4-n-propoxyphenyl)pyridazine, 0.8 g sodium cyanamide and 3.6 g tetrabutylammonium chloride are boiled under reflux in 30 ml dry toluene for 5 hours. The reaction mixture is then evaporated in vacuo and the residue is boiled up briefly with 200 ml 2 N sodium hydrogen sulphate solution, while stirring thoroughly, the reaction product precipitating as a fine crystalline precipitate. The precipitate is filtered off with suction, washed with water and dried in vacuo. For purification, it is boiled up briefly with 50 ml isopropanol, filtered off with suction and dried in vacuo. This gives 1.5 g (83.3%) of the title compound of m.p. 187° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:21][CH2:22][CH3:23].[Cl:24][C:25]1[N:26]=[C:27]([C:32](O)=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:24][C:25]1[N:26]=[C:27]([C:32]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:21][CH2:22][CH3:23])=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCC)C2)oc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)oc1C
Yield: 43.6 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-ethoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (112h) (0.66 g, 2.03 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), dichloromethane (5 mL) and DMA (3 mL), to obtain 0.21 g of the title compound as a yellow amorphous solid (44%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[C:6]([C:3]1([CH2:2][O:1][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:5][CH2:4]1)#[N:7]
Reactant: N#CC1(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(C#N)CC2)cc1
Reaction time: 3 h

Procedure:
At 0° C., to a solution of 1-hydroxymethyl-cyclopropanecarbonitrile (3.7 g, 38 mmol) in CH2Cl2 (40 mL) was added pyridine (3.62 g, 45.8 mmol) and p-toluenesulfonyl chloride (7.27 g, 38 mmol). After stirred for 3 h, the solution was concentrated and the residue was used for next step reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([C:18]3([O:28][CH3:29])[CH2:22][CH2:21][N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:19]3)[CH:14]=[C:15]([F:17])[CH:16]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:31][OH:32]>>[F:17][C:15]1[CH:16]=[C:11]([S:10][C:7]2[CH:6]=[CH:5][C:4]([C:1](=[N:31][OH:32])[CH3:2])=[CH:9][CH:8]=2)[CH:12]=[C:13]([C:18]2([O:28][CH3:29])[CH2:22][CH2:21][N:20]([CH2:23][C:24]([F:25])([F:27])[F:26])[CH2:19]2)[CH:14]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)=O)cc3)c2)CCN(CC(F)(F)F)C1
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(C(C)=NO)cc3)c2)CCN(CC(F)(F)F)C1
Yield: 81 %

Procedure:
Using an analogous procedure to that described in Example 27, 3-[3-(4-acetylphenylthio)-5-fluorophenyl]-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine was reacted with hydroxylamine hydrochloride to give 3-{5-fluoro-3-[4-(1-hydroxyiminoethyl)phenylthio]phenyl}-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine as a gum in 81% yield.