Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3](O)=O.[NH2:14][C:15]1[C:23]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.Cl.[NH2:52]CCC(OCC)=O>N1C=CC=CC=1>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]1[N:52]=[C:17]([OH:18])[C:16]2[C:15](=[C:23]([O:24][C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][CH:20]=2)[N:14]=1
Reactant: O=C(O)C(F)(F)c1ccc(F)cn1
Reactant: CCOC(=O)CCN
Reactant: Nc1c(OC(F)(F)F)cccc1C(=O)O
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2c(OC(F)(F)F)cccc12
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetic acid from Example 33 step A (863 mg, 4.52 mmol) and 2-amino-3-(trifluoromethoxy)benzoic acid (1 g, 4.52 mmol) in pyridine (15 mL) was added triphenyl phosphite (1.3 mL, 4.97 mmol) and the mixture was heated in a microwave synthesizer at 150° C. for 10 min. The mixture was cooled to rt and then ethyl 3-aminopropanoate hydrochloride (763 mg, 4.97 mmol) was added and the mixture heated in a microwave synthesizer at 190° C. for 4 min. The crude mixture was concentrated under reduced pressure. THF (30 mL) was added followed by sodium ethoxide (21% in EtOH, 5 mL) and the mixture stirred at 60° C. for 0.5 h. The cooled mixture was concentrated under reduced pressure, dissolved in water and the pH adjusted to <4 by addition of 4 N HCl. The precipitate was collected by filtration, washed with water, and allowed to dry to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(trifluoromethoxy)quinazolin-4-ol (1.31 g, 77%) as a crude tan solid which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:34][CH3:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:22]>>[CH2:34]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:32][CH2:33]1)[CH3:35]
Reactant: CCN(CC)CCCCC1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Product: CCN(CC)CCCCC1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 43 %

Procedure:
Prepared analogously to Example 1 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[4-(diethylamino)butyl]piperidine in a yield of 43% of theory.
Reaction SMILES: C(O[CH:4](OCC)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:6])C.[OH-].[NH4+].CCOCC>S(=O)(=O)(O)O>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[N:7][C:5]([OH:6])=[CH:4]2
Reactant: CCOC(OCC)C(=O)NCc1ccccc1F
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Product: Oc1cc2cccc(F)c2cn1
Yield: 60 %

Procedure:
2,2-Diethoxy-N-(2-fluorobenzyl)acetamide (4.1 g, 16.0 mmol) was stirred in concentrated sulfuric acid (10 mL) for 16 hours. The reaction mixture was poured onto ice and neutralized by the addition of ammonium hydroxide forming a precipitate which was removed by filtration. The filtrate was extracted with ethyl acetate three times, and the combined organic phases were rinsed with brine then dried (Na2SO4) and concentrated to dryness affording an oily solid. Trituration with ether afforded the title compound (1.56 g, 9.6 mmol, 60% over 2 steps). LC-MS (3) Rt=1.00 min; m/z (ESI+) 164 (M+H).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][NH:29][CH3:30]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:29]([CH3:30])[CH3:28])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CNC
Solvent: CC#N
Product: CN(C)CC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N-methylmethanamine (0.5 ml, 2.0 M in MeOH), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 289 (M+, 1), 84 (2), 69 (2), 59 (3), 58 (bp).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH2:15][CH:16]=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH:18][C:19]1([CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH2:30][S:29]C2CCCC2C=CC(C(O)=O)=CC=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[OH:18][C:19]1([CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH2:30][S:29][CH:16]2[CH2:15][CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[Cl:1])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)c1ccc(CCCC=O)c(Cl)c1
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Product: CCOC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)c(Cl)c1

Procedure:
This compound is prepared by the method described in Example 2, Step B, except that an equivalent quantity of ethyl 3-chloro-4-(4-oxobutyl)benzoate is substituted for the ethyl 4-(4-oxobutyl)benzoate of Example 2, Step B. The title compound is obtained as a viscous, brownish oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC(C)(N)CO
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNC(C)(C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and 2-amino-2-methyl-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H35N6O5SF2 [(M+H)+] 557.2352, observed 557.2359.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:28]([C:29]([NH2:31])=[O:30])=[C:17]3[NH:18][CH2:19][CH2:20][C@@H:21]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:16]3[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([CH2:48]/[CH:49]=[CH:50]/[C:51](O)=[O:52])[CH2:44][CH2:43]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:29]([C:28]1[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[N:15][N:16]2[C@H:21]([CH:22]3[CH2:23][CH2:24][N:25]([C:51](=[O:52])/[CH:50]=[CH:49]/[CH2:48][N:45]4[CH2:46][CH2:47][N:42]([CH2:41][CH2:40][NH:39][C:37](=[O:38])[O:36][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:43][CH2:44]4)[CH2:26][CH2:27]3)[CH2:20][CH2:19][NH:18][C:17]=12)(=[O:30])[NH2:31]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC[C@H]2C1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCN1CCN(C/C=C/C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN1CCN(C/C=C/C(=O)N2CCC([C@@H]3CCNc4c(C(N)=O)c(-c5ccc(Oc6ccccc6)cc5)nn43)CC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.9 %

Procedure:
A mixture of (S)-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (1.26 g, 3.03 mmol), (E)-4-(4-(2-((tert-butoxycarbonyl)amino)ethyl)piperazin-1-yl)but-2-enoic acid (948.4 mg, 3.03 mmol), HATU (1.21 g, 3.18 mmol), DIEA (782 mg, 6.06 mmol) in 30 mL of DMF was stirred at RT for 15 hr. The mixture was poured into 300 mL of water and extracted with EA (100 mL). The organic phase was washed with water (100 mL×3) and concentrated to give 1.25 g (58%) of product as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J=8.4 Hz, 2H), 7.42 (t, J=8.4 Hz, 2H), 7.17 (t, J=7.4 Hz, 1H), 7.12-7.02 (m, 4H), 6.67 (br s, 1H), 6.64-6.53 (m, 3H), 4.53-4.40 (m, 1H), 4.14-4.05 (m, 1H), 3.32-3.25 (m, 2H), 3.10-2.91 (m, 5H), 2.45-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.96-1.84 (m, 1H), 1.78-1.65 (m, 1H), 1.62-1.50 (m, 1H), 1.37 (s, 9H), 1.31-1.10 (m, 3H). MS (ESI) m/e [M+1]+713.0.
Reaction SMILES: [C:1]([C:3]1[C:7]([OH:8])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:21][C:6]1[N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:11][C:10]=2[Cl:20])[N:4]=[C:3]([C:1]#[N:2])[C:7]=1[OH:8]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1O
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-hydroxypyrazole (1.0g) and N-bromosuccinimide (0.55g) in chloroform (20ml) was stirred at room temperature for 75 minutes, then washed with water (3×20 ml), filtered through phase-separation paper and evaporated. The residue was purified by dry-column chromatography (eluant ether: hexane 1:1 then 3:1) to give 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-hydroxypyrazole as a buff colored solid, m.p. 145°-151° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:5]([CH2:7][C:8](OCC)=[O:9])=O.[ClH:17].[NH2:18]O.C(N(CC)CC)C>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:7]=[C:8]([Cl:17])[O:9][N:18]=2)[CH:13]=[C:14]([F:16])[CH:15]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)c1cc(F)cc(F)c1
Reactant: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Fc1cc(F)cc(-c2cc(Cl)on2)c1
Yield: 34 %

Procedure:
A mixture of ethyl 3,5-difluorobenzoylacetate (1.87 g, 8.19 mmol) and hydroxylamine hydrochloride (626 mg, 9.01 mmol) in acetic acid (24 ml) is stirred at reflux for 1 hr. The crude reaction mixture is concentrated in vacuo and azeotroped with toluene twice. The crude material is suspended in phosphorus oxychloride (37 ml) and triethyl amine (2.37 ml, 17.1 mmol) is added slowly. The reaction mixture is stirred at reflux for 2 days, concentrated in vacuo and azeothroped with toluene 3 times. The residue is dissolved in dichloromethane and passed on a plug of silica gel (elution with dichloromethane. After concentration in vacuo, the crude material is purified by flash chromatography (silica gel, dry loading, 5% diethyl ether in hexane) to give 3-(3,5-difluorophenyl)-5-chloroisoxazole (600 mg, 35%) as an off-white solid.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9](C)([O-])[CH3:10].[K+].C(Br)C=C.O>O1CCCC1>[CH:1]1([O:7][CH2:10][CH:9]=[CH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: OC1CCCCC1
Agent: CC(C)(C)O[K]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: C=CCBr
Product: C=CCOC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 870 g of tetrahydrofuran were dissolved 200 g (2 mol) of cyclohexanol and 224 g (2 mol) of potassium t-butoxide. With stirring at room temperature, 242 g (2 mol) of allyl bromide was added dropwise so that the temperature might not exceed 60° C. At the end of addition, the solution was heated at 60° C. on an oil bath and ripened for one hour at the temperature. The solution was allowed to cool down to room temperature, and 11.2 g (0.1 mol) of t-butoxypotassium was added. With stirring at room temperature, 12.1 g (0.1 mol) of allyl bromide was added dropwise. The solution was heated at 60° C. on an oil bath and ripened for one hour at the temperature. The solution was cooled in an ice bath, and 550 g of water was added. The organic layer was collected. The solvent was distilled off in vacuum, yielding 280 g of a crude end product. The product was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[CH2:4][CH2:3]1.CS([C:18]1[N:23]=[CH:22][C:21]2=[CH:24][CH:25]=[C:26]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[N:20]2[N:19]=1)=O>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH:11][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=5)[N:20]4[N:19]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: Cn1cc(-c2ccc3cnc(S(C)=O)nn23)cn1
Product: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cnn(C)c5)n4n3)c2)CC1
Yield: 29.6 %

Procedure:
3-(4-Methylpiperazin-1-yl)aniline (0.110 g, 0.574 mmol) and 2-Methanesulfinyl-7-(1-methyl-1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazine (0.100 g, 0.383 mmol) were reacted in an analogous manner to Example 881D at 170° C. for 4 hours. Product was purified on Gilson HPLC, lyophilized and free-based with NaHCO3 to afford title compound as a yellow solid (44 mg, 27%) LC/MS: 389 (M+H)HPLC: retention time 1.781 minutes, purity=90%. 1H NMR (400 MHz, DMSO, δ, ppm): 9.65 (br s, 1H), 9.26 (s, 1H), 8.88 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 7.32 (d, J=6.69 Hz, 2H), 7.26 (dd, J=8.61, 8.13 Hz, 1H), 7.04 (d, J=4.8 Hz, 1H), 6.91 (d, J=4.8 Hz, 1H), 6.68 (d, J=7.4 Hz, 1H), 3.94 (s, 3H), 3.78 (d, J=13.0 Hz, 2H), 3.52 (d, J=12.0 Hz, 2H), 3.18-3.16 (m, 2H), 3.00-2.93 (m, 2H), 2.88 (d, J=4.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]=O>C(O)(=O)C>[C:21]([O:20][C:18]([C:10]12[CH2:16][C:14]3([OH:25])[CH2:13][CH:12]([CH2:17][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([CH2:15]3)[CH2:9]1)[CH2:11]2)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)C12CC3CC(C1)CC(C(=O)OC(C)(C)C)(C3)C2
Reactant: O=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C12CC3CC(O)(C1)CC(C(=O)OC(C)(C)C)(C3)C2

Procedure:
A mixture of 10 mmol of the obtained 1.3-di(t-butoxycarbonyl)adamantane, 2 mmol of NHPI, 0.1 mmol of acetylacetonatocobalt Co(AA)2, and 25 ml of acetic acid was stirred in an atmosphere of oxygen at 75° C. for 6 hours. As a result, there was obtained 1,3-di(t-butoxycarbonyl)-5-hydroxyadamantane.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[ClH:31].[CH2:38]([N:37]([CH3:36])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)cc2)C3)cc1
Reactant: CCCCNC
Product: CCCCN(C)CCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)cc2)C3)cc1
Product: Cl

Procedure:
This product was synthesized as described in general procedure 2 except 4-(6-(4-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate was used instead of 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and N-methylbutan-1-amine was used instead of piperidine to afford N-(4-(2-(butyl(methyl)amino)ethyl)phenyl)-6-(4-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine hydrochloride. M.p.=145-150° C. 1H NMR 400 MHz (DMSO) δ 10.33 (bs, 1H), 9.65 (s, 1H), 8.35-8.30 (m, 2H), 7.81 (d, J=8.8 Hz, 2H), 7.54-7.45 (m, 2H), 7.36-7.31 (m, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.16-7.09 (m, 3H), 4.44 (t, J=6.4 Hz, 1H), 3.35-2.95 (m, 8H), 2.79 (d, J=4.8 Hz, 3H), 1.72-1.63 (m, 2H), 1.39-1.30 (m, 2H), 0.92 (t, J=7.2, 3H). LCMS m/e 495 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([NH2:21])=[C:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33](OCC)(OCC)OCC>C(OC(=O)C)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]3[C:20]=2[N:21]=[CH:33][N:22]3[C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2N)CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2ncn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 140 °C

Procedure:
4-[5-Amino-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.6 mmol) was dissolved in mixture of triethyl orthoformate (4 mL) and acetic anhydride (4 mL), and then the mixture was refluxed at 140° C. for 15 hours. The crude product was quenched with saturated sodium bicarbonate and extracted with ethyl acetate, then dried in vacuo. Solid was precipitated out in acetonitrile/water and provided Compound B4 as a peach solid (205 mg, 67%). 1H NMR (CDCl3, 400 MHz) δ 1.48 (s, 9H), 1.95-1.91 (m, 2H), 2.14-2.11 (m, 2H), 3.12 (s, 3H), 3.34-3.27 (m, 2H), 3.94-3.91 (m, 2H), 5.61 (m, 1H), 8.06 (d, 2H), 8.19 (d, 2H), 8.29 (s, 1H), 8.61 (s, 1H). Exact mass calculated for C22H27N5O5S 473.17, found 474.3 (MH+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12]([CH:14]1[CH2:26][CH2:25][N:17]2[C:18]3[C:23]([CH:24]=[C:16]2[CH2:15]1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH3:10].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25][N:17]2[C:18]3[C:23]([CH:24]=[C:16]2[CH2:15]1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH3:10]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1CCn2c(cc3ccccc32)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(cc3ccccc32)C1
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a -78° C. THF (12 mL) solution of lithium diisopropylamide (generated in situ from diisopropylamine (3.8 mL) and 15% n-butyl lithium in hexane (17 mL) at 0° C.) was added dropwise a THF solution of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylic acid ethyl ester. After 30 minutes, the temperature was brought to 0° C. After 1 hour, ethyl chloroformate (2.6 mL) was added over one hour. The reaction was allowed to come to room temperature overnight. The reaction was quenched with saturated NH4Cl and extracted t-butyl methyl ether (3×). The extract was washed with water, dried, filtered, and concentrated to give a residue. The residue was purified by flash chromatography eluting with 15% ethyl acetate/hexane to give the title compound 1.29 g (33% yield) as off white crystals (M. Pt. 69° C.).
Reaction SMILES: [N:1]#[N:2].[N+:3]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[C:11]2[S:16]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])(=[O:18])=[O:17])([O-:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(O)CCC.C1C=CC=CC=1>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[CH2:37]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:16]([C:11]1[C:12]2[C:7](=[C:6]([N+:3]([O-:5])=[O:4])[CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:18])=[O:17])[CH2:32][CH2:33][CH3:34]
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1cccc2c([N+](=O)[O-])cccc12)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: c1ccccc1
Solvent: CCCCO
Solvent: O
Product: CCCCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c([N+](=O)[O-])cccc12
Yield: 95 %

Procedure:
A mixture of 1.0 gram of N2 -(5-nitro-1-naphthalenesulfonyl)-L-arginine, 1.0 gram of p-toluenesulfonic acid monohydrate in 5 ml of n-butyl alcohol and 30 ml of benzene was refluxed for 5 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 100 ml of ethyl ether was added to the residue, giving a crystalline mass of N2 -(5-nitro-1-naphthalenesulfonyl)-L-arginine butyl ester p-toluenesulfonate in 95% yield; mp. 94° - 95° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O)=CC=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([CH2:12][CH2:13][C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[N+:21]=[N-:22]
Reactant: Cc1ccc(S(=O)(=O)OCCC#C[Si](C)(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#CCCN=[N+]=[N-]
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of 4-(trimethylsilyl)but-3-ynyl 4-methylbenzenesulfonate (1.38 g; 4.65 mmol) and sodium azide (0.908 g; 13.96 mmol) in DMF (5 mL) was heated at 60° C. for 2 hours and concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with an aqueous solution of saturated ammonium chloride, dried and concentrated under reduced pressure to yield 0.700 g (90%) of (4-azidobut-1-ynyl)trimethylsilane which was used without further purification.
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)[N:9]=2.[S:32]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([CH3:35])(=[O:34])=[O:33]>ClCCl.CO>[CH:29]1([CH2:28][N:7]2[C:6]([N:39]3[CH2:40][CH2:41][N:36]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:37][CH2:38]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:31][CH2:30]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CC1
Reaction time: 4 h
Yield: 66.7 %

Procedure:
A dimethyl sulfoxide solution (1.0 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (101.9 mg, 0.26 mmol) and N-mesylpiperazine (125.8 mg, 0.77 mmol) was heated at 140° C. and stirred for 4 hours followed by the addition of N-mesylpiperazine (83.8 mg, 0.51 mmol) and the resulting mixture was further stirred at 140° C. for 3 hours. The reaction mixture was left standing to cool followed by the addition of dichloromethane-methanol (10:1) and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the reaction mixture was filtrated, then the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=15:1) to give the title compound (89.2 mg, 68%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[OH:8][CH2:9][C:10]1C=CNN=1.S(Cl)(Cl)=[O:16].[Na]>C(O)CO>[OH:8][CH2:9][CH2:10][O:16][CH2:2][C:3]1[CH:7]=[CH:6][NH:5][N:4]=1
Reactant: ClCc1cc[nH]n1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc[nH]n1
Agent: [Na]
Solvent: OCCO
Product: OCCOCc1cc[nH]n1

Procedure:
3-Chloromethylpyrazole, prepared by reacting 3-hydroxymethylpyrazole with thionyl chloride, is reacted with the sodium salt of ethylene glycol to give 3-(2-hydroxyethoxymethyl)-pyrazole. Treatment of 3-(2-hydroxyethoxymethyl)pyrazole with thionyl chloride gives 3-(2-chloroethoxymethyl)pyrazole.