Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([NH:10][CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:1][C:36]([NH:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])=[O:12])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: NC(c1ccccc1)C(NC(=O)Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)NC(c1ccccc1)C(NC(=O)Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [R-(R*,R*)] and [S-(R*,R*)]N-(2-amino-1,2 -diphenylethyl)-N'-(4-nitrophenyl)urea (0.1 g, 0.27 mmol) in dichloromethane (10 mL) is added phenyl isocyanate (0.03 g, 0.27 mmol) in one portion. The resulting mixture is stirred 1 hour at room temperature before filtering off the solid product. The product is suspended in hot diethyl ether, filtered, and dried in vacuo at 114° C. for 4 hours, mp 246°-247° C. IR (KBr): 3355, 1656, 1554, 1498, 1330, 1233, 699 cm-1 ; NMR (DMSO-d6): 5.03 (m, 2H), 6.55-7.37 (m, 17H), 7.59 (d, 2H, J=9.2 Hz), 8.11 (d, 2H, J=9.2 Hz), 8.60 (s, 1H), 9.43 (s, 1H). Analysis calculated for C28H25 5O4.1.0H2O: C, 65.49; H, 5.30; N, 13.64. Found: C, 65.44; H, 5.03; N, 13.77.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3].[Cl:31]C1C2C=CC=CC=2C2C(=C3C(=C(C=O)C=2)C=CC=C3)C=1.NC(C)(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[C:22]([Cl:31])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=Cc1cc2c3ccccc3c(Cl)cc2c2ccccc12
Agent: CC(N)(CO)CO
Product: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3c(Cl)cc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined in 1C, 12-chloro-6-chrysenecarbaldehyde (4A), and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((12-chloro-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate.1/3H2O mp 233°-233.5° (dec), (EtOH/Et2O), (C, H, Cl, N, S).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:18].[Al+3].[Cl-].[Cl-].[Cl-].Cl.CCOC(C)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:18]
Reactant: COc1ccc(C(=O)c2ccc(Br)c(F)c2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(c1ccc(O)cc1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 112.1 %

Procedure:
To a stirred solution of (4-bromo-3-fluorophenyl)[4-(methyloxy)phenyl]methanone (185) (3.20 g, 10.4 mmol) in benzene (80 mL) was slowly added AlCl3 (5.91 g, 44.2 moL., 4.3 eq) via a powder addition funnel under a nitrogen atmosphere at room temperature. The stirred reaction mixture was heated at reflux for 3 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and then poured onto a mixture of 1 N HCl (150 mL) and ice (300 g). The quenched reaction mixture was transferred to a separatory funnel and EtOAc (200 mL) added. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic phase washed with brine (200 mL), dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give 3.44 g of a brown solid. Crystallization from toluene yielded 2.68 g (88%) of the title compound 186 as a brown crystalline solid. 1H NMR (400 MHz, DMSO-d6): δ 6.91 (d, J=8.7 Hz, 2 H), 7.43 (d, J=8.2 Hz, 1 H), 7.61 (d, J=8.2 Hz, 1 H), 7.69 (d, J=8.7 Hz, 2 H), 7.89 (t, J=7.1 Hz, 1H), 10.54 (s, 1 H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:35][C:36]1[CH:37]=[C:38]([N:43]2[C:47](=[O:48])[C@@:46]3([C@H:52]([C:53]4[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=4)[CH2:51][NH:50][CH2:49]3)[N:45]([CH3:61])[C:44]2=[O:62])[CH:39]=[C:40]([Cl:42])[CH:41]=1>CN(C=O)C>[Cl:35][C:36]1[CH:37]=[C:38]([N:43]2[C:47](=[O:48])[C@@:46]3([C@H:52]([C:53]4[CH:54]=[CH:55][C:56]([C:57]#[N:58])=[CH:59][CH:60]=4)[CH2:51][N:50]([C:11]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[N:4]5)=[O:13])[CH2:49]3)[N:45]([CH3:61])[C:44]2=[O:62])[CH:39]=[C:40]([Cl:42])[CH:41]=1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Reactant: O=C(O)c1ccc2nccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(C(=O)c1ccc3nccnc3c1)C[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
To a solution of quinoxaline-6-carboxylic acid (56.2 mg, 0.318 mmol) in 7 ml DMF were added EDCI (62 mg, 0.32 mmol), TEA (53.9 μl, 0.38 mmol) and HOBt (49.3 mg, 0.36 mmol). After 30 min, a solution of Example 15 (103.4 mg, 0.249 mmol) in 1 ml DMF was added. The reaction mixture was then stirred overnight at RT before evaporation to dryness. The residue was partitioned between DCM (50 ml) and 1N solution of HCl (20 ml). The DCM layer was washed with 10% solution of sodium carbonate (2×20 ml), dried over sodium sulfate, concentrated and purified by reverse phase HPLC (gradient from CH3CN/H2O/TFA: 5/95/0.05 to CH3CN/H2O/TFA: 80/20/0.05) to yield the titled compound (35 mg). Retention time: 2.16 min., 571 (M+1) (LCMS conditions: LC Micromass platform (APCI+, DAD (210-400 nm)), Column: TSK gel Super ODS 4.6 mm ID×5 cm, Flow rate: 2.75 mL/min, Gradient: from 100% eluent A to 100% eluent B in 2 min., with a plateau with 100% eluent B during 1 min. Eluent A: H2O (0.05% TFA), Eluent B: CH3CN/H2O/TFA (80/20/0.05)).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:21][C:22]([F:39])([F:38])[CH:23]([C:28]1[CH:29]=[CH:30][C:31]([O:36][CH3:37])=[C:32]([CH:35]=1)[CH:33]=O)[C:24]([F:27])([F:26])[F:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:33][C:32]2[CH:35]=[C:28]([CH:23]([C:22]([F:39])([F:21])[F:38])[C:24]([F:25])([F:26])[F:27])[CH:29]=[CH:30][C:31]=2[O:36][CH3:37])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Yield: 103.7 %

Procedure:
To a stirred and ice-cooled solution of Compound 12 (100 mg, 0.3 mmol) and Compound 9 (100 mg, 0.3 mmol) in dry CH2Cl2 (10 ml) was added NaBH(OAc)3 (210 mg, 1 mmol) in one portion. After the mixture was stirred at room temperature for 20 hours. The mixture was poured into NaHCO3 aq., and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated in vacuo to give Compound 13 as a yellow oil (170 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[C:3]=12.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C@@H:27]2[CH2:26][CH2:25][C@H:24]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([C:11]4[CH:12]=[N:13][C:14]([O:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:15][CH:16]=4)=[N:9]3)[CH2:29][CH2:28]2)[CH2:34][CH2:33]1
Reactant: CN1CCNCC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)nc1)nn2C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 0.17 h

Procedure:
A mixture of 4-[4-amino-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclo-hexanone (Intermediate AI) (0.90 g, 0.0022 mol), N-methylpiperazine (0.676 g, 0.0067 mol) and acetic acid (0.405 g, 0.0067 mol) in 1,2-dichloroethane (40 mL) was stirred for 10 min and sodium triacetoxyborohydride (0.62 g, 0.0029 mol) was added at once. The mixture was stirred at ambient temperature under an atmosphere of nitrogen for 24 hours and sodium triacetoxyborohydride (0.30 g, 0.0014 mol) was added. The mixture was stirred for another 48 hours, the solvent removed under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate solution (80 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer further extracted with dichloromethane twice (50 mL). The combined organic extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to yield a yellow oil. The compound was further purified by flash chromatography on silica gel using dichloromethane/triethylamine/methanol (89:10:1) as a mobile phase to yield cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AJ): TLC (dichloromethane/triethylamine=9:1) Rf 0.29 and trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: TLC (dichloromethane/triethylamine=9:1) Rf 0.14.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[C:6](C(OCC)=O)[C:7](=[O:15])[NH:8]2)[CH3:2]>O.O1CCOCC1.Cl>[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[CH:6][C:7](=[O:15])[NH:8]2)[CH3:2]
Reactant: CCOC(=O)c1c(O)c2c(CC)nc(CC)cc2[nH]c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc2[nH]c(=O)cc(O)c2c(CC)n1
Yield: 55.9 %

Procedure:
Compound B (1 g) was dissolved in a mixture of water (1 ml), 1,4-dioxan (2 ml) and concentrated hydrochloric acid (1 ml) and the mixture was heated at reflux for 3 hours. The reaction mixture was then cooled and the suspended solid was collected by filtration. The solid was washed with ethanol and ether and dried under vacuum to give 5,7-diethyl-4-hydroxy-1,6-naphthyridin-2(1H)-one (C) (0.42 g), m.p. 322°-325° C.; NMR (d6 -DMSO): 1.3(dt, 6H), 2.99(q, 2H), 3.47(q, 2H), 6.0(s, 1H), 7.28(s, 1H), 12.3(s, 1H); mass spectrum (CI, ammonia): 219 (M+H)+ ; microanalysis, found: C, 55.7; H, 5.9; N, 10.5%; C12H14N2O2.HCl.0.25H2O requires: C, 55.6; H, 5.6; N, 10.8%.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH:12]([CH3:16])[C:13]([NH2:15])=[O:14])[C:3]1=[O:17]>CC(O)=O.[Zn]>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH:12]([CH3:16])[C:13]([NH2:15])=[O:14])[C:3](=[O:17])[CH2:2]2
Reactant: CC(C(N)=O)N1C(=O)C(Br)(Br)c2cc(Cl)ccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C(N)=O)N1C(=O)Cc2cc(Cl)ccc21
Reaction time: 1 h

Procedure:
Zinc dust (23.71 g, 0.58 mol) was added to a stirred solution of compound 31 (theorical: 58.4 mmol) in AcOH (110 ml) at 0° C. After 1 hour, the reaction mixture was filtered through a Celite pad. The filtrate was diluted with AcOEt and cold water. The pH was adjusted to 7 and the layers were separated. The aqueous phase was extracted again with AcOEt. Organic layers were dried over Na2SO4 and concentrated. The beige solid was cristallized in AcOEt and afforded 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide 32 as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[C:28]([CH3:35])[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:45][C@@H:46]1[NH:51][CH2:50][CH2:49][N:48]([S:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:47]1>CN(C=O)C>[F:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([N:51]2[CH2:50][CH2:49][N:48]([S:52]([C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=3)(=[O:53])=[O:54])[CH2:47][C@@H:46]2[CH3:45])=[O:34])=[C:28]([CH3:35])[CH:27]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: Cc1cc(F)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(F)ncc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
HATU (440 mg, 1.16 mmol) was added to a solution of 6-fluoro-4-methyl-3-pyridinecarboxylic acid (supplied by Frontier Scientific) (150 mg, 0.97 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.422 ml, 2.42 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (358 mg, 1.16 mmol) was added and stirring was continued for 1.25 h. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organic layers were concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in hexanes, gave the title compound (432 mg) as a yellow gum.
Reaction SMILES: O.OO.N[C:5]([NH2:7])=[O:6].[OH-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:42][CH2:41][C:20]2([CH2:23][N:22]([C@H:24]3[C:32]4[C:27](=[CH:28][C:29]([C:33]5[CH:34]=[N:35][C:36](C#N)=[CH:37][CH:38]=5)=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH2:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CCO>[C:10]([O:14][C:15]([N:17]1[CH2:42][CH2:41][C:20]2([CH2:23][N:22]([C@H:24]3[C:32]4[C:27](=[CH:28][C:29]([C:33]5[CH:34]=[N:35][C:36]([C:5](=[O:6])[NH2:7])=[CH:37][CH:38]=5)=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH2:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ccc(C#N)nc4)ccc31)C2
Reactant: NC(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ccc(C(N)=O)nc4)ccc31)C2
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a solution of water (150 mL) and urea hydrogen peroxide (916 mg, 9.45 mmol) was added sodium hydroxide (220 mg, 5.51 mmol) and the reaction was stirred at room temperature. Once a clear solution was obtained, the reaction was placed in an ice bath and fitted with an addition funnel. A solution of 2-[(R)-5-(6-cyano-pyridin-3-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (4-1c, 700 mg, 1.58 mmol) in 50 mL EtOH was added dropwise via the funnel over 30 minutes. The reaction was warmed to room temperature and was stirred overnight. The reaction mixture (a white suspension) was filtered and the solids were washed with 50 mL water and air-dried to give 440 mg (60%) of the title compound as an off-white powder. MS (ES+) 463.1 (M+H)+. 1H NMR (DMSO-d6) δ 1.39 (s, 9H), 1.54-1.62 (m, 4H), 1.81-1.91 (m, 1H), 2.06 (dd, 1H), 2.76-2.87 (m, 1H), 2.94-3.02 (m, 3H), 3.10 (d, 2H), 3.24 (br s, 4H), 3.86 (dd, 1H), 7.40 (d, 1H), 7.55 (d, 1H), 7.62-7.68 (m, 2H), 8.09 (d, 1H), 8.12 (br s, 1H), 8.22 (dd, 1H), 8.89 (d, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:45])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][C@H](N)[CH2:40][CH2:39]2)=[O:36])[CH:12]=[CH:13][CH:14]=1.[S:46]([NH2:50])([NH2:49])(=[O:48])=[O:47]>C1COCC1>[Cl:8][C:9]1[C:10]([F:45])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][CH:38]2[CH2:43][CH2:42][N:49]([S:46]([NH2:50])(=[O:48])=[O:47])[CH2:40][CH2:39]2)=[O:36])[CH:12]=[CH:13][CH:14]=1
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N[C@H]2CC[C@H](N)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCN(S(N)(=O)=O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 110 °C
Reaction time: 0.42 h

Procedure:
To a stirred solution of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-trans-cyclohexylamine trifluoroacetic acid salt (50 mg, 0.091 mmol) in THF (3 mL), sulfamide (Aldrich, 40 mg, 0.416 mmol) was added and the mixture was stirred at 110° C. for 25 min. on microwave oven. The reaction was quenched with addition of water. The mixture was extracted with EtOAc (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC (25-90, acetonitrile/water) to give a white solid. 49 mg.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27].C(N(CC)CC)C.C(#N)C>[Cu]I>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([O:12][CH2:11][C:8]3[N:6]4[N:7]=[C:2]([C:29]#[C:28][C:26]([CH3:27])([OH:30])[CH3:25])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[CH:14][CH:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: C#CC(C)(C)O
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2c(OCc3nnc4ccc(C#CC(C)(C)O)nn34)ccnc2c1
Temperature: 90 °C
Yield: 51.3 %

Procedure:
A 25×200 mm test tube was charged with 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.150 g, 0.439 mmol), 2-methylbut-3-yn-2-ol (0.213 ml, 2.19 mmol), copper (I) iodide (0.0209 g, 0.110 mmol), triethylamine (1.83 ml, 13.2 mmol), and acetonitrile (5.00 ml, 96.2 mmol), flushed with argon, sealed, and placed in a 90° C. oil bath for 30 minutes. PdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol) was added in one portion, the tube flushed with argon, sealed, then heated in a 90° C. oil bath for 4 hours. The reaction mixture was filtered thru a pad of silica gel (eluting with EtOAc/DCM/MeOH), then concentrated to yield a dark brown oil. This was purified by MPLC, using a 40 g RediSep column, eluting with 1-7% MeOH/DCM over 40 minutes. The appropriate fractions were collected to give 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylbut-3-yn-2-ol (0.0877 g, 51.3% yield). MS (ESI pos. ion) m/z: 390 (MH+). Calc'd exact mass for C21H19N5O3: 389.
Reaction SMILES: [H][H].[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH:3]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: c1ccccc1
Reactant: [H][H]
Product: c1ccc(C2CCCCC2)cc1

Procedure:
contacting benzene and hydrogen under hydroalkylation conditions to produce cyclohexylbenzene;
Reaction SMILES: [C:1]([O:10]CC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[NH2:14][NH2:15]>C(O)C>[C:1]([NH:14][NH2:15])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)OCC
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCCCCCC(=O)NN
Reaction time: 15 h

Procedure:
Production of the spacer-gel derivative: Ethyl caprylate was converted into the corresponding hydrazide by hydrazinolysis, by initially admixing 10 ml. of this ethyl ester with 10 ml. of 98% hydrazine hydrate. Ethanol (22 ml.) was added as solvent, until the reaction mixture cleared, following which the solution was left at room temperature for 15 hours. The crystallized out resulting caprylhydrazide was filtered off and washed with ice water and then with aqueous methanol (1:1) of room temperature.
Reaction SMILES: [H-].[Na+].[Si]([CH:10]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:12]=2[O:11]1)(C(C)(C)C)(C)C.[CH3:23][O:24][C:25](=[O:28])[CH2:26]Cl.Cl>CN(C=O)C.O>[CH3:23][O:24][C:25](=[O:28])[CH2:26][N:14]1[C:13]2[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:12]=2[O:11][CH2:10][C:15]1=[O:16]
Reactant: COC(=O)CCl
Reactant: CC(C)(C)[Si](C)(C)C1Oc2ccc(CO)cc2NC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)COc2ccc(CO)cc21
Temperature: 0 °C
Yield: 70.2 %

Procedure:
To a suspension of NaH (0.3 g, 0.01 mol) in dry DMF (15 mL) was added TBDMS-6-(hydroxymethyl)2H-1,4-benzoxazin-3(4H)-one (2 g, 0.0068 mol) at 0° C. with stirring and allowed to stir at RT for 2 h. The reaction mixture was cooled to 0° C., added methylchloroacetate (1 g, 0.0088 mol) and stirred at RT for 12 h. The reaction mixture was further cooled to 0° C., added 50 mL of 1.5N HCl solution and stirred at RT for 12 h. The reaction mixture was diluted with water (200 mL), extracted with ethylacetate (3×150 mL). The combined organic layer was washed with 10% aqueous NaHCO3 solution, brine and dried. The solvent was removed under vacuum and crude purified by column chromatography over silica gel (CHCl3/Methanol, 99.5:0.5) to give methyl-[6-(hydroxymethyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate (1.2 g, 70%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][CH:13]([CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:12][C@@H:13]([CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(C)CCCCCO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC[C@H](C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A solution of p-toluenesulfonyl chloride (19.9 g, 0.1 mol) dissolved in toluene (30 ml) was dropwise added with stirring under ice cooling, to a solution of 6-methyloctanol (15.4 g, 0.1 mol) prepared according to the method of a literature (M.C.L.C. 27,417 (1974)) and dissolved in dry pyridine (43 ml), followed by slowly returning the temperature to room temperature, allowing the resulting material to stand overnight, extracting the reaction mixture with toluene after completion of the reaction, washing the resulting organic layer with 6N-hydrochloric acid, then with 2N-NaOH aqueous solution, further with water until the washing water became neutral, drying the layer, and distilling off toluene to obtain oily (S)-6-methyloctyl-p-toluenesulfonate (26.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](/[N:14]=[C:15](\N(C)C)/C)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:20][C:21]1[CH:26]=[C:25]([NH:27][NH2:28])[N:24]=[C:23]([CH3:29])[N:22]=1>C(O)(=O)C>[Cl:20][C:21]1[CH:26]=[C:25]([N:27]2[C:12]([CH2:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:14][CH:15]=[N:28]2)[N:24]=[C:23]([CH3:29])[N:22]=1
Reactant: COc1ccc(CC(=O)/N=C(/C)N(C)C)cc1OC
Reactant: Cc1nc(Cl)cc(NN)n1
Solvent: CC(=O)O
Product: COc1ccc(Cc2ncnn2-c2cc(Cl)nc(C)n2)cc1OC

Procedure:
A solution of (Z)-2-(3,4-dimethoxyphenyl)-N-(1-(dimethylamino)ethylidene)acetamide (1-2, 90 mg, 0.360 mmol, 1.0 eq) and 4-chloro-6-hydrazinyl-2-methylpyrimidine (57 mg, 0.360 mmol, 1.0 eq) in acetic acid (3 ml) was heated at 90° C. for 30 min. The reaction appeared complete by LCMS. The reaction mixture was concentrated and partitioned between dichloromethane (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to afford 4-chloro-6-(5-(3,4-dimethoxybenzyl)-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (1-3). 1H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.79 (s, 1H), 6.80 (m, 3H), 4.74 (s, 2H), 3.84 (s, 3H), 3.83 (s, 311), 2.76 (s, 3H). LRMS m/z (M+H) 346.4 found, 346.1 required