Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[O:24][CH:25]=[CH:26][C:27]=3[CH3:28])[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.[CH:82]1([NH2:87])[CH2:86][CH2:85][CH2:84][CH2:83]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:82]1([NH:87][C:2]2[N:7]3[N:8]=[C:9]([C:23]4[O:24][CH:25]=[CH:26][C:27]=4[CH3:28])[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:12]=4)=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:86][CH2:85][CH2:84][CH2:83]1
Reactant: NC1CCCC1
Reactant: Cc1ccoc1-c1nn2c(Cl)cccc2c1-c1ccnc(NC2CCCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1ccoc1-c1nn2c(NC3CCCC3)cccc2c1-c1ccnc(NC2CCCC2)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 4-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (150 mg, 0.38 mmol) in cyclopentylamine (10 mL) was added racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (76 mg, 0.12 mmol), cesium carbonate (247 mg, 0.76 mmol) and palladium (II) acetate (17 mg, 0.076 mmol). The resulting mixture was stirred at 100° C. for 3 hours. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (3:7 ethyl acetate:hexane) to give 147 mg (87%) of N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine as a yellow solid. 1H-NMR (CDCl3): δ 8.07 (d, 1H), 7.85 (d, 1H), 7.50 (d, 1H), 7.31 (t, 1H), 6.42 (d, 1H), 6.25 (d, 1H), 6.04 (d, 1H), 6.00 (d, 1H), 5.06 (d, 1H), 4.36 (m, 1H), 3.98 (m, 1H), 2.08 (m, 4H), 2.05 (s, 3H), 1.81–1.52 (m, 12H). MS m/z 443 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[Br:15])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:20]>CN(C)C=O>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[Br:15])[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
Place (2-bromo-5-fluoro-phenyl)-carbamic acid tert-butyl ester (2.00 g, 6.90 mmol) and dimethylformamide (40 mL) in a round bottom flask. Cool the solution to 0° C., add sodium hydride (60% dispersion in mineral oil) (0.303 g, 7.59 mmol), remove the ice bath and stir this suspension for 25 minutes allowing it to warm slowly towards ambient temperature. Cool the resulting mixture to 0° C. once again, and add iodomethane (0.56 mL, 8.96 mmol). Stir the resulting mixture overnight, allowing it to warm to ambient temperature. Quench the reaction with brine and extract the resulting mixture into ethyl acetate. Combine the extracts and wash with brine; then dry (sodium sulfate) and concentrate in vacuo. Purify the resulting material by flash chromatography (silica gel; 35%-50% dichloromethane gradient in hexanes) to provide the desired product.
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15][CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)[OH:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:18][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)[CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:30])=[O:29]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1ccc(Cl)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(OS(C)(=O)=O)c1ccc(Cl)c(F)c1
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Triethylamine (“TEA”) (0.741 mL, 5.31 mmol; d. 0.726) was added to a cold (0° C.) solution of 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol (1.08 g, 3.54 mmol) in DCM (10 mL), followed by addition of methanesulfonyl chloride (0.329 mL, 4.25 mmol). After 1 hour, the reaction mixture was diluted with DCM, and the organic layer was washed with saturated aqueous NaHCO3, dried, filtered and concentrated to afford 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (1.30 g, 3.39 mmol, 95.8% yield). 1H NMR (400 MHz, CDCl3) δ 7.33 (m, 1H), 7.18 (m, 1H), 7.10 (m, 1H), 6.63 (m, 1H), 5.74 (d, 1H), 5.32 (d, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=[O:10])([CH3:3])[CH3:2].S(=O)(=O)([OH:16])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[C:9]([OH:16])=[O:10])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1C=O
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Isopropyl-2-methoxybenzaldehyde (2.8 g, 15.7 mmol) was dissolved in acetone (40 mL). To this solution was added sulfamic acid (2.29 g, 23.57 mmol) and sodium chlorite (1.71 g, 18.85 mmol) in water (40 mL). The mixture was stirred at rt in an open flask for 12 hrs. The acetone was removed and the mixture was extracted with Et2O. The organic layer was dried over MgSO4, filtered and concentrated to afford the title compound. MS (DCI/NH4+) m/z 212 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O>[Pd].CCO.CO>[C:16]1([NH:15][CH2:14][C:5]2[C:4]([NH2:1])=[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=[N:12]3)=[CH:7][CH:6]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1c(CNc2ccccc2)ccc2cccnc12
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Nc1c(CNc2ccccc2)ccc2cccnc12
Reaction time: 4 h
Yield: 101.6 %

Procedure:
Palladium on Carbon (10%, 36 mg) was added to a solution of (8-nitro-quinolin-7-ylmethyl)-phenyl-amine (Intermediate 205) (478 mg, 1.69 mmol) in EtOH (10 ml) and the mixture was stirred under an atmosphere of hydrogen for 4 h. The mixture was diluted with MeOH (40 ml), filtered through celite and the filtrate was concentrated in vacuo to give the title compound (428 mg, 89%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:8]2[C:9](=[O:28])[N:10]([CH3:27])[N:11]=[C:12]([O:14][CH2:15][C@H:16]3[CH2:18][C@@H:17]3[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][N:20]=3)[CH:13]=2)[N:3]=[N:2]1.[H-].[Na+].CI.[CH3:42]OC1C=CC(CN(CC2C=NN(C)N=2)C2C(=O)N(C)N=C(OC[C@H]3C[C@@H]3C3C=CC(OC)=CN=3)C=2)=CC=1>C1COCC1.O.CCOC(C)=O>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:7]([CH2:6][C:4]2[N:3]=[N:2][N:1]([CH3:42])[CH:5]=2)[C:8]2[C:9](=[O:28])[N:10]([CH3:27])[N:11]=[C:12]([O:14][CH2:15][C@H:16]3[CH2:18][C@@H:17]3[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][N:20]=3)[CH:13]=2)=[CH:31][CH:32]=1
Reactant: COc1ccc(CN(Cc2cnn(C)n2)c2cc(OC[C@H]3C[C@@H]3c3ccc(OC)cn3)nn(C)c2=O)cc1
Reactant: COc1ccc(CN(Cc2c[nH]nn2)c2cc(OC[C@H]3C[C@@H]3c3ccc(OC)cn3)nn(C)c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc(CN(Cc2cn(C)nn2)c2cc(OC[C@H]3C[C@@H]3c3ccc(OC)cn3)nn(C)c2=O)cc1
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To a solution of compound 2 (100 mg, 0.20 mmol) in THF (20 mL) was added NaH (12 mg, 0.30 mmol) at 0° C. After stirred for 10 min, MeI (57 mg, 0.40 mmol) was added. The mixture was stirred for 2 h at room temperature and then diluted with H2O (20 mL) and EtOAc (50 mL). The organic phase was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC using PE/EtOAc=4/1 to give 4-((4-methoxybenzyl)((1-methyl-1H-1,2,3-triazol-4-yl)methyl)amino)-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one (3) (55 mg, yield: 53%) as a yellow solid and 4-((4-methoxybenzyl)((2-methyl-2H-1,2,3-triazol-4-yl)methyl)amino)-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one (4). ESI-MS: 461.2 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1O[CH:9]=[CH:8][C:6](=[O:7])[C:5]=1[OH:11]>O>[CH3:1][N:2]1[CH:9]=[CH:8][C:6](=[O:7])[C:5]([OH:11])=[C:4]1[CH3:3]
Reactant: Cc1occc(=O)c1O
Reactant: CN
Solvent: O
Product: Cc1c(O)c(=O)ccn1C

Procedure:
A solution of 40% methylamine in water is added to a solution of maltol dissolved in hot distilled water. The pH of this solution is adjusted to 9.8 by the addition of HCl solution. The mixture is kept under reflux overnight and then decolorized with activated charcoal. The solvent is removed under reduced pressure. The white product is obtained upon recrystallization from hot water.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>C1COCC1>[F:15][C:11]1([F:14])[CH2:10][CH2:9][C:8]([CH2:16][NH2:17])([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: N#CC1(c2ccc(Cl)nc2)CCC(F)(F)CC1
Agent: Cl
Solvent: C1CCOC1
Product: NCC1(c2ccc(Cl)nc2)CCC(F)(F)CC1

Procedure:
A solution of 1-(6-chloropyridin-3-yl)-4,4-difluorocyclohexanecarbonitrile (2.02 mmol) in 20 mL THF was added to a solution of BH3 in THF (6.07 mmol, 1 M). After heating to reflux for 1 h, the reaction mixture was cooled in an ice bath before a 2N HCl solution was slowly added. The mixture was then heated to reflux for another 20 min. The reaction mixture was extracted twice with DCM, basified with 1N NaOH solution and extracted 3 times with DCM. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give the desired product as yellow oil.
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:4]=1[CH2:5][C:6]1[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=12.[CH3:19]I>[Br-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C1C=CC=CC=1>[CH3:19][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:6]2[CH2:5][C:4]3[C:15]([C:7]1=2)=[CH:16][CH:17]=[CH:18][CH:3]=3
Reactant: CI
Reactant: c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cn1c2c(c3ccccc31)Cc1ccccc1-2
Reaction time: 2 h
Yield: 86.3 %

Procedure:
In a 0.5 l bulb were placed 100 ml 50% aqueous NaOH, 100 ml benzene, 6.1 g (28 mmol)of 5,10-dihydroindeno[1,2-b]indole, prepared in the Example 1,1.8 ml (28 mmol) of MeI and o.5 g of trimethylcetylammonium bromide. After having stirred the obtained mixture for 2 hours, the formation of an organic phase was observed; said phase was separated, washed twice with water (100 ml) and dried over Na2SO4. After removal of the solvent, the residue was recrystallized from ethanol, obtaining 5.3 g of N-methyl-5,10-dihydroindeno[1,2-b]indole(yield=84%).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:17]2[N:13]([N:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[C:21]=3[CH3:29])[C@H:16]2[O:18][CH3:19])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.O[Li].O>C1COCC1.O>[Cl:28][C:22]1[C:21]([CH3:29])=[C:20]([C:15]2[C@@H:16]([O:18][CH3:19])[C@@H:17]3[C@H:10]([OH:9])[CH2:11][CH2:12][N:13]3[N:14]=2)[CH:25]=[CH:24][C:23]=1[C:26]#[N:27]
Reactant: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@@H](OC(=O)c3ccccc3)[C@@H]12
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@@H](O)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,3aS,4R)-2-(3-chloro-4-cyano-2-methylphenyl)-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-4-yl benzoate (80 mg, 0.0.195 mmol) in THF (2 mL) at 0° C. was added a solution of LiOH.H2O (25 mg, 0.586 mmol) in water and the reaction mixture was stirred at room temperature for overnight. Once the starting material had disappeared (monitored by TLC), reaction mixture was extracted with ethyl acetate. Organic layer was washed with saturated NaHCO3 solution, water, and brine and then dried over Na2SO4 and concentrated. Purification of the crude by column chromatography over silica gel using 2% MeOH in DCM provided the title compound.
Reaction SMILES: [Na].[OH:2][N:3]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:5]2[C:4]1=[O:13].[CH2:14](Cl)[CH3:15]>>[CH2:14]([O:2][N:3]1[C:4](=[O:13])[CH:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:6]2[C:7]1=[O:8])[CH3:15]
Reactant: CCCl
Reactant: O=C1C2CCCCC2C(=O)N1O
Agent: [Na]
Product: CCON1C(=O)C2CCCCC2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 79.4 %

Procedure:
In an autoclave 60 g of a 20 wt % solution of the sodium salt of N-hydroxyhexahydrophthalimide (0.063 mol) and 5.0 g (0.078 mol) of ethyl chloride were mixed together. The mixture was heated to 100° C. After reaching this temperature the mixture was stirred for a further 5 hours while the temperature was maintained at 100° C. After 5 hours' reaction the excess ethyl chloride was blown out and the reaction mixture was discharged. The reaction product was extracted from the mixture with toluene. Gas chromatographic analysis of the toluene extract showed that the yield was 79% of N-ethoxyhexa-hydrophthalimide (0.050 mol).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=O.C([O-])(=O)C.[Na+].[Cl-].O[NH3+:23].C(O)(=O)C>O>[C:14]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1)#[N:23]
Reactant: [NH3+]O
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)Cc1ccccc1-2
Yield: 63.3 %

Procedure:
25 g of 2-fluorenecarboaldehyde, 11.6 g of sodium acetate, 9.7 g of hydroxy ammonium chloride and 150 ml of acetic acid were stirred at 130 for 18 hours. The reaction mixture was allowed to room temperature, poured into 200 ml of water and the precipitate was collected by filtration. The crude product was purified by column chromatography, giving 15.57 g (63%) of 2-cyanofluorene.
Reaction SMILES: [H-].[Na+].[C:3](=[N:7][OH:8])([NH2:6])[CH2:4][CH3:5].[C:9]1([C:15]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:16]2[CH2:21][CH:20]([C:22](OC)=O)[CH2:19][N:18]=[CH:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[C:32]1([C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:16]2[CH2:21][CH:20]([C:22]3[O:8][N:7]=[C:3]([CH2:4][CH3:5])[N:6]=3)[CH2:19][N:18]=[CH:17]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: CCC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
Prepared by a procedure similar to Example 9, where sodium hydride (60% dispersion in mineral oil 56 mg, 1.4 mmol) and propionamidoxime (123 mg, 1.4 mmol) were suspended in dry THF in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (540 mg, 1.4 mmol) was added, dissolved in dry THF and reflux continued 18 hours. The solvents were evaporated in vacno and the residue was chromatographed (silica, chloroform/methanol 9:1) to yield 1-triphenylmethyl-1,4,5,6-tetrahydro-5-(3-ethyl-1,2,4-oxadiazol-5-yl)pyrimidine 420 mg (70%). This product was dissolved in trifluoroacetic acid (2 mL), with stirring at room temperature for 24 hours. The yellow solution was then evaporated in vacuo, and the residue recrystallized from methanol/ether to yield 144 mg (49%) white crystals, mp 116°-118° C. identified by 300 MHz nmr.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: SCc1ccccc1Cl
Reactant: C#Cc1ccc(Br)cc1
Agent: [Na]
Product: Clc1ccccc1C(/C=C\c1ccc(Br)cc1)SC(/C=C\c1ccc(Br)cc1)c1ccccc1Cl

Procedure:
A solution of 4-bromophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-bromostyryl 2-chlorobenzylsulfide. The title compound was obtained in 84% yield following oxidation. 1HNMR (CDC13) δ 4.57 (2H, s), 6.70 (1H, d, JH,H=11.58), 7.18-7.58 (8H aromatic+1H ethylenic).
Reaction SMILES: [NH2:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C@H:6]1[CH3:18])(=[O:4])=[O:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:60]1[CH:65]=[C:64]([O:66][CH3:67])[N:63]=[C:62]([S:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[C:71]=2[F:77])[N:61]=1>O1CCOCC1.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]>[F:77][C:71]1[C:72]([F:76])=[CH:73][CH:74]=[CH:75][C:70]=1[CH2:69][S:68][C:62]1[N:61]=[C:60]([NH:1][S:2]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C@H:6]2[CH3:18])(=[O:3])=[O:4])[CH:65]=[C:64]([O:66][CH3:67])[N:63]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(N)(=O)=O
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl (3R)-4-(aminosulfonyl)-3-methylpiperazine-1-carboxylate ((the product from step 0.554 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.429 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product from example 35 step i), 0.400 g) in dioxane (20 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 60 mins. The reaction mixture was then reduced in vacuo and the residue separated between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (3×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow oil. Yield: 0.75 g
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[CH:12][C:13]([F:29])=[C:14]([C@:16]2([CH2:27][F:28])[CH2:21][C@@H:20]([C:22]([F:25])([F:24])[F:23])[O:19][C:18]([NH2:26])=[N:17]2)[CH:15]=1.[C:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1)#[C:31][CH3:32]>O1CCOCC1.O.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:29][C:13]1[CH:12]=[CH:11][C:10]([C:35]2[CH:36]=[N:37][CH:38]=[C:33]([C:30]#[C:31][CH3:32])[CH:34]=2)=[CH:15][C:14]=1[C@:16]1([CH2:27][F:28])[CH2:21][C@@H:20]([C:22]([F:25])([F:24])[F:23])[O:19][C:18]([NH2:26])=[N:17]1
Reactant: NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: CC#Cc1cncc(B(O)O)c1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC#Cc1cncc(-c2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)c1
Yield: 55.5 %

Procedure:
A mixture of potassium phosphate (0.168 g, 0.792 mmol), (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (8a, 0.0985 g, 0.264 mmol), (5-(prop-1-yn-1-yl)pyridin-3-yl)boronic acid (0.106 g, 0.660 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (9.35 mg, 0.013 mmol) in dioxane/water (2.0/0.5 mL) was irradiated at 110° C. for 30 min. The reaction mixture was diluted with water and extracted with DCM three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography: 12 g, 0-100% EtOAc/DCM. The product was obtained as a white solid (0.060 g, 55% yield). MS m/z=410 [M+H]+. Calculated for C20H16F5N3O: 409.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH3:12][N:13]([CH3:15])[NH2:14]>C(O)C>[CH3:12][N:13]([CH3:15])[N:14]=[C:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CN(C)N
Solvent: CCO
Product: CCOC(=O)C1CCCC1=NN(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Oxo-cyclopentanecarboxylic acid ethyl ester (1.00 mL, 6.91 mmol) was dissolved in ethanol (10 mL). N,N-Dimethylhydrazine (0.53 mL, 6.91 mmol) was added. The reaction was stirred at 25° C. for 16 h. The resulting mixture was concentrated in vacuo to afford the crude product, ethyl 2-(2,2-dimethylhydrazono)cyclopentane-carboxylate, which was used in the next step without further purification. LC-MS (ESI) calcd for C10H18N2O2 198.26, found 199.2 [M+H+].
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]([C@H:11]1[CH2:16][C@H:15]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]3[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])[CH2:14][CH2:13][N:12]1C(OC(C)(C)C)=O)=[O:10]>C(Cl)Cl>[Cl:37][C:33]1[C:32]([F:38])=[C:31]([NH:30][C:21]2[C:20]3[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:18]([O:17][C@@H:15]4[CH2:14][CH2:13][NH:12][C@@H:11]([C:9]([NH2:8])=[O:10])[CH2:16]4)[CH:19]=3)[N:24]=[CH:23][N:22]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](C(N)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
TFA (2 ml) was added over a period of 5 minutes to a stirred solution of tert-butyl (2R,4R)-2-(aminocarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1-carboxylate (0.13 g, 0.232 mmol) in DCM (2 ml) at 0° C., was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour after which time, the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped twice with toluene and the residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 5%) to give (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxamide (9) (0.102 g, 100%) as a yellow solid; Mass Spectrum: (M+H)+ 446.1.
Reaction SMILES: [O-][N+:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[N:12]3[C@@H:18]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][O:16][CH2:15][C:13]3=[N:14][C:4]=2[CH:3]=1.[NH4+:28].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:28][C:3]1[C:4]2[N:14]=[C:13]3[CH2:15][O:16][CH2:17][C@H:18]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:12]3[C:5]=2[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 2 h

Procedure:
tert-Butyl [(11S)-5-oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methylcarbamate (1.69 g, 4.57 mmol) was dissolved in 20 mL of CH2Cl2 and treated with 2 mL of concentrated NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (958 mg, 5.02 mmol) was carefully added. Rapid stirring was continued for 2 hours. The reaction mixture was treated with 25 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed with 2% Na2CO3 solution (3×20 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10-30% CMA/CHCl3) gave tert-butyl [(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methylcarbamate (1.39 g) as a salmon colored foam.