Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39]>CC#N>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:33][CH2:32][N:31]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNC4)cn3)cc2)no1
Reactant: CN(C)C(=O)CCl
Agent: Cl
Solvent: CC#N
Product: CN(C)C(=O)CN1CCC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Temperature: 85 °C
Yield: 66.7 %

Procedure:
To a stirred suspension of N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride (150 mg, 0.30 mmol) in CH3CN (3 mL) was added TEA (126 μL, 0.90 mmol), KI (10 mg, 0.060 mmol), and 2-chloro-N,N-dimethylacetamide (21 μL, 0.30 mmol). The resulting mixture was heated at 85° C. for 1 h. LC-MS indicated that the reaction was complete. The reaction mixture was evaporated under reduced pressure and the residue was purified by reverse phase HPLC to give N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(1-(2-(dimethylamino)-2-oxoethyl)pyrrolidin-3-yloxy)picolinamide (110 mg, 67%). LC-MS (ESI) m/z 550 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([CH:23]([OH:25])[CH3:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:25][CH:23]([C:14]1[CH:13]=[C:12]2[C:17]([O:18][CH2:19][CH2:20][N:21]3[C:11]2=[N:10][C:9]([C:8]2[N:4]([CH:2]([CH3:1])[CH3:3])[N:5]=[CH:6][N:7]=2)=[CH:22]3)=[CH:16][CH:15]=1)[CH3:24])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethan-1-ol (200 mg, 0.590 mmol) in DCM (20 mL) at 0° C. was added TEA (296 mg, 2.93 mmol) and MsCl (136 mg, 1.19 mmol). The reaction mixture was stirred 0° C. for 2 h and then allowed to warm to room temperature. The reaction was quenched with sat. NaHCO3 (10 mL), the resultant mixture was washed with sat. NaCl (20 mL). The organic phase was dried and concentrated to afford 1-{4-[1-(Propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate (246 mg, 100% yield) as a brown solid, which was directly used in next step without further purification.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:15])[N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12.[CH3:16]N(C)C=O.[OH-].[Na+].CI>O>[CH3:16][N:2]1[C:3](=[O:15])[N:4]2[C:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10]2)=[N:1]1
Reactant: CN(C)C=O
Reactant: O=c1[nH]nc2n1C=Cc1ccccc1C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: Cn1nc2n(c1=O)C=Cc1ccccc1C2

Procedure:
To a solution of 8 parts of 2,11-dihydro-3H-s-triazolo-[3,4-b][3]benzazepin-3-one in 80 volume parts of dimethylformamide is added 9 volume parts of 5N aqueous sodium hydroxide solution and then 3 volume parts of methyl iodide is added dropwise under stirring. After stirring for 1 hour, the reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and the solvent is distilled off. The precipitate is collected by filtration to give 2,11-dihydro-2-methyl-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Recrystallization from isopropyl ether gives light-brown needles melting at 123° -124° C.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][CH:12]1[C:36](=[O:37])[N:14]2[CH:15]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:16]([OH:19])[CH2:17][S:18][C@H:13]12.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([NH:11][CH:12]1[C:36](=[O:37])[N:14]2[CH:15]([C:20]([O:22][CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:16]([OH:19])[CH2:17][S:18][C@H:13]12)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Temperature: 3 °C
Reaction time: 0.17 h

Procedure:
Formic acid (0.4 ml) and acetic anhydride (1 ml) were stirred at 40° C. for 30 minutes. The reaction mixture was cooled in an ice-water bath and added dropwise to a mixture of benzhydryl 7-amino-3-hydroxycepham-4-carboxylate (1.0 g) in methylene chloride (30 ml) at 3° C. The mixture was stirred at 3° C. for 10 minutes and adjusted to pH 7.0 with 5% aqueous solution of sodium bicarbonate, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give benzhydryl 7-formamido-3-hydroxycepham-4-carboxylate (1.05 g) as powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-])=O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=[N+]([O-])CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To the mixture of 1-chloro-4-(4-(2-nitroethyl)phenoxy)-2-(trifluoromethyl)benzene (17 g, 49.2 mmol) and nickel(II) chloride hexahydrate (46.6 g, 197 mmol) in methanol (300 mL) at 0° C. was added NaBH4 (3.72 g, 98 mmol) portion wise. The reaction mixture was stirred at rt overnight. Purification via a column chromatography afforded the title compound as a yellow oil (8.86 g, 51.4% yield). LCMS: rt=2.51 min, [M+H+]=316.1
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[C@@H:19]([CH3:21])[OH:20].[CH:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH2:29]>C(OCC)(=O)C>[CH2:31]([O:30][CH:28]([O:20][C@H:19]([CH3:21])[C:18]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:29])[CH2:32][CH2:33][CH3:34]
Reactant: CC(C)COC(=O)[C@@H](C)O
Reactant: C=COCCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: CCCCOC(C)O[C@H](C)C(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A catalytic amount of pyridinium para-toluenesulfonate was added to 29.2 g (0.2 mole) of isobutyl (R)-(+)-lactate and 22.0 g (0.22 mole) of n-butyl vinyl ether. The resulting mixture was stirred at room temperature for 4 hours to give rise to a reaction. Thereto was added 100 ml of ethyl acetate, followed by washing with 100 ml of a saturated aqueous sodium hydrogen carbonate solution, 40 ml of water and 40 ml of a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent, whereby was obtained 46.8 g (yield: 94.9%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=2)=[N+:13]([O-])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OC(=O)C)(=[O:33])C>>[CH2:1]([C:9]1[C:14](=[O:33])[NH:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c[n+]2[O-])cc1
Reactant: CC(=O)OC(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c(=O)[nH]2)cc1
Reaction time: 1 h

Procedure:
2.20 g (5.4 mmol) of 5-octyl-2-(4-octyloxyphenyl)pyridine N-oxide are refluxed in 30 ml of acetic anhydride for 4 hours. The acetic anhydride is then distilled off, and the residue is taken up in 10 ml of 1:1 methylene chloride/methanol, and the mixture is stirred with methanolic potassium hydroxide solution for 1 hour. Washing with water and concentrated ammonium chloride solution, drying over sodium sulfate, filtration, removal of the solvent by distillation and recrystallization from 8:2 n-hexane/ethyl acetate give 1.79 g of 3-octyl-6-(4-octyloxyphenyl)-1H-2-pyridone. ##STR14##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22](C1C=CC(C(O)(C)C)=CC=1)(=[O:24])=[O:23].CC1(C)C(C)(C)OB(C2C=CC3N(C=C(NC(=O)C)N=3)N=2)O1.BrC1C=C(NS([N:69]2[CH2:74][CH2:73][O:72][CH2:71][CH2:70]2)(=O)=O)C(Cl)=NC=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22]([N:69]1[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1)(=[O:23])=[O:24]
Reactant: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(C(C)(C)O)cc4)c3)ccc2n1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)N1CCOCC1
Agent: CC(=O)Nc1cn2nc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Product: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)N4CCOCC4)c3)ccc2n1
Yield: 26 %

Procedure:
Following the procedure described for compound N-(6-(6-chloro-5-(4-(2-hydroxypropan-2-yl)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 35), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (122 mg, 404 μmol) (Example 35, Step 3) was reacted with N-(5-bromo-2-chloropyridin-3-yl)morpholine-4-sulfonamide from Step 1 (120 mg, 336 μmol) to afford the title compound as a light green solid (40 mg, 26% yield). MS (ESI positive ion) m/z: 452 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.12 (s, 3H), 3.12-3.18 (m, 4H), 3.60-3.68 (m, 4H), 7.86 (d, J=9.39 Hz, 1H), 8.14 (d, J=9.39 Hz, 1H), 8.33 (s, 1H), 8.54 (d, J=2.15 Hz, 1H), 8.90 (s, 1H), 10.14 (s, 1H), 10.97 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: OB(O)c1ccccc1F
Product: Fc1ccccc1-c1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 305(MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[C:3]1=[O:31].Br[C:33]1[CH:43]=[CH:42][CH:41]=[C:40]([N:44]2[CH2:56][CH2:55][N:47]3[C:48]4[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=4[CH:54]=[C:46]3[C:45]2=[O:57])[C:34]=1[CH2:35][O:36][C:37](=[O:39])[CH3:38]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.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>[CH3:1][N:2]1[C:3](=[O:31])[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)=[CH:5][C:6]([C:33]2[CH:43]=[CH:42][CH:41]=[C:40]([N:44]3[CH2:56][CH2:55][N:47]4[C:48]5[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=5[CH:54]=[C:46]4[C:45]3=[O:57])[C:34]=2[CH2:35][O:36][C:37](=[O:39])[CH3:38])=[CH:7]1
Reactant: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
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: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 125 °C
Reaction time: 0.12 h
Yield: 33.7 %

Procedure:
In a 10-mL glass vessel equipped with a magnetic stirring bar were placed 1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-1H-pyridin-2-one 197f (210 mg, 0.49 mmol), 113a (250 mg, 0.60 mmol), Pd(PPh3)4 (50 mg, 0.043 mmol) in 2 N Na2CO3 (2 mL) and 1,2-dimethoxyethane (5 mL). The vessel was sealed with a septum and placed into the microwave cavity. After the reaction mixture was stirred at 125° C. for 7 min., it was purified by flash chromatography (dichloromethane:methanol, 85:15) to give 34% (105 mg) of acetic acid 2-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-6-(1-oxo-3,4,6,7,8,9-hexahydro-1H-pyrazino[1,2-a]indol-2-yl)-benzyl ester 113b as solids.
Reaction SMILES: ClC1C=C[C:5]2[N:6]([C:8]([C:11]([C:13]3C=C4C(=CC=3)N=CC=C4)=O)=CN=2)[N:7]=1.Cl[C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:30]([C:33]([C:39]3[CH:40]=[C:41]4[C:46](=[CH:47][CH:48]=3)[N:45]=[CH:44][CH:43]=[CH:42]4)([OH:38])[C:34]([F:37])([F:36])[F:35])=[CH:31][N:32]=2)[N:29]=1.CN(C=O)C.FC([Si](C)(C)C)(F)F.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:35][C:34]([F:37])([F:36])[C:33]([C:30]1[N:28]2[N:29]=[C:24]([C:11]3[CH:13]=[N:7][N:6]([CH3:5])[CH:8]=3)[CH:25]=[CH:26][C:27]2=[N:32][CH:31]=1)([C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[N:45]=[CH:44][CH:43]=[CH:42]2)[OH:38]
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Reactant: OC(c1ccc2ncccc2c1)(c1cnc2ccc(Cl)nn12)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(F)(F)F
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3ncc(C(O)(c4ccc5ncccc5c4)C(F)(F)F)n3n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-2,2,2-trifluoro-1-quinolin-6-yl-ethanol (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanone (Stage 1.2, 411 mg, 1.331 mmol) was dissolved in THF (1.5 mL) and DMF (1.5 mL) together with (trifluoromethyl)trimethylsilane (0.255 mL, 1.598 mmol) and the mixture was cooled down to 0° C. TBAF solution (1 M, 0.067 mL) was then added slowly. After 5 min, the RM was allowed to warm up to rt. After 24 h of stirring, it was warmed up to 50° C. and stirred for 24 h more. The reaction was then quenched with 1 N HCl. The precipitate formed was filtered off and identified as remaining pure starting material The solution was basified with pellets of NaOH. The second precipitate formed and filtered off was starting material as well. The aqueous layer was extracted twice with EtOAc and then the joined organics were washed with brine and dried over Na2SO4. After removing the solvent, the residue was purified by MPLC with DCM and MeOH to give the title compound as a brown solid (tR 0.8 min (conditions 2), MH+=379).
Reaction SMILES: [O:1]1[C@H:5]2[C:6]3[C:11]([CH2:12][C@H:4]2[NH:3]C1=O)=[CH:10][CH:9]=[CH:8][CH:7]=3.[OH-].[Na+]>C(O)C.O>[NH2:3][C@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]1[OH:1]
Reactant: O=C1N[C@@H]2Cc3ccccc3[C@@H]2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N[C@H]1Cc2ccccc2[C@H]1O
Yield: 96.3 %

Procedure:
A suspension of (±) cis 3,3a,4,8b-tetrahydroindeno[2,1 -d]oxazol-2-one (Preparation 27) (5.73 g, 0.033 mol) in a mixture of ethanol (100 ml) and water (20 ml) was treated with sodium hydroxide pellets (8.0 g, 0.2 mol). After stirring at room temperature until the sodium hyroxide pellets had dissolved the mixture was heated under reflux in an argon atmosphere for 5 h. The solution was concentrated in vacuo to approximately one quarter the original volume then diluted with brine (50 ml) and extracted into chloroform (3×100 ml). The combined organic extracts were dried over Na2SO4 and then concentrated in vacuo to give a brown solid (4.74 g) which was crystallised from i-propanol-diethyl ether to give the title compound as a colourless solid (3.5 g, 72%) m.p. 104.5°-106° C. Mother liquors afforded a further 0.41 g, m.p. 103.5°-105° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>O1CCCC1>[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][O:16][CH:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]1
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2cccc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.31 g, 83 mmol) was added to an ice-cooled solution of 1-tert-butoxycarbonyl-4-hydroxy-piperidine (16.64 g, 83 mmol) in tetrahydrofuran (200 mL) and the mixture was stirred at 0° C. for 30 minutes. 3-Bromobenzyl bromide (20.66 g, 83 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction was then quenched with water (50 mL) and concentrated in vacuo. The aqueous residue was extracted with ethyl acetate (2×100 mL) and the combined organic phases were washed with brine (100 mL), dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate, 90:10 to 80:20, to afford the title compound as a colourless oil in 61% yield, 18.64 g.
Reaction SMILES: [CH2:1]([N:11]=[C:12]=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCCl.C(Cl)Cl>[CH2:14]([O:21][NH:22][C:12]([NH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NOCc1ccccc1
Reactant: CCCCCCCCCCN=C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCCCCCNC(=O)NOCc1ccccc1
Yield: 66.3 %

Procedure:
To a solution of decyl isocyanate (19.6 g, 0.11 mol) in 1,2-dichloroethane (100 ml) was added a solution of benzyloxyamine (0.114 mol) in methylene chloride (100 ml). The solution was refluxed for 20 minutes, evaporated, and the residue triturated with pentane to give N-benzyloxy-N'-decylurea as a white solid (22.36 g, 67% yield). This urea (2.95 g, 10 mmol) was dissolved in DMF (30 ml) at 40° C. Sodium hydride (425 mg of a 60% dispersion in oil) was added. Within 15 minutes, a precipitate formed. After 30 minutes, methyl iodide (0.64 ml) was added, and the mixture was stirred for one hour at room temperature. The resulting solution was poured in 1% HCl, and the resulting solid was washed with water, collected by filtration, and air-dried. Recrystallization from pentane provided N-benzyloxy-N-methyl-N'-decylurea as a white solid (2.25 g, 73% yield). Hydrogenolysis as in Example 2 above, and recrystallization from ethanol-water, provided the title compound as a white solid (1.43 g, 91% yield), mp 74°-76° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:10].BrBr.CC(O)=O>CC(O)=O.C(OC(=O)C)C>[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: Br
Agent: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of acetophenone (500 mg, 4.16 mmol) in AcOH (20 mL) and catalytic amount of aq. HBr, 10% Br2/AcOH (2.12 mL) was added at 0° C. The reaction mixture was stirred for 2 h at r.t. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethylacetate (100 mL) and washed with water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 1:9 EtOAc:hexane) to afford the title compound (825 mg, 4.1 mmol, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[NH:5][C:4](=[O:10])[CH:3]=1.C(O[CH:14](OCC)[CH2:15][CH:16](OCC)OCC)C>C(O)C.O>[CH3:8][N:7]1[C:2]2[N:1]=[CH:14][CH:15]=[CH:16][C:3]=2[C:4](=[O:10])[NH:5][C:6]1=[O:9]
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Reactant: CCOC(CC(OCC)OCC)OCC
Solvent: O
Solvent: CCO
Product: Cn1c(=O)[nH]c(=O)c2cccnc21
Temperature: 25 °C
Yield: 19.4 %

Procedure:
14.34 g (101.7 mmol) 6-amino-1-methyluracil and 26 mL (108 mmol) 1,1,3,3-tetraethoxypropane are dissolved in a mixture of 250 mL ethanol and 1 liter water and refluxed for 3 hours. After cooling down to room temperature, the precipitated intermediate is isolated by filtration washed with water and dried. 7.71 g of the condensation product of the acetal and the amino group is added to 12.5 mL concentrated sulfuric acid and the mixture is heated to 160° C. After cooling down to room temperature, the mixture is poured into 125 g ice. The crude product precipitates from the medium, is isolated by filtration, washed to neutral pH and dried. 4.84 g of the crude product is dissolved in 2 l refluxing methanol. 300 mL silicagel is added and the mixture is evaporated under reduced pressure. The crude product loaded onto the silicagel is purified by preparative column chromatography using chloroform/methanol 9:1. 3.49 g (19%) 1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione is isolated (m.p. 277–285° C., Lit. 285° C.).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[S:17](Cl)(=[O:19])=[O:18].Cl.Cl.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:47])[CH2:38][O:39][CH2:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][NH:42]3)[CH2:33][CH2:32]2)[CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:11]1([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH3:8])[C:10]=1[S:17]([N:42]1[CH2:43][CH2:44][CH2:45][CH2:46][CH:41]1[CH2:40][O:39][CH2:38][C:37]([N:34]1[CH2:33][CH2:32][N:31]([CH:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[CH2:36][CH2:35]1)=[O:47])(=[O:19])=[O:18]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CN1CCC(N2CCN(C(=O)COCC3CCCCN3)CC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(C3CCN(C)CC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Triethylamine (0.221 ml, 1.608 mmol) and then 2,4,6-trimethylbenzenesulfonyl chloride (105 mg, 0.482 mmol) were added at 0° C. to a solution of 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-(piperidin-2-ylmethoxy)ethanone trihydrochloride (180 mg, 0.402 mmol) in tetrahydrofuran (10 ml). The reaction mixture was heated slowly to room temperature, stirred for 15 h at that temperature and then refluxed for 1 h. Saturated sodium hydrogen carbonate solution (5 ml) was then added to the mixture, and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo, and the crude product was then purified by column chromatography (silica gel) using ethyl acetate/methanol/ammonia solution (25% aq.) (300:100:5). Yield: 90 mg (43%), yellow oil; MS, m/z 520.3 (MH+)