Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH:2]1[CH:7]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:6][CH2:5][N:4]([CH2:18][CH:19]([OH:21])[CH3:20])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[ClH:28].[C:29](#[N:31])[CH3:30]>C(O)C>[ClH:28].[ClH:28].[F:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([CH:7]3[CH2:6][CH2:5][N:4]([CH2:18][CH:19]([OH:21])[CH2:20][N:31]4[CH2:11][C:12]5[C:30](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:29]4)[CH2:3][CH2:2]3)=[N:9][O:10][C:11]=2[CH:16]=1
Reactant: CC#N
Reactant: CC(O)CN1CCC(c2noc3cc(F)ccc23)C(N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1Cc2ccccc2C1

Procedure:
To a stirred mixture of 1-(3-amino-2-hydroxypropyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.24 g, 7.6 mmol), K2CO3 (1.61 g, 11.7 mmol) in acetonitrile (100 ml) was added αα'-dibromo-o-xylene (1.54 g, 6.1 mmol). The mixture was heated at reflux for 4 hours then cooled. The insolubles were filtered. The dark red solution was concentrated down. The residue was purified by flash chromatography over s silica gel column (SiO2, 30 g; eluted with 1% CH3OH in dichloromethane). The product so obtained weighed 940 mg as an oil. This oil was dissolved in ethanol and was treated with a solution of HCl in ethanol (188 mg of AcCl in ethanol). The dark solids were collected and recrystallized again in ethanol to yield off-white crystals (1.01 g), m.p. 240°-243° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[C:41](O)(=[O:44])[CH2:42][CH3:43].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[CH3:19][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:41](=[O:44])[CH2:42][CH3:43])[CH:8]=[N:7][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:20]
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3)ccc21
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)NCc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
To a solution of 6-(5-aminomethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (example 36, 0.05 g, 0.187 mmol) in dry DMF (1 mL) were added EDCI (0.039 g, 0.206 mmol), Hünig's base (0.060 g, 0.468 mmol) and propionic acid (0.021 g, 0.282 mmol) and the reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with EtOAc, poured into sat. NH4Cl solution (5 mL) and extracted with EtOAc (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH(1% NH4OH)-DCM gradient to give the title compound (0.029 g, 48%) as a white solid. MS: 324.4 (M+H+).
Reaction SMILES: O=S1(=O)C[CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([CH:46]([CH3:48])[CH3:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4]C1.ClCCN(C)C>>[CH3:6][N:5]([CH3:4])[CH2:8][CH2:9][NH:10][C@:11]12[CH2:45][CH2:44][C@@H:43]([CH:46]([CH3:47])[CH3:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:42])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1
Reactant: CC(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)CCCl
Product: CC(C)[C@@H]1CC[C@]2(NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 2-chloro-N,N-dimethylethanamine as the alkylating reagent in Step 3. The product was isolated as a colorless oil (0.9 mg, 37%). LCMS: m/e 605.56 (M+H)+, 2.35 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.02 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 3.89-3.72 (m, 2H), 3.70-3.55 (m, 1H), 3.07-2.91 (m, 1H), 3.00 (s, 6H), 2.60-2.40 (m, 1H), 2.34-1.04 (m, 26H), 1.18 (s, 3H), 1.12 (s, 3H), 1.07 (s, 3H), 0.93 (d, J=6.7 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H), 0.83 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]I)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].C([O-])([O-])=O.[K+].[K+].[N:30]1[CH:35]=[C:34]([CH2:36][C:37]2[C:38](=[O:44])[NH:39][C:40](=[S:43])[NH:41][CH:42]=2)[CH:33]=[N:32][CH:31]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:43][C:40]3[NH:41][CH:42]=[C:37]([CH2:36][C:34]4[CH:33]=[N:32][CH:31]=[N:30][CH:35]=4)[C:38](=[O:44])[N:39]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21]
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Reactant: N#Cc1cc(CCI)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(CCSc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 61.4 %

Procedure:
A mixture of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-(2-iodoethyl)benzonitrile (200 mg, 0.443 mmol), K2CO3 (122 mg, 0.886 mmol), and 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (107 mg, 0.487 mmol) in DMF (4 mL) was heated with a microwave reactor at 60° C. for 15 min. Purification via reverse phase flash chromatography then afforded the title compound (148 mg, 61.4% yield). LCMS: rt=3.34 min, [M+H+]=544
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].O1CCOCC1.[H-].[Li+].Br[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=1>C(Cl)Cl.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>[CH3:28][O:27][C:25]1[CH:26]=[C:21]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])[CH:22]=[C:23]([O:29][CH3:30])[CH:24]=1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: COc1cc(Br)cc(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(OC)cc(S[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a solution of triisopropylsilanethiol (0.49 g, 2.6 mmol) in 1,4-dioxane (5 mL, 60 mmol) was added lithium hydride (23 mg, 2.9 mmol). After 10 minutes, 1-bromo-3,5-dimethoxy-benzene (500 mg, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (270 mg, 0.23 mmol) were added and the reaction mixture was heated to 60° C. for 16 h. The reaction mixture was diluted with DCM, filtered and concentrated. The resulting residue was dissolved in DCM and purified using silica gel chromatographie (40 g silica gel column) eluting with hexanes:DCM (3:1) to afford the title product.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:31][O:32][C:33](=[O:34])[C:35]1[CH:40]=[CH:39][C:38]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)cc1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-methoxycarbonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (40%).
Reaction SMILES: [O-2].[Mg+2:2].[P:3]([OH:7])([OH:6])([O-:5])=[O:4].[K+]>>[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[Mg+2:2].[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[Mg+2:2].[Mg+2:2]
Reactant: O=P([O-])(O)O
Agent: [K+]
Agent: [Mg+2]
Agent: [O-2]
Product: O=P([O-])([O-])[O-]

Procedure:
A fire resistant board with an estimated B—fire rating was made as follows. Dry ingredients including 435 grams magnesium oxide (Martin Marietta HR 98), 425 grams monopotassium phosphate (300 mesh), 250 grams wollastonite, plus 250 grams class fly ash produced a magnesium phosphate cementitious material. This was mixed with wet ingredients: 15 grams super plasticizer [Rheobuild 10000], 500 grams dry mPCM (Ciba Chemicals [now BASF/Ciba] DPNT-0176) and 820 grams of water. The dry ingredients were mixed thoroughly with the wet and placed in a 26 cm×31 cm×1.27 cm mold. A layer of 2.5 oz. nonwoven veil fiberglass fabric was placed on both sides. The board hardened and was de-molded in 8 hours. A Perkin Elmer Pyrus DSC1 Differential Scanning Calorimeter was used to test board enthalpy. The tested board enthalpy level was 29.7 J/g (427 KJ/m2), with a density of 1.15 g/cm^3. A propane torch was positioned 7 cm from the board face. The torch flame was directed at the center of the board and held in place for 10 seconds, and the flame extinguished when the torch was removed. The torch was applied a second time for 30 seconds when the torch was removed the flame again extinguished.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:13]=2)O1.Cl[C:24]1[C:36]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([C:38]([F:41])([F:40])[F:39])([OH:37])[C:28]=2[CH:27]=[C:26]([CH3:42])[CH:25]=1.C(=O)([O-])O.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:18]([O:17][C:15](=[O:16])[CH2:14][N:12]1[CH:13]=[C:9]([C:24]2[C:36]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([OH:37])([C:38]([F:40])([F:41])[F:39])[C:28]=3[CH:27]=[C:26]([CH3:42])[CH:25]=2)[CH:10]=[N:11]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: Cc1cc(Cl)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Reactant: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(-c2cnn(CC(=O)OC(C)(C)C)c2)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Temperature: 110 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To a suspension of t-butyl [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetate (24.8 g), (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol (20.0 g), and sodium hydrogen carbonate (11.3 g) in toluene/water (200 ml/60 ml) were added palladium acetate (750 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.75 g) at room temperature and the mixture was stirred at 110° C. for 2 hr. To the reaction mixture were added water (80 ml) and activated carbon (2.0 g) at room temperature and the mixture was stirred for 1 hr. The mixture was filtered through celite, and the solid was washed with tetrahydrofuran (100 ml). The filtrate was partitioned and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layer was successively washed twice with water (100 ml) and once with saturated brine (100 ml), anhydrous sodium sulfate and silica gel (40 g) were added, and the mixture was stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was treated with n-hexane/ethyl acetate (2/1, 120 ml) solution, and the resulting slurry was filtered to give the title compound (17.8 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][N:23]([C@H:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1)[C:24]([C:26]1[N:27]=[C:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[S:29][CH:30]=1)=[O:25].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[N:6]([CH2:7][C:8]([N:34]2[CH2:35][CH2:36][CH:31]([C:28]3[S:29][CH:30]=[C:26]([C:24]([N:23]([CH3:22])[C@H:37]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[CH2:40][CH2:39][CH2:38]4)=[O:25])[N:27]=3)[CH2:32][CH2:33]2)=[O:10])[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: CN(C(=O)c1csc(C2CCNCC2)n1)[C@@H]1CCCc2ccccc21
Reactant: O=C(O)Cn1nc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3Cl)CC2)n1)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 5-chloro-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (140 mg, 0.61 mmol) (i.e. the product of Example 13, Step E) in dichloromethane (2 mL) and a catalytic amount of N,N-dimethylformamide (1 drop) was treated with oxalyl chloride (0.1 mL, 1.1 mmol) and stirred at ambient temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure and re-dissolved in dichloromethane (1 mL). The reaction mixture was added to a stirred suspension of N-methyl-2-(4-piperidinyl)-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide monohydrochloride (i.e. the product of Example 6, Step C) (280 mg, 0.72 mmol), triethylamine (0.2 mL, 1.5 mmol), and potassium carbonate (300 mg, 2.1 mmol) in dichloromethane (2 mL). The reaction mixture was then heated to reflux for 4 h, and then cooled to ambient temperature. The resulting suspension was diluted with dichloromethane (10 mL), filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography using 50-100% ethyl acetate in hexanes as eluant to give 130 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=[CH:9][C:2]=12>ClCCl.[O-2].[O-2].[Mn+4]>[N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=[CH:9][C:2]=12
Reactant: OCc1ccc2nsnc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc2nsnc2c1

Procedure:
This was prepared by oxidation of benzo[1,2,5]thiadiazol-5-yl-methanol (2a) with manganese dioxide in dichloromethane by the method of Example (4c).
Reaction SMILES: C[O:2][C:3]([C@@H:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9][CH2:8]1)=O.[BH4-].[Na+]>CCO>[C:24]([O:23][C:22]([NH:21][C@@H:5]([CH2:6][CH:7]1[CH2:8][CH2:9][CH:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:11][CH2:12]1)[CH2:3][OH:2])=[O:28])([CH3:26])([CH3:25])[CH3:27]
Reactant: COC(=O)[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
To a solution of tert-butyl (S)-1-(methoxycarbonyl)-2-(4-(t-butyldimethylsilyloxy)-cyclohexyl)ethylcarbamate (25 g, 60 mmol) in EtOH (500 mL) at 0° C. was added NaBH4 (18 g, 480 mmol) in portions. The mixture was stirred for 6 h at rt and then evaporated. The residue was partitioned between water (200 mL) and EtOAc (2×200 mL). The combined organic layers were washed with brine, dried over MgSO4, and evaporated to give (2S)-2-(t-butoxycarbonylamino)-3-(4-(t-butyldimethylsilyloxy)cyclohexyl)propan-1-ol (23 g, yield 98%). 1H NMR (CDCl3, 400 MHZ) δ 0.08(d, 6 H), 0.89(d, 9 H), 1.30(m, 4 H), 1.40 (t, 2 H), 1.45 (s, 9 H), 1.61(m, 1H), 1.58 (m, 1 H), 1.68 (t, 4 H), 1.85 (d, 1 H) 3.50 (m, 1 H), 3.65 (m, 1 H), 3.73 (m, 1 H), 3.91 (s, 1 H), 4.53(s, 1 H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@H:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:12]=2)[CH:7]=[CH:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:9][C@H:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([N:21]3[CH2:22][CH2:23][N:24]([C:34]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:43])[CH2:25][CH2:26]3)[N:12]=2)[CH:7]=[CH:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C=C[C@@H](Oc2nc(N3CCNCC3)nc3ccccc23)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H]1C=C[C@@H](Oc2nc(N3CCN(C(=O)OCc4ccccc4)CC3)nc3ccccc23)C1

Procedure:
To a solution of 4-[(1S,4R)-(4-acetoxycyclopent-2-en-1-yl)oxy]-2-(1-piperazinyl)quinazoline (2.07 g) in dry methylene chloride (15 ml) is added triethylamine (1.63 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (0.92 ml) in dry methylene chloride (5 ml). The mixture is stirred under ice-cooling for 2 hours, and the reaction mixture is diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform) to give 4-[(1S,4R)-(4-acetoxycyclopent-2-en-1-yl)oxy]-2-[4-(benzyloxycarbonyl)piperazin-1-yl]quinazoline (2.36 g) as crystals.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: NCCCSc1ccncc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 95.2 %

Procedure:
To a solution of 700 mg (2.90 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 1.62 ml (11.6 mmol) of triethylamine in 30 ml of methylene chloride was added 1.18 ml (3.48 mmol) of stearoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.20 g of the desired compound (95.2%, colorless powder), mp: 88.0°-89.0° C.
Reaction SMILES: [Na+].O1C=CCCC1C([O-])=O.O1CCCCC1C(O)=O.C(Cl)(=O)C(Cl)=O.C(N1CCNCC1)C1C=CC=CC=1.C([N:46]1[CH2:51][CH2:50][N:49]([C:52]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)=[O:53])[CH2:48][CH2:47]1)C1C=CC=CC=1>>[O:55]1[CH2:56][CH2:57][CH2:58][CH2:59][CH:54]1[C:52]([N:49]1[CH2:50][CH2:51][NH:46][CH2:47][CH2:48]1)=[O:53]
Reactant: O=C(C1CCCCO1)N1CCN(Cc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)C1CCCCO1
Agent: O=C([O-])C1CCC=CO1
Product: O=C(C1CCCCO1)N1CCNCC1

Procedure:
To prepare the compound of formula III, the 3,4-dihydro-2H-pyran-2 carboxylic acid sodium salt is hydrogenated to the tetrahydro-pyran-2-carboxylic acid. This compound converted to the acid chloride with oxalyl chloride and is then treated with N-benzyl piperazine. The resultant N-benzyl-N'-(tetrahydropyran-2-carbonyl)piperazine is hydrogenated to give N-(tetrahydro-pyran-2-carbonyl)piperazine. This compound is reacted with the known compound 4-amino-2-chloro-6,7-dimethoxyquinazoline to give the active drug 2-[4-(tetrahydro-pyran-2-carbonyl)piperazinyl]-4-amino-6,7-dimethoxyquinazoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.[CH:27](O)=[O:28]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][CH:27]=[O:28])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: O=CO
Product: COc1cc(NC=O)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 9.8 %

Procedure:
A mixture of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) and formic acid (2.1 mL, 55.6 mmol) was stirred at 90° C. for 2 h. After concentration purification of the residue by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:95:5) afforded the title compound (21 mg, 10%) as a yellow solid. MS: m/e=377.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]=[CH:16][C:17]#[N:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(=[O:24])C.C(O)C>O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]=[CH:16][C:17]#[N:18])(=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: N#CC=Cc1ccc(Cl)cc1Cc1ccccc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: N#CC=Cc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 28.8 g (0.14 mol) of 3-[2-benzyl-4-chlorophenyl]-2-propenenitrile, 50 g (0.5 mol) of chromium trioxide, 100 ml of methylene chloride, and 300 ml of acetic acid was stirred at room temperature overnight. The excess chromium trioxide was discharged by the slow addition of 30 ml of ethanol. The mixture was diluted with 800 ml of water and extracted with 500 ml of ether. The ether solution was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The ether solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].C1C[O:13][CH2:12]C1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl>O>[Cl:1][C:2]1[C:3]2[NH:9][C:12](=[O:13])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cl)c1N
Reactant: C1CCOC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Product: O=c1[nH]c2cccc(Cl)c2[nH]1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a solution of 3-chloro-benzene-1,2-diamine (0.820 g, 5.75 mmol) and THF (25 mL), was added carbonyl diimidazole (1.12 g, 6.90 mmol) at 0° C. The mixture was stirred for 16 h and allowed to warm to 23° C. A solution of 1M aqueous HCl (25 mL) was added to the reaction mixture at 0° C., followed by water (100 mL) and the mixture was stirred for 1 h. The precipitated solid was filtered and dried under high vacuum for 18 h to yield the titled compound, which was used in the next step without further purification (0.800 g, 83%). MS (ESI/CI): mass calcd. for C7H5ClN2O, 168.0; m/z found, 169.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 11.13 (s, 1H), 10.88 (s, 1H), 7.00-6.86 (m, 3H).