Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[C:14]1([C:20]2[O:21][CH2:22][CH:23]([OH:32])[CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:25]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCCl>[C:14]1([C:20]2[O:21][CH2:22][CH:23]([O:32][C:10](=[O:11])[NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:4][CH:5]=3)[CH:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:25]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: OC1COC(c2ccccc2)=NC1c1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)OC1COC(c2ccccc2)=NC1c1ccccc1
Yield: 74.4 %

Procedure:
4-(Trifluoromethyl)phenyl isocyanate (0.8 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.26 g) in 1,2-dichloroethane (30 cc). The solution obtained is heated to reflux for 5 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 40 g) contained in a column 1 cm in diameter, collecting 20-cc fractions. Fractions 2 and 3, eluted with a mixture of ethyl acetate and cyclohexane (3:7 by volume), are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in petroleum ether, (4RS, 5RS)-2,4-diphenyl-5-[4-(trifluoromethyl)phenylcarbamoyloxy]-5,6-dihydro-4H-1,3-oxazine (1.4 g), m.p. 140° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:23]>CC(C)=O>[Cl:23][C:9]1[C:10]2[C:5](=[C:4]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]ncc2c1Cc1ccncc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: COc1ccc2c(Cl)nncc2c1Cc1ccncc1
Temperature: 85 °C
Yield: 62 %

Procedure:
A suspension under N2 of 6-methoxy-5-pyridin-4-ylmethyl-2H-phthalazin-1-one (2.26 g,), prepared as described in example 141, in POCl3 (40 ml) was heated for 3 hours at 85° C., then dried. The residue was taken up in a saturated NaHCO3 solution up to alkalinity, then filtered and extracted with ethyl acetate. The solid was dissolved in a CH2Cl2/CH3OH/ethyl acetate mixture, dried over Na2SO4 and filtered. The solution was joined to the previous organic phase and dried to give a residue which was taken up in acetone and filtered yielding 1.5 g of the title compound (yield: 62%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[CH3:44][NH:45][CH3:46]>>[CH3:44][N:45]([CH3:46])[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Solvent: C1CCOC1
Product: CN(C)c1ccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3ccccn3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (30 mg, 0.055 mmol) was dissolved in a solution of dimethylamine in tetrahydrofuran (2M, 545 μl, 1.091 mmol), and the reaction mixture stirred at room temperature overnight. The solvent was removed in vacuo to give a yellow oil, which was purified by chromatography on silica gel (gradient: 10-100% ethyl acetate in isohexane) to afford (R)-(6-((6-(dimethylamino)pyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (25 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.38 min, m+H=559.3; 1H NMR (400 MHz, CDCl3): δ 8.62 (1H, ddd, J=4.8, 1.8, 0.9 Hz), 8.43 (1H, d, J=2.5 Hz), 7.88 (1H, dt, J=8.0, 1.1 Hz), 7.81 (1H, td, J=7.7, 1.8 Hz), 7.60 (1H, dd, J=9.1, 2.5 Hz), 7.46-7.40 (3H, m), 7.28 (1H, s), 7.20-7.12 (2H, m), 6.47 (1H, d, J=2.2 Hz), 6.39 (1H, dd, J=9.1, 0.8 Hz), 5.47 (1H, dd, J=12.0, 2.2 Hz), 4.29 (1H, d, J=16.9 Hz), 3.84-3.79 (1H, m), 3.14 (6H, s), 2.92-2.75 (2H, m), 2.70 (1H, d, J=12.0 Hz), 2.51-2.44 (2H, m).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[F:19].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc2c(-c3ccc(F)c(F)c3)cccn2n1
Temperature: 110 °C
Reaction time: 18 h
Yield: 102.8 %

Procedure:
A suspension of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (5.33 g, 25 mmol), 3,4-difluorophenylboronic acid (5.92 g, 37.5 mmol) and 2M aqueous sodium carbonate solution (62.5 mL, 125 mmol) in 1,4-dioxane (250 mL) was treated with 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.02 g, 1.25 mmol) at room temperature and then stirred for 18 hours at 110° C. The reaction was cooled to room temperature and separated between water (312 mL) and ethyl acetate (500 mL). The aqueous layer was extracted with further ethyl acetate (500 mL). The organic layers were washed with saturated aqueous sodium chloride solution (300 mL), combined, dried over sodium sulfate, filtered off and evaporated. The brown solid was trituration with diethyl ether (130 mL) and dichloromethane (25 mL) to yield the title compound as a light brown solid (6.33 g, 97%). MS ISP (m/e): 247.2 (100) [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:19])([CH2:14][OH:15])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)(CO)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a solution of diethyl 2-(4-bromophenyl)-2-methylmalonate (850 mg, 2.6 mmol) in dry THF (5 mL) at 0° C. was added a 1.0M solution of lithium aluminum hydride in THF (2.6 mL, 2.6 mmol). After stirring for 2 h at 0° C., the mixture was quenched by slow addition of water (5 mL). The mixture was made acidic by addition of 1N HCl and was then extracted with dichloromethane (2×20 mL). The organics were combined, dried over Na2SO4 and evaporated to give 2-(4-bromophenyl)-2-methylpropane-1,3-diol (500 mg, 79%) 1H NMR (400 MHz, DMSO-d6) δ 7.47-7.43 (m, 2H), 7.35-7.32 (m, 2H), 4.59-4.55 (m, 2H), 3.56-3.51 (m, 4H), 1.17 (s, 3H).
Reaction SMILES: [N-:1]([C:4]#[N:5])[C:2]#[N:3].[Na+].Cl.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[O:18][CH2:17][C:16]2([CH2:23][O:22][CH:21]([CH2:24][CH2:25][CH2:26][NH2:27])[O:20][CH2:19]2)[CH2:15][O:14]1>>[C:2]([NH:1][C:4](=[NH:5])[NH:27][CH2:26][CH2:25][CH2:24][CH:21]1[O:20][CH2:19][C:16]2([CH2:17][O:18][CH:13]([CH2:12][CH2:11][CH2:10][NH:9][C:4]([NH:1][C:2]#[N:3])=[NH:5])[O:14][CH2:15]2)[CH2:23][O:22]1)#[N:3]
Reactant: NCCCC1OCC2(CO1)COC(CCCN)OC2
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Product: N#CNC(=N)NCCCC1OCC2(CO1)COC(CCCNC(=N)NC#N)OC2

Procedure:
The reaction of sodium dicyanamide with 3,9-bis(3-aminopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane dihydrochloride proceeds as shown by the following formula (5) to produce 3,9-bis(3-cyanoguanidinopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane aimed at. ##STR12##
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]2[NH:8][C:9](=[C:11]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=3)[C:12]([NH2:14])=[O:13])[S:10][C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]2[NH:8][C:9](=[C:11]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=3)[C:12]([NH2:14])=[O:13])[S:10][C:6]=2[CH:5]=1
Reactant: NC(=O)C(=C1Nc2ccc([N+](=O)[O-])cc2S1)c1nccc(C(F)(F)F)n1
Agent: [Pd]
Solvent: CO
Product: NC(=O)C(=C1Nc2ccc(N)cc2S1)c1nccc(C(F)(F)F)n1
Reaction time: 24 h

Procedure:
Compound 32A was prepared from compound 26A as follows. To a solution of 2-[6-nitrobenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (280 mg, 0.73 mmol) in MeOH (25 mL) was added a slurry of 10% palladium on carbon (200 mg) in MeOH (10 mL), and the mixture was stirred under hydrogen at atmospheric pressure for 24 hr. The mixture was filtered and the filtrate concentrated to give crude 2-[6-aminobenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide as a red powder. This was purified by flash column chromatography eluting with 19:1 EA/MeOH to give pure 2-[6-aminobenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide, compound 32A (160 mg, 62% yield) as a yellow powder.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11]([NH:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1)=[S:12])(=[O:9])=[O:8].[Na].[CH3:31]I.O>C(#N)C.C(O)C>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11](=[N:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1)[S:12][CH3:31])(=[O:8])=[O:9]
Reactant: COc1nc(NC(=S)NS(=O)(=O)c2ccccc2-c2ccccc2)nc(OC)n1
Reactant: CI
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: COc1nc(N=C(NS(=O)(=O)c2ccccc2-c2ccccc2)SC)nc(OC)n1
Yield: 47.2 %

Procedure:
4.31 g of 1-(2-biphenylylsulfonyl) 3-(4,6-dimethoxy-1,3,5-triazin-2-yl)thiourea were suspended in 50 ml of dry acetonitrile, and a solution of 0.3 g of metallic sodium in 10 ml of ethanol was added to the suspension, and the mixture was heated under reflux for 30 minutes. After cooling, 1.85 g of methyl iodide were added, and the mixture was heated under reflux for 5 hours. After cooling, the reaction mixture was poured into 100 ml of water, and extracted with methylene chloride. Methylene chloride was distilled off under reduced pressure from the extract, and the residue was recrystallized from ethanol to give 2.1 g of 1-(2-biphenylylsulfonyl) 3-(4,6-dimethoxy-1,3,5-triazin-2-yl) 2-methylisothiourea represented by the following formula: ##STR29##
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][C@H:6]2[CH2:8][C@@H:3]1[CH2:4][C:5]2=[O:9].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].OO.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1([F:10])[CH2:7][C@H:6]2[CH2:8][C@@H:3]1[CH2:4][C@H:5]2[OH:9]
Reactant: O=C1C[C@H]2C[C@@H]1CC2(F)F
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@@H]1C[C@H]2C[C@@H]1CC2(F)F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of (1R,4R)-5,5-difluorobicyclo[2.2.1]heptan-2-one (0.540 g, 3.7 mmol) in anhydrous tetrahydrofuran (8.00 mL) at −78° C. under nitrogen was added drop-wise L-Selectride (1.0 M solution in tetrahydrofuran, 7.40 mL). After stirring at −78° C. for 3 h, 30% H2O2 (6.0 mL) and 10% NaOH (aq., 10.0 mL) were added. The mixture was warmed to r.t. and then stirred at 65° C. for 10 h. After cooling to ambient temperature, the mixture was extracted with EtOAc (50 mL×2). The combined organic portions were washed with brine, and conc. in vacuo. Flash column chromatography (0 to 30% of ethyl acetate in hexanes) gave the title compound as a white solid.
Reaction SMILES: C([CH:8]1[C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH2:13][F:14])[CH2:11][CH2:10][N:9]1C(OCC)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:14][CH2:13][C:12]1([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:11][CH2:10][NH:9][CH2:8]1
Reactant: CCOC(=O)N1CCC(CF)(NC(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(CF)CCNC1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A solution of ethyl benzyl-3-(tert-butoxycarbonylamino)-3-(fluoromethyl)pyrrolidine-1-carboxylate (2.27 g, 6.44 mmol) and ammonium formate (3.03 g, 32.2 mmol) in ethanol (60 mL) was flushed with nitrogen for 15 minutes. 10% Pd/C (0.69 g, 0.644 mmol) was added and the mixture heated at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature, filtered through a pad of Celite and washed with ethanol (30 mL) and concentrated under reduced pressure to afford tert-butyl 3-(fluoromethyl)pyrrolidin-3-ylcarbamate (1.4 g, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)[CH3:2].FC(F)(F)C(O)=[O:18].N([O-])=O.[Na+].[OH-].[NH4+]>>[CH2:1]([C:3]1[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:18])[NH:8]2)[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCc1cc(CC)c2cccnc2n1
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Product: CCc1cc(CC)c2ccc(=O)[nH]c2n1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-amino-,5,7-diethyl-1,8-naphthyridine (7.0 g., 0.035 mole) in 45 ml. of trifluoroacetic acid is added sodium nitrite (2.66 g., 0.0385 mole) in small portions over 1 hour at -5° C. The mixture is stirred at -5° C. for 2 hours and for an additional hour at room temperature. The reaction mixture is poured into 300 g. of crushed ice and is made alkaline with a slight excess of concentrated ammonium hydroxide. A yellow solid separates and is filtered and washed with a little ice water. Recrystallization from ethyl acetate affords 5,7-diethyl-1,8-naphthyridin-2-(1H)-one melting at 159°-161° C.
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26](I)[CH:27]=1)[O:24][CH:23]([C:29]([F:32])([F:31])[F:30])[C:22]([C:33]([O-:35])=[O:34])=[CH:21]2.[Br-].[CH2:37]([Zn+])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1COCC1>[CH2:37]([C:26]1[CH:27]=[C:18]([Cl:17])[CH:19]=[C:20]2[C:25]=1[O:24][CH:23]([C:29]([F:32])([F:31])[F:30])[C:22]([C:33]([OH:35])=[O:34])=[CH:21]2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C([O-])C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Reactant: [Zn+]Cc1ccccc1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(Cl)cc(Cc3ccccc3)c2OC1C(F)(F)F
Temperature: 60 °C
Yield: 12 %

Procedure:
To a chilled solution of 0.031 g (0.054 mmole) of bis(dibenzylideneacetone) palladium (0) and 0.025 g (0.107 mmol) of tri-2-furylphosphine in 5 mL degassed THF was added 0.500 g (0.535 mmol) of Wang resin 6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate followed by addition of 3.21 mL (1.605 mmol) of a 0.5 M soln of benzylzinc bromide. The reaction mixture was heated to 60° C. overnight. The reaction mixture was transferred and washed as follows: THF (×5), aqueous NH4Cl (×5), H2O (×5), MeOH (×5), and CH2Cl2 (×5). The resin was treated with 2 mL (TFA:CH2CL2, 1:1) for 30 minutes. The filtrate was collected and treatment was repeated. The resin was washed with CH2Cl2 (×2) and all filtrates were combined and concd. The resulting oil was purified using reverse phase chromatography to afford 0.024 g (12%) of a white crystalline solid: 1H NMR (CDCl3/400 MHz) 4.00 (s, 2H), 5.91 (q, 1H, J=7.1 Hz), 7.20 (m, 1H), 7.27 (m, 5H), 7.41 (d, 1H, J=2.5 Hz), 7.87 (s, 1H); 19F NMR (CDCl3/400 MHz) −79.4 (d, 3F, J=6.8 Hz); MS (ES+) 369 (M+1, 100); HRMS (ES−) m/z calcd for (M−H: C18H11O3ClF3) 367.0343, found 367.0333.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][CH:8]=1)#[N:2].FC(F)(F)C(O)=O.O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2cccc(C#N)c2)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(Oc2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.9 %

Procedure:
To the solution of tert-butyl 4-(3-cyanophenoxy)benzoate (178 mg, 0.6 mmol) in dichloromethane 50 ml) was added trifluoroacetic acid (12.5 ml) the solution was stirred at room temperature for 12 hours, water (50 mL) was added and washed 3 times, the organic layer was evaporated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=10:1) to give 4-(3-cyanophenoxy)benzoic acid (40 mg, 28%)
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH2:5]CCC.[CH3:9][CH:10]([OH:16])[CH2:11][CH2:12][CH:13]([OH:15])[CH3:14].C(Br)C=C>COCCOC.O.CCOCC>[CH2:5]([O:15][CH:13]([CH3:14])[CH2:12][CH2:11][CH:10]([OH:16])[CH3:9])[CH:4]=[CH2:3]
Reactant: CC(O)CCC(C)O
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: COCCOC
Product: C=CCOC(C)CCC(C)O
Temperature: 25 °C

Procedure:
12.0 g (0.25 mol) of 50% sodium hydride dispersion in mineral oil are freed from the mineral oil with hexane and covered with a layer of 150 cc of absolute 1,2-dimethoxy ethane. A solution of 35.4 g (0.3 mol) of 2,5-hexandiol in 60 cc of absolute 1,2-dimethoxy ethane is added at 5°-10° over a period of 90 minutes and while stirring to the resulting suspension. After stirring for 2 hours at 50°, the mixture is cooled to 10° and 24.2 g (0.2 mol) of allyl-bromide in 40 cc of dry 1,2-dimethoxy ethane are added dropwise. The mixture is slowly heated to 60° and stirred at this temperature for 16 hours. After this period the reaction mixture is cooled to room temperature. After adding 200 cc amounts of ether and water the mixture is vigorously stirred for 15 minutes and the organic phase is separated off in a separating funnel. The ether extract is washed with saturated salt solution, dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with hexane/ethyl acetate (2:1), whereby, according to gas-chromatography, pure 5-allyloxy-2-hexanol is obtained as a colourless oil.
Reaction SMILES: NN.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:17][O:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[S:16][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1>C(O)C>[NH2:19][O:18][CH2:17][C:15]1[S:16][C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[C:4]([NH2:3])[C:13]=2[N:14]=1
Reactant: Nc1nc2ccccc2c2sc(CON3C(=O)c4ccccc4C3=O)nc12
Agent: NN
Solvent: CCO
Product: NOCc1nc2c(N)nc3ccccc3c2s1
Yield: 88.5 %

Procedure:
Hydrazine (2.25 mL, 71.7 mmol) was added to a suspension of 2-[(4-amino[1,3]thiazolo[4,5-c]quinolin-2-yl)methoxy]-1H-isoindole-1,3(2H)-dione (5.4 g, 14 mmol) in ethanol (200 mL), and the reaction was heated at reflux for one hour and filtered hot to remove a solid. The filtrate was concentrated under reduced pressure and further dried in a vacuum oven overnight The resulting solid (4.89 g) was triturated with ethanol (200 mL) for two hours, filtered, washed with ethanol, and dried in a vacuum oven to provide 3.05 g of 2-(aminooxy)methyl[1,3]thiazolo[4,5-c]quinolin-4-amine as an orange solid containing some phthalhydrazide. The filtrate was concentrated under reduced pressure to provide an additional 1.91 g of the product mixture.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[N:5]=[C:4]([CH:16]2[CH2:18][CH2:17]2)[CH:3]=1.CO.C1(N=C=O)C=CC=CC=1.[OH-].[Na+]>>[CH:16]1([C:4]2[CH:3]=[C:2]([NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:8])[NH:1][N:5]=2)[CH2:18][CH2:17]1
Reactant: Nc1cc(C2CC2)nn1C(=O)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1cc(C2CC2)n[nH]1
Yield: 20.6 %

Procedure:
To 5-amino-3-cyclopropyl-N-phenyl-1H-pyrazole-l-carboxamide (0.5 g, 2 mmol) in 6 ml of methanol 0.5 ml (4.6 mmol)of phenylisocyanate and 2 ml of 10% NaOH were added. The mixture was refluxed for about 2h, then cooled, quenched with 10% HCl and extracted with ethyl acetate. The organic phase was washed with 10% HCl, water and brine. Concentration and chromatography on silica gel, eluting with 8% to 20% acetone in methylene chloride, afforded 100 mg (20% yield) of N-(3-cyclopropyl-1H-pyrazol-5-yl)-N′-phenylurea as a colorless, glassy solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[N:30]=[CH:29][C:28]3[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=3)[C:22]2=[O:36])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16](Br)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2].[CH2:37]([N:39]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40]1)[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[N:30]=[CH:29][C:28]3[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=3)[C:22]2=[O:36])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:44][C:41]2[CH:42]=[CH:43][N:39]([CH2:37][CH3:38])[N:40]=2)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CCn1ccc(N)n1
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCn1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a 1-dram vial was added 142c (40 mg, 0.074 mmol), 1-ethyl-1H-pyrazol-3-amine (1.2 equiv), cesium carbonate (1.5 equiv), Xantphos (10 mol %) and tris(dibenzylideneacetone)dipalladium(0) (5 mol %) in dry 1,4-dioxane (0.2 M). The reaction was then stirred at 80° C. for 3 hours. After cooling to room temperature, the reaction was then diluted with dichloromethane (3 mL) and washed with water (2×3 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product 142d was then carried on to the subsequent step without purification.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19]O)=[CH:14][CH:15]=2)[O:10][C:9]([C:21]2[N:22]=[CH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl-].[NH4+].C(=O)([O-])[O-].[K+].[K+].[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>ClCCl>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][N:55]3[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]3)=[CH:14][CH:15]=2)[O:10][C:9]([C:21]2[N:22]=[CH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:8]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#CCO)ccc12
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(CC#Cc2ccc3c(=NOC(C)(C)C)cc(-c4cc5ccccc5cn4)oc3c2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 17.7 %

Procedure:
To a cold solution of 7-(3-Hydroxy-prop-1-ynyl)-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 54A) (230 mg, 0.577 mmol) and triethylamine (0.18 ml, 1.27 mmol) in dichloromethane (3 ml) was added dropwise methanesulfonyl chloride (90 μl, 1.15 mmol). The reaction mixture was stirred for 4 hours at 0° C. and poured onto a saturated solution of ammonium chloride. The product was extracted with dichloromethane, washed with brine, dried over sodium sulfate and concentrated to dryness. The residue methansulfonic ester was dissolved in acetone (3 ml) and treated with potassium carbonate (239 mg, 1.73 mmol) and methyl piperazine (87 mg, 0.866 mmol) and the mixture was stirred at 25° C. for 20 hours. The mixture was poured onto water and extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate and absorbed over silica gel for purification by flash chromatography (ethyl acetate/methanol 90/10 then ethyl acetate/7N ammoniac in methanol: 90/10) to yield 2-isoquinolin-3-yl-7-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-chromen-4-one O-tert-butyl oxime (49 mg, 18%) as a brown solid.