Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:22][C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=2[F:31])[C:26]#[N:27])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)[CH2:8][CH2:7]1)[CH3:5].[CH3:32][C:33]1[C:38]([C:39](O)=[O:40])=[C:37]([CH3:42])[N:36]=[CH:35][N:34]=1>>[C:26]([C:25]1[CH:28]=[CH:29][C:30]([F:31])=[C:23]([CH:24]=1)[CH2:22][N:12]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)[CH:9]1[CH2:10][CH2:11][N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:39]([C:38]2[C:33]([CH3:32])=[N:34][CH:35]=[N:36][C:37]=2[CH3:42])=[O:40])[CH2:7][CH2:8]1)#[N:27]
Reactant: CC(CCN)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc3[nH]ccc3c2)CC1
Reactant: Cc1ncnc(C)c1C(=O)O
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc3[nH]ccc3c2)CC1
Yield: 57.5 %

Procedure:
Using general procedure E, 3-{[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(1H-indol-5-yl)-amino]-methyl}-4-fluoro-benzonitrile (see EXAMPLE 244) (45 mg, 0.11 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (20 mg, 0.13 mmol) afforded COMPOUND 245 as a white solid (35 mg, 60%). 1H NMR (CDCl3) δ 0.88-1.25 (m, 5H), 1.54-1.64 (m, 1H), 1.76-1.92 (m, 3H), 2.13-2.20 (m, 1H), 2.51 (s, 6H), 2.51-2.57 (m, 1H), 2.69-2.84 (m, 3H), 3.31-3.37 (m, 2H), 3.82-3.85 (m, 1H), 3.98 (s, 2H), 6.39 (s, 1H), 6.72 (d, 1H, J=8.6 Hz), 7.00 (s, 1H), 7.08-7.14 (m, 2H), 7.21 (d, 1H, J=8.6 Hz), 7.43-7.45 (m, 1H), 7.65 (d, 1H, J=6.4 Hz), 8.02 (s, 1H), 8.50 (br s, 1H), 8.83 (s, 1H). 13C NMR (CDCl3) δ 13.74, 22.36, 29.89, 30.88, 31.26, 40.33, 43.81, 44.17, 52.34, 60.54, 60.81, 102.63, 108.63, 110.70, 111.94, 116.61, 116.72, 116.92, 118.91, 125.26, 128.77, 131.10, 132.79, 134.50, 157.98, 163.38. ES-MS m/z 554 (M+H). Anal. Calcd. for C32H36N7OF.0.2CH2Cl2: C, 67.77; H, 6.43; N, 17.18; F, 3.33. Found: C, 68.16; H, 6.64; N, 16.86; F, 3.05.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@H:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:7].C(N(CC)CC)C.O>C(Cl)Cl>[C:1]([NH:5][C@H:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH2:16]1)[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C[C@H](N)c1cc(Cl)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
Acetyl chloride (1.71 mL, 24.0 mmol) was added to a solution crude tert-butyl 4-{2-[(1S)-1-aminoethyl]-4-chlorophenyl}piperidine-1-carboxylate (5.42 g of ˜70% pure material, 11.2 mmol) and triethylamine (6.69 mL, 48.0 mmol) in methylene chloride at approximately 0° C. After 2 h, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 35–50% ethyl acetate/hexanes as eluent) provided tert-butyl 4-{2-[(1S)-1-(acetylamino)ethyl]-4-chlorophenyl }piperidine-1-carboxylate as a pale yellow foam. If desired, traces of the minor R-enantiomer could be removed using preparative chiral high pressure liquid chromatography on CHIRALPAK AD Phase (7.5% ethanol/heptanes as eluent) to give in order of elution: R-enantiomer as a colorless solid followed by the S-enantiomer as a colorless solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:9]=[CH:8][N:7]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=1.[CH2:19]1[O:27][CH:20]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[OH:27][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][N:2]([CH2:3][CH2:4][C:5]1[CH:9]=[CH:8][N:7]([S:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:6]=1)[CH3:1]
Reactant: CNCCc1ccn(S(=O)(=O)c2ccccc2)c1
Reactant: c1ccc(C2CO2)cc1
Solvent: CC#N
Product: CN(CCc1ccn(S(=O)(=O)c2ccccc2)c1)CC(O)c1ccccc1

Procedure:
A mixture of N-methyl-2-(1-phenylsulphonyl-3-pyrrolyl)ethylamine (4 g), styrene oxide (2.06 g) and acetonitrile (50 ml) were refluxed for 2 days. The solution was evaporated and the brown oil was purified by chromatography on silica, eluting with dichloromethane, chloroform then with increasing amounts of methanol (1→25%) in chloroform to give the title product as a brown oil.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:15][C:16]([C:18]1C=CC=C[C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40]([OH:42])=O)=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[CH3:44][C:32]1[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:15])=[O:17])=[CH:6][CH:1]=[CH:2][CH:3]=3)=[CH:29][CH:28]=2)[C:39]2[C:34]([C:33]=1[CH3:43])=[CH:35][C:36]([C:40](=[O:42])[NH:9][CH2:8][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10])=[CH:37][CH:38]=2
Reactant: C[C@@H](CN)c1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC[C@H](C)c3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (R)-2-phenylpropan-1-amine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 517 (M+H).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: O=[N+]([O-])c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-2-nitro-phenoxy)-ethyl]-pyrrolidine (600 mg, 1.66 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (363 mg, 1.70 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[C:13](=O)[C:12]2=[C:15]([CH3:20])[CH:16]=[CH:17][C:18]([CH3:19])=[C:11]2[C:10]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Li+].[Al+3].[H-].[H-].[H-]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][C:12]2[C:11](=[C:18]([CH3:19])[CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C)c2c1C(=O)N(NC(=O)OC(C)(C)C)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C)c2c1CN(NC(=O)OC(C)(C)C)C2
Yield: 34.6 %

Procedure:
63.9 g of N-(t-butyloxycarbonylamino)-3,6-dimethylphthalimide in 400 ml of absolute tetrahydrofuran are slowly dripped into a suspension of 20 g of aluminum lithium hydride in absolute tetrahydrofuran. The mixture is heated over 2 hours to the boiling point. Conventional processing yields 20 g of N-(t-butyloxycarbonylamino)-4,7-dimethylisoindoline.
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][C:7]=2[C:16]([F:19])([F:18])[F:17])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Li+]>O1CCOCC1>[CH:1]1([C:6]2[CH:15]=[CH:14][C:9]([CH2:10][OH:11])=[CH:8][C:7]=2[C:16]([F:17])([F:18])[F:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(C2CCCC2)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Product: OCc1ccc(C2CCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 1651.3 %

Procedure:
To a solution of methyl 4-cyclopentyl-3-(trifluoromethyl)benzoate (8.16 g, 30.0 mmol) in 1,4-dioxane (200 mL) Was added lithium borohydride solution (2 M in tetrahydrofuran, 30.0 mL, 59.9 mmol). The mixture was heated under reflux for 2.5 h. The mixture was allowed to cool to room temperature and carefully quenched with 1 N aqueous HCl solution to pH 5. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound as a colorless oil (121 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.56-1.63 (m, 2H), 1.66-1.77 (m, 2H), 1.81-1.91 (m, 2H), 2.03-2.15 (m, 2H), 3.37 (quintet, J=8.00 Hz, 1H), 4.71 (d, J=4.29 Hz, 2H), 7.45-7.47 (m, 1H), 7.49 (d, J=1.14 Hz, 1H), 7.60 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.COCCOC>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:35]3[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3ccncc3)c12
Temperature: 85 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (258 mg, 0.68 mmol) was mixed with K2CO3 (207 mg, 2.2 eq), pyridine-4-boronic acid (110 mg, 1.3 eq), Pd(Ph3)4 (43 mg, 0.05 eq), 3 mL of 1,2-dimethoxyethane and 0.5 mL of water. The mixture was heated and stirred in an 85° C. oil bath for 5 h. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removal of solvent gave the crude product, which was purified by column chromatography to give 156 mg of 3-methyl-4-pyridin-4-yl-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][Si:8]([CH3:32])([CH3:31])[O:9][CH2:10][C@@:11]12[C@@H:28]3[C@H:19]([C@H:20]4[C@@:24]([CH2:26][CH2:27]3)([CH3:25])[C:23](=[O:29])[CH2:22][CH2:21]4)[CH2:18][CH2:17][C:16]1=[CH:15][C:14](=[O:30])[CH2:13][CH2:12]2.[Cl-].[NH4+]>CS(C)=O>[CH3:31][Si:8]([CH3:7])([CH3:32])[O:9][CH2:10][C@@:11]12[C@@H:28]3[C@H:19]([C@H:20]4[C@@:24]([CH2:26][CH2:27]3)([CH3:25])[C:23](=[O:29])[CH2:22][CH2:21]4)[CH2:18][CH:17]=[C:16]1[CH2:15][C:14](=[O:30])[CH2:13][CH2:12]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CCC2=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CCC2=O

Procedure:
To a solution of potassium t-butoxide in dimethylsulfoxide at 25° C. under nitrogen is added a solution of 19-trimethylsiloxy-4-androstene-3,17-dione in dimethylsulfoxide with stirring. After 15 minutes the mixture is poured onto a cold aqueous ammonium chloride solution. The solid so obtained is rapidly filtered, washed well with water and dissolved in ether. The ether solution is washed well with water, dried over sodium sulfate and the ether removed at room temperature to yield 19-trimethylsiloxy-5-androstene-3,17-dione.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][CH:2]=1.[CH3:8][C:9]1([CH3:20])[O:18][C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH:11]2[O:19][CH:10]12>>[CH3:8][C:9]1([CH3:20])[O:18][C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C@@H:11]([N:1]2[CH:6]=[CH:5][C:4](=[O:7])[N:3]=[CH:2]2)[C@@H:10]1[OH:19]
Reactant: CC1(C)Oc2ccncc2C2OC21
Reactant: O=c1ccnc[nH]1
Product: CC1(C)Oc2ccncc2[C@@H](n2ccc(=O)nc2)[C@@H]1O

Procedure:
This example was also prepared by heating an equimolar mixture of 4(3H)-pyrimidone and 3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-pyrano[3,2-c]pyridine at 60° C. for 1 hour followed by chromatography as above.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]>C(O)C>[C:21]([C:20]1[CH:19]=[C:18]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: N#Cc1cccc(N)c1
Solvent: CCO
Product: N#Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Yield: 76 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.04 g (25.8 mmol) 3-aminobenzonitrile was heated to reflux. Removed heat at 3.5 hours and made basic with saturated sodium bicarbonate. Stripped solvents and air dried. Slurried residue with hexane and collected solids. Washed with water and dried in vacuo. Boiled in large volume ethyl acetate, collected solids and dried in vacuo, giving 5.15 g of yellow-brown solid: mass spectrum (electrospray m/e): 316.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33][C:34]1[CH:35]=[C:36]([CH2:40][CH2:41]O)[CH:37]=[CH:38][CH:39]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:2]([O:1][CH2:41][CH2:40][C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([Br:33])[CH:35]=2)[CH:3]=1
Reactant: OCCc1cccc(Br)c1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c(OCCc2cccc(Br)c2)c1
Reaction time: 3 h
Yield: 89.6 %

Procedure:
Methyl 3-hydroxy-4-methoxybenzoate (500 mg, 2.75 mmol) and triphenylphosphine (1.08 g, 4.12 mmol) were dissolved in THF (13 ml), the solution was cooled in an ice bath and 2-(3-bromophenyl)-ethanol (662 mg, 3.29 mmol) and DIAD (886 mg, 4.12 mmol) were added sequentially. Stirring was continued for 3 h at room temperature. The reaction mixture was evaporated to dryness and the residue purified by preparative RP HPLC (water/ACN gradient) to give 900 mg of the title compound.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1)#[N:2].[BrH:27]>[Pd].C(O)C>[BrH:27].[NH2:2][CH2:1][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)[CH2:10][C:11]([CH3:15])([CH3:16])[O:12]2)=[CH:7][CH:6]=1
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC#N)cc2O1
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCCN)cc2O1

Procedure:
A solution of 7-cyanomethyloxy-2,2-dimethyl-4-(3-trifluoromethylphenyl) chroman (5.4 g) and 10% palladium on charcoal (0.5 g) in ethanol (75 ml) was hydrogenated at atmospheric pressure. The catalyst was removed by filtration and the filtrate evaporated under reduced pressure to give an oil which was treated with ethereal hydrogen bromide to give the title compound (4 g) as a very hygroscopic noncrystalline compound.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Li]CCCC.[CH:23](N1CCOCC1)=[O:24].Cl>C1COCC1.O>[CH:23]([C:17]1[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:24]
Reactant: O=CN1CCOCC1
Reactant: CC(C)(C)C(=O)Nc1ccc2ccccc2n1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc2ccccc2cc1C=O
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 2-pivaloylaminoquinoline (5.00 g, 21.92 mmol) in THF (75 mL) at −78° C. was added dropwise BuLi (5.48 mL, 10 M in hexane, 54.80 mmol). After 2 hours at −78° C. the dianion was quenched by the addition of N-formylmorpholine (3.79 g, 37.88 mmol). The reaction mixture was allowed to warm to room temperature and poured into 2M aqueous HCl (20 mL). The pH of the aqueous phase was adjusted to 7.0 by addition of 2M HCl and the aqueous phase was diluted with water (100 mL) and extracted with diethyl ether (2×100 mL). The organic phase was dried (MgSO4) and evaporated to dryness in vacuo. The crude product was recrystallized from petrol ether/ethyl acetate to give 2.92 g (52%) of the title compound.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][N:8]([CH3:23])[C:9]1[N:14]=[C:13]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C:13]1[N:14]=[C:9]([N:8]([CH3:23])[CH2:7][CH2:6][NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH:10]=[CH:11][CH:12]=1
Reactant: C=CC(=O)NCCN(C)c1cccc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)NCCN(C)c1cccc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 110d (2.0 g, 6.25 mmol) and TFA (2.0 mL) in DCM (10.0 mL) was stirred at rt overnight. The mixture was concentrated and diluted with EA (30 mL), neutralized with 1M NaOH. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (PE/EA=1/1) to give N-(2-((6-aminopyridin-2-yl)(methyl)amino)ethyl)acrylamide 110e (550 mg, 40%) as yellow oil. ESI-LCMS: m/z=221.2
Reaction SMILES: Br[C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][O:5][CH:6]=1.[CH2:13]([SH:17])[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.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>C(OCC)(=O)C.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].O1CCOCC1>[CH2:13]([S:17][C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][O:5][CH:6]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCS
Reactant: Brc1conc1-c1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCSc1conc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a degassed solution of dioxane (40 ml) containing 64 (1.0 g, 4.44 mmol), were added 1.2 eq (0.62 ml) of butane-1-thiol and 2 eq of triethylamine (1.52 ml). The resulting mixture was stirred for another 2 hours under N2. Successively were added 2.5 mol % of Pd2(dba)3 (100 mg) and 5 mol % of Xantphos (128 mg). After the addition, the resulting solution was stirred for 18 hours at 95° C. under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether) to afford 3-(4-butylsulfanyl-isoxazol-3-yl)-pyridine (65A) as an oil (0.26 g, 25%). (TLC diethyl ether Rf 0.54). 1H-NMR (400 MHz, CDCl3): δ 9.24 (d, J=2 Hz, 1H), 8.72 (dd, J=5 Hz, 2 Hz, 1H), 8.49 (s, 1H), 8.31 (dt, J=8 Hz, 2 Hz, 1H), 7.45-7.41 (m, 1H), 2.61 (t, J=7 Hz, 2H), 1.52-1.43 (m, 2H), 1.39-1.29 (m, 2H), 0.83 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=1.[NH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.C(O)C.Cl>C(O)C>[ClH:1].[CH3:13][N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=[C:2]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[N:11]=1
Reactant: COc1ccc2nc(Cl)nc(N(C)c3ccccc3)c2c1
Reactant: Cc1ccccc1N
Agent: Cl
Solvent: CCO
Product: COc1ccc2nc(Nc3ccccc3C)nc(N(C)c3ccccc3)c2c1
Yield: 57.7 %

Procedure:
A mixture of 2-chloro-4-(N-methylphenylamino)-6methoxyquinazoline (5.4 g, 0.027M), o-toluidine (4.28 g, 0.04M) in ethanol (50 ml) was heated in a Berchof pressure vessel at 140° for 5 hours (maximum pressure 40 psi). After cooling, ethanol/HCl was added and the solid which crystallised out was filtered off and recrystallised from isopropanol/ether to yield the title compound (4.23 g, m.p. 258°-260°).
Reaction SMILES: [CH2:1]([N:3]([CH3:14])[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7]2)[CH3:2].[C:15]([O:18][CH2:19][C:20]1[C:25]([Br:26])=[CH:24][CH:23]=[CH:22][C:21]=1Br)(=[O:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>[Cu](I)I.O1CCOCC1>[C:15]([O:18][CH2:19][C:20]1[C:21]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N:3]([CH2:1][CH3:2])[CH3:14])[CH:5]=3)[C:9]2=[O:13])=[CH:22][CH:23]=[CH:24][C:25]=1[Br:26])(=[O:17])[CH3:16]
Reactant: CCN(C)c1ccc2c(c1)CNC2=O
Reactant: CC(=O)OCc1c(Br)cccc1Br
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCN(C)c1ccc2c(c1)CN(c1cccc(Br)c1COC(C)=O)C2=O
Temperature: 105 °C
Yield: 50 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 106c (390 mg, 2.05 mmol), 102d (1.26 g, 4.10 mmol), cesium carbonate (1.34 g, 4.10 mmol), N,N′-dimethylethylenediamine (181 mg, 2.05 mmol) and 1,4-dioxane (12 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper iodide (195 mg, 1.03 mmol) was added. A reflux condenser was attached to the flask, and the reaction mixture was heated at 105° C. for 16 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (150 mL) and water (75 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 70:30 hexanes/ethyl acetate) to afford 106d in 50% yield (427 mg) as a white solid: mp 97-99° C.; 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J=8.5 Hz, 1H), 7.63 (dd, J=8.0, 1.5 Hz, 1H), 7.30-7.25 (m, 2H), 6.80 (dd, J=8.5, 2.0 Hz, 1H), 6.66 (d, J=1.5 Hz, 1H), 5.21 (s, 2H), 4.69 (s, 2H), 3.51 (q, J=7.0 Hz, 2H), 3.21 (s, 3H), 1.99 (s, 3H), 1.19 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 417.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][NH:7][CH2:6][CH2:5]2.[Br-].[K+].I(C1C=CC=CC=1)=[O:16]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8](=[O:16])[NH:7][CH2:6][CH2:5]2
Reactant: Fc1cc2c(cc1Cl)CCNC2
Reactant: O=Ic1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=C1NCCc2cc(Cl)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A mixture of 6-chloro-7-fluoro-1,2,3,4-tetrahydro-isoquinoline (130 mg, 0.7 mmol), potassium bromide (83.5 mg, 0.7 mmol) and iodoso benzene (0.46 g, 2.1 mmol) in water (4 mL) was stirred at room temperature overnight. The mixture was then extracted with EtOAc and the organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product. Flash column chromatography separation (silica gel, 12 g, 30% EtOAc in hexane) then afforded the tile compound (58 mg, 41%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[C:3]#[N:4].[S:6](=[O:10])(=[O:9])([OH:8])[OH:7].[CH3:11][OH:12]>>[S:6]([OH:10])([OH:9])(=[O:8])=[O:7].[CH3:1][N:2]([CH3:5])[C:3](=[NH:4])[O:12][CH3:11]
Reactant: CN(C)C#N
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=N)N(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of dimethylcyanamide (10.0 g, 142.7 mmol) in methanol (50 mL) was added dropwise sulfuric acid (14.0 g, 142.7 mmol) over 2 hours at 20-30° C. The mixture was stirred at 20-30° C. for 4 hours and then concentrated in vacuo. To the residue was added acetone (50 mL) and stirred at 20-30° C. After crystallized, the mixture was stirred at 20-30° C. for 30 minutes, then at 0-10° C. for 1 hour and filtered. The crystals were washed with acetone (20 mL) and dried in vacuo to give N,N,O-trimethylisourea sulfate (22.86 g, 80.0% yield) as white granulated solids.