Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][CH:33]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH3:34])=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[Br:41]C(F)(F)C(F)(F)Br>O1CCCC1>[Br:41][C:24]1[N:23]([C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])[C:31]2[C:26]([C:25]=1[CH2:32][CH:33]([N:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[CH3:34])=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: CC(Cc1cn(C(=O)OC(C)(C)C)c2ccccc12)N1CCCCC1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccccc12)N1CCCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (5.3 ml, 31.6 mmol) in anhydrous tetrahydrofuran (50 ml) cooled to −78° C. under an atmosphere of nitrogen was added in a dropwise manner n-butyllithium (12.6 ml of a 2.5M solution in hexanes, 31.6mmol). On complete addition the reaction mixture was allowed to warm to 0° C. and stirred at this temperature for 5 minutes. Re-cooled to −78° C. and a solution of the 1-tert-butoxycarbonyl-3-[2-(piperidin-1-yl)prop-1-yl]-1H-indole in anhydrous tetrahydrofuran (50 ml) added via a cannula at such a rate that the temperature did not rise above −50° C. On complete addition the reaction mixture was stirred at −78° C. for 4 hours then 1,2-dibromotetrafluoroethane (3.78 ml, 31.6 mmol) added; the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed in vacuo and the residue purified by column chromatography on silica eluting with 2% CH3OH in CH2Cl2+0.5% 0.88 ammonia to give the title compound (1.5 g, 34%); δH (360 MHz; CDCl3) 1.32 (3H, d, J 6.7 Hz, CH3), 1.71 (9H, s, O2C(CH3)3), 2.99-3.05 (1H, m, indole CHAHB), 3.55-3.67 (1H, m, indole CHAHBCH), 3.74 (1H, d, J 13.2 Hz, indole CHAHB), 7.26-7.33 (2H, m, indole H5+H6), 7.92 (1H, dd, J 6.6 and 3.7 Hz, indole H4), 8.05 (1H, d, J 5.8 and 2.2 Hz, indole H7), piperidine protons very broad and merged into baseline; m/z (ES+) 421/423 (M++H, 100%).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[N:38][C:39]([O:47][CH3:48])=[C:40]([CH:46]=1)[C:41]([N:43]([CH3:45])[CH3:44])=[O:42]>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:37]=[N:38][C:39]([O:47][CH3:48])=[C:40]([CH:46]=2)[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ncc(Br)cc1C(=O)N(C)C
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Product: COc1ncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cc1C(=O)N(C)C
Yield: 38 %

Procedure:
The title compound was synthesized as described for Intermediate I-28 in 38% yield starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman -3-amine and 5-bromo-2-methoxy-N,N-dimethylnicotinamide. The reaction mixture was irradiated in a microwave at 140° C. for 45 min: 1H NMR (400 MHz, DMSO-d6) ppm 8.19 (d, 1 H), 7.68 (d, 1 H), 7.25-7.40 (m, 8 H), 7.11-7.22 (m, 3 H), 6.70-6.80 (m, 2 H), 4.32-4.38 (m, 1 H), 3.97-4.04 (m, 1 H), 3.96 (s, 3 H), 3.62-3.75 (m, 4 H), 3.02-3.13 (m, 2 H), 2.99 (s, 3 H), 2.91-2.98 (m, 1 H), 2.85 (s, 3 H); MS (ESI) m/z 508[M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C=O)C>[Br:19][C:15]1[C:14]([CH3:18])=[C:10]([C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A solution of Example 104A (10 g, 40 mmol) and tetrabutylammonium tribromide (19.2 g, 40 mmol) in DMF (250 mL) was treated slowly with water (250 mL). The resulting suspension was stirred for 18 hours and partitioned between water (1.2 L) and ethyl acetate (500 mL). The organic layer was washed with water (2×1 L), dried (Na2SO4), filtered, and concentrated. The residue was dissolved in dichloromethane (900 mL), washed with water (5×1 L) and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (11.7 g). MS (ESI(−)) m/e 328, 330 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.60 (br s, 1H), 9.68 (s, 1H), 7.63 (d, 1H), 7.39 (d, 1H), 2.37 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:19].CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:19]=[CH:22][N:23]([CH3:25])[CH3:24]
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Temperature: 140 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-2-methyl-3,4-dihydro-quinazolin-4-one (1.0 g, 3.69 mmol) and dimethylformamide dimethyl acetal (0.64 mL, 4.8 mmol) in dimethylformamide (4 mL) was heated to 140° C. for 24 hours. Additional dimethylformamide dimethyl acetal (0.32 mL, 2.4 mmol) was added and heating was continued for an additional 24 hours. The reaction was cooled to ambient temperature and concentrated at reduced pressure (60° C. bath temperature). The dark residue was triturated with methanol and the pale orange solid which formed was collected and dried to give 0.75 g (62%) of 3-(2-chloro-phenyl)-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one which had: mp 228-230° C.; 1H 1H NMR δ 8.19 (d, J=8 Hz, 1 H), 7.91 (d, J=12.3 Hz, 1 H), 7.71-7.18 (m, 7 H), 4.10 (d, J=12.3 Hz, 1 H), 2.81 (br s, 6 H). Analysis calculated for C18H16ClN3O: C, 66.36; H, 4.95; N, 12.90. Found: C, 66.20; H, 5.03; N, 12.79.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.BrC1C=CC(C2N([C:39]3C=C[C:42]([S:45](N)(=O)=O)=[N:43][CH:44]=3)N=C(C(F)(F)F)C=2Cl)=CC=1>>[S:45]1[CH:39]=[C:44]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]([C:13]4[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=4)[N:11]=[C:10]([C:23]([F:24])([F:25])[F:26])[CH:9]=3)=[CH:4][CH:3]=2)[N:43]=[CH:42]1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cn1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cscn3)cc2)cn1

Procedure:
The title compound was prepared according to the procedure of step 3 in the Example 4 using 5-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (Example 4, step 1), instead of 5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>>[C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: CCCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCCN1CCC(c2c[nH]c3ccc(NC(=O)CC)nc23)CC1
Yield: 684.5 %

Procedure:
Beginning with 0.10 gm (0.39 mMol) 5-amino-3-(1-propylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.040 mL (0.046 mMol) propionyl chloride, 0.099 gm (81%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:30]([CH3:32])[CH3:31])[C:27]([OH:29])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])C1C=CC=CC=1.[C:33]1([C:39]2[NH:40][C:41](C(OCC)=O)=[N:42][N:43]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:31][CH:30]([CH3:32])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:1]([C:41]4[NH:40][C:39]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[N:43][N:42]=4)=[O:8])=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)c1nnc(-c2ccccc2)[nH]1
Reactant: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4nnc(-c5ccccc5)[nH]4)cc3)cc2C1=O
Yield: 77 %

Procedure:
The compound of example 629 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 628.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][NH2:16])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([C:27](=O)[CH2:28][CH3:29])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25](/[C:27](=[N:16]/[NH:15][C:13](=[O:14])[C:12]2[CH:17]=[CH:18][CH:19]=[C:10]([S:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)(=[O:9])=[O:8])[CH:11]=2)/[CH2:28][CH3:29])[CH:26]=1
Reactant: CCC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CC(=O)O
Solvent: CO
Product: CC/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 31.6 %

Procedure:
3-(Morpholinosulfonyl)benzohydrazide (40 mg, 0.140 mmol) and 1-(5-chloro-2-hydroxyphenyl)propan-1-one (25.9 mg, 0.140 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (20 mg). 1H NMR (400 MHz, acetone-d6): δ 8.26 (m, 2H), 8.00 (d, 1H, J=7.6 Hz), 7.84 (t, 1H, J=8.0 Hz), 7.64 (d, 1H, J=2.4 Hz), 7.33 (m, 1H), 6.98 (d, 1H, J=9.2 Hz), 3.69 (m, 4H), 3.10 (q, 2H, J=7.6 Hz), 2.99 (m, 4H), 1.26 (t, 3H, J=7.6 Hz). ESI-MS: 452.1 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:10])([F:9])[S:5](F)(=[O:7])=[O:6]>ClCCl>[CH3:1][NH:2][S:5]([C:4]([F:10])([F:9])[F:3])(=[O:7])=[O:6]
Reactant: O=S(=O)(F)C(F)(F)F
Reactant: CN
Solvent: ClCCl
Product: CNS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A weighed pressure reactor (available from Parr Instrument Co., Moline, Ill.) is charged with dichloromethane (100 mL) and is then cooled using liquid nitrogen. Methylamine is introduced from a cylinder via a stainless steel tube that is connected to a valve on the reactor. The reactor is periodically weighed, and methylamine is added until 20 g have been added. Trifluoromethanesulfonylfluoride is then introduced into the reactor from a cylinder via a stainless steel tube until 97.9 g have been added. The pressure reactor is then sealed and is placed in a motorized rocker and is rocked and allowed to warm to room temperature. After a period of about 6 hours after the reactor reaches room temperature, it is slowly vented to the atmosphere by opening the valve. The product residue is washed with 10 weight percent aqueous HCl and the organic phase is then dried over MgSO4. The mixture is filtered and the solvent is removed from the filtrate using a rotary evaporator to afford the product.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[C:22](=[O:23])[N:21]([CH3:24])[C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[CH:12]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:25]1([NH:28][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]3[C:22](=[O:23])[N:21]([CH3:24])[C:14]4[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=4[CH:12]=3)[CH:4]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: CSc1ncc2cc(-c3cc(C(=O)O)ccc3C)c(=O)n(C)c2n1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 14.9 %

Procedure:
4-Methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzoic acid (150 mg, 0.44 mmol) was taken up in 2 mL DMF, and cyclopropylamine (50 mg, 0.88 mmol) was added, followed by EDCI (1.2 g, 0.527 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 90 minutes, then partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (EtOAc/hexanes 1:1) to give 25 mg of N-cyclopropyl-4-methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzamide MS (M+H)=381.
Reaction SMILES: C[Si:2]([CH3:12])([CH3:11])[N:3]([CH2:8][CH:9]=C)[Si:4]([CH3:7])([CH3:6])[CH3:5].[Cl:13]C([SiH3])Cl>C1(C)C(C)=CC=CC=1>[CH3:7][Si:4]([CH3:5])([CH3:6])[N:3]1[CH2:8][CH2:9][CH2:12][Si:2]1([Cl:13])[CH3:11]
Reactant: C=CCN([Si](C)(C)C)[Si](C)(C)C
Reactant: [SiH3]C(Cl)Cl
Solvent: Cc1ccccc1C
Product: C[Si](C)(C)N1CCC[Si]1(C)Cl
Temperature: 65 °C

Procedure:
N-trimethylsilyl-2-chloro-2-methy-1-aza-2-silacyclopentane (cyclic APMCS, which may be referred to as c-APMCS) was prepared as follows. To a 300 mL nitrogen purged bottle equipped with stir bar was added 20.1 g (0.1 mol) of N,N-bis(trimethylsilyl)allyl amine, 11.5 g (0.1 mol) of dichloromethylsilane, and 0.81 mL of 2.4 wt % Karsted's Catalyst in xylene. The solution was stirred for 72 hrs, then heated at 65° C. for 2 hrs, and heated at 100° C. for a further 3 days. The product was distilled at 85-90° C. at 25 mm Hg. GC/MS confirmed structure. Proton NMR was also used to determine structure.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=[CH:12][C:11]=1[N+:29]([O-])=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>[Pd].C1(C)C=CC=CC=1.CO>[NH2:29][C:11]1[CH:12]=[CH:13][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][C:10]=1[N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1N
Yield: 89.5 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-methyl-N-[2-nitro-5-(2-phenylphenoxy)phenyl]carbamate (8.3 g), palladium on carbon (10%, 0.66 g) and toluene/methanol=7/3 (100 ml) and the reaction mixture was purified to give the title compound (6.9 g).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7](=[O:10])[CH2:8][CH3:9])[C:4](=O)[CH3:5].[S-:11][C:12]#[N:13].[K+]>O>[CH3:5][C:4]1[NH:13][C:12](=[S:11])[NH:2][C:3]=1[C:7](=[O:10])[CH2:8][CH3:9]
Reactant: CCC(=O)C(N)C(C)=O
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCC(=O)c1[nH]c(=S)[nH]c1C

Procedure:
Ten grams of 3-amino-2,4-hexanedione hydrochloride are dissolved in 100 ml water. Fifteen grams of potassium thiocyanate are added and the mixture is heated on the steam bath for 10 minutes. On cooling, the title compound is obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16]C(C)(C)[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][S:23]([NH2:26])(=[O:25])=[O:24])[O:12]1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>CCO>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[C@@H:11]2[O:12][C@H:13]([CH2:21][NH:22][S:23]([NH2:26])(=[O:24])=[O:25])[C@@H:14]([OH:18])[C@H:15]2[OH:16])=[CH:30][CH:29]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNS(N)(=O)=O)O[C@H]2n1cnc2c(Cl)ncnc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)NC[C@H]1O[C@@H](n2cnc3c(NCc4ccc(F)cc4)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 0.17 h
Yield: 23.2 %

Procedure:
A solution of N-{[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl}sulfamide (25.0 mg, 0.0618 mmol), 4-fluorobenzylamine (14.1 μL, 0.124 mmol), and DIPEA (10.8 μL, 0.0618 mmol) in EtOH (0.4 mL) was heated at 100° C. for 10 minutes using microwave irradiation. Upon cooling, the mixture was concentrated and the residue dissolved in TFA/water (1 mL, 9:1). The solution was stirred for 10 minutes, concentrated, taken up in MeOH, then concentrated. The residue was purified by reverse phase HPLC to yield 6.5 mg (23%) of final compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[CH:9]=[N:8]1.[CH3:47][C@H:48]1[CH2:50][O:49]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH2:47][C@@H:48]([OH:49])[CH3:50])[CH2:30][CH2:29]5)=[N:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:36])=[O:35])[CH:14]=2)[CH:9]=[N:8]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (270 mg. 0.41 mmol) was alkylated using (S)-2-methyloxirane (48 mg, 0.82 mmol), DIPEA (159 mg, 1.23 mmol) and ethanol (10 mL) to get 350 mg (crude) of the titled compound. MS: m/z=680.2 (M+1).
Reaction SMILES: CO[C:3]([C:5]1(OC)[CH2:9][CH2:8][CH:7]([O:10][CH3:11])[O:6]1)=O.[CH:14]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([C:31]([F:34])([F:33])[F:32])=[C:27]([NH2:30])[CH:28]=3)[NH:23][C:22](=[O:35])[C:21]2=[O:36])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>COC1CCC(OC)O1.C(O)(=O)C>[CH:14]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([C:31]([F:32])([F:33])[F:34])=[C:27]([N:30]4[CH:3]=[CH:5][CH:9]=[C:8]4[C:7]([O:10][CH3:11])=[O:6])[CH:28]=3)[NH:23][C:22](=[O:35])[C:21]2=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Nc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2C1CCCCC1
Reactant: COC(=O)C1(OC)CCC(OC)O1
Agent: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)c1cccn1-c1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2C1CCCCC1

Procedure:
In place of 2,5-dimethoxytetrahydrofuran, 1.2 g (6.1 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran were dissolved with 2 g (6.1 mmol) of 1-cyclohexyl-6-trifluoromethyl-7-amino-2,3(1H,4H)-quinoxalinedione in 100 ml of acetic acid and refluxed for 30 minutes. The mixture was then worked up as in Example 3f.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:6]([OH:8])=O)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]([CH3:30])([CH3:29])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:4][C@H:5]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:6]([NH:28][C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C:21]([O:20][CH3:19])([CH3:29])[CH3:30])[N:24]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: COC(C)(C)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
To a solution of (S)-3-cyclopropyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (85 mg, 0.35 mmol) and 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 94, 64 mg, 0.38 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.18 g, 0.42 mmol) in methylene chloride (8 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) dropwise and the resulting solution stirred at room temperature for 4 h. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (25 mL), a saturated sodium bicarbonate solution (25 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-40 g column, 50-70% ethyl acetate/hexanes) to give (S)-3-cyclopropyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (46 mg, 34%) as an off white solid: [α]30D=−38.1°, (c=0.21, chloroform); HR-ES(+) m/e calcd for C22H28N4O3 [M+H]+ 397.2234, observed 397.2235; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.03-1.69 (m, 9H), 2.00-2.28 (m, 1H), 3.15 (s, 4H), 3.99 (s, 2H), 4.36-5.39 (m, 4H), 6.42 (d, J=1.81 Hz, 1H), 7.25-7.88 (m, 6H), 10.80 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)=[N:7][N:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=12)=[O:4].[F-:25].[K+].O>CC(N(C)C)=O>[Br:24][C:20]1[CH:19]=[C:18]([C:6]2[C:5]([C:3](=[O:4])[CH2:2][F:25])=[C:9]3[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][N:8]3[N:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: [F-]
Reactant: O=C(CBr)c1c(-c2cccc(Br)c2)nn2cc(C(F)(F)F)ccc12
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(CF)c1c(-c2cccc(Br)c2)nn2cc(C(F)(F)F)ccc12
Yield: 49.9 %

Procedure:
A solution of 2-bromo-1-[2-(3-bromophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (300 mg, 0.65 mmol, obtained from composite batches), KF (190 mg, 3.27 mmol) in DMA (10 mL) was heated for 3 h at 80° C. Water (25 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined and purified by LC (2-10% EtOAc in hexanes) to yield the desired product (130 mg, 42%) as a pale yellow glass. ESIMS (M+H)+=401.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[CH:18](OCC)=O>C(OCC)C>[CH3:3][C@H:2]([NH:1][CH3:18])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC=O
Reactant: CC(N)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN[C@@H](C)Cc1ccccc1
Temperature: 100 °C

Procedure:
Amphetamine free base (100 mg, 0.71 mmol) was dissolved in ethyl formate (10 mL). The solution was heated under pressure in an ACE pressure reactor for 2 hours at 100° C. The reaction mixture was cooled down, and the solvent was evaporated under reduced pressure. The resulting carbamate derivative was dissolved in dried diethyl ether (5 mL). The solution was added dropwise to a suspension of lithium aluminium hydride (40.4 mg, 1.07 mmol) in diethyl ether (10 mL). The reaction mixture was refluxed for 5 hours. Thereafter, water was carefully added after the reaction mixture had been cooled down to 0° C. on an ice bath. The lithium salt was filtered over Celite™ diatomaceous earth in Buchner funnel. The granules obtained were washed thoroughly with excess diethyl ether. The combined ether phases were washed with 5% sodium hydroxide and brine before being dried with magnesium sulfate. The solvent was evaporated to yield 96 mg methamphetamine free base.