Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C([C@H]([C@@H](C(O)=O)O)O)(O)=O.[C:40]1(=[O:56])[N:44]([CH:45]2[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]2)[C:43](=[O:51])[C:42]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:41]12.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:47]4[CH2:48][CH2:49][CH2:50][C@@H:45]([N:44]5[C:43](=[O:51])[C:42]6=[CH:52][CH:53]=[CH:54][CH:55]=[C:41]6[C:40]5=[O:56])[CH2:46]4)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1C1CCCNC1
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccccc4C3=O)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 140 °C
Reaction time: 2 h

Procedure:
10.00 kg (22.06 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-bromoxanthine, 12.59 kg (33.09 mol) of 3-(phthalimido)piperidine D-tartrate and 17.5 liters of N-methyl-2-pyrrolidone are initially charged in the reactor. The reactor contents are heated to 140° C. After the temperature has been attained, 11.41 kg (88.24 mol) of diisopropylethylamine are metered in within 20 minutes. The feed vessel is flushed with 2.5 liters of N-methyl-2-pyrrolidone and the reaction mixture is subsequently stirred at 140° C. for 2 hours. After the reaction has ended, the reaction mixture is cooled to 60° C. and diluted with 80 liters of methanol. The resulting suspension is stirred at 50° C. for 30 minutes, then cooled to 23° C. and stirred for a further 30 minutes. Subsequently, the product is centrifuged off and washed 3 times with 20 liters each time of methanol. Drying is effected at 45° C. in a drying cabinet under inertization.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1>>[F:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1cnc(Cl)nc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-fluoropyrimidine. ESI-MS (m/z): 410, 471 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.CCN(CC)CC.[F:17][C:18]1([F:33])[O:22][C:21]2[CH:23]=[CH:24][C:25]([C:27]3([C:30](Cl)=[O:31])[CH2:29][CH2:28]3)=[CH:26][C:20]=2[O:19]1>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:30]([C:27]2([C:25]3[CH:24]=[CH:23][C:21]4[O:22][C:18]([F:33])([F:17])[O:19][C:20]=4[CH:26]=3)[CH2:29][CH2:28]2)=[O:31])[CH:5]=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(N)nc(Cl)c1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
To a solution of 6-chloro-4-methylpyridin-2-amine (300 mg, 2.1 mmol) and Et3N (1.8 mL, 13 mmol) in dichloromethane (5 mL) was added a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (1.6 g, 6.3 mmol) in dichloromethane (5 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (10 mL) and was washed with 1N aqueous HCl (1×20 mL) and saturated aqueous NaHCO3 (1×20 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexane to yield N-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (700 mg, 91%). ESI-MS m/z calc. 366.1. found 366.9 (M+1)+. Retention time 2.15 minutes.
Reaction SMILES: [H-].[Na+].CC[O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:37]=O)[C:23]2[C:28]([C:29]=1[O:30]COC)=[C:27]([CH2:34][CH2:35][CH3:36])[CH:26]=[CH:25][CH:24]=2>CN(C)C=O.[Cl-].[Na+].O>[OH:30][C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:34][CH2:35][CH3:36])[C:22](/[CH:37]=[C:8](\[CH3:9])/[C:6]([OH:5])=[O:7])=[CH:21][C:20]=1[O:19][CH3:18]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CCCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Temperature: 10 °C
Reaction time: 1 h
Yield: 115.7 %

Procedure:
45 g of 60% sodium hydride was suspended in 650 ml of N,N-dimethylformamide and cooled to 10° C. 355 g of triethyl 2-phosphonopropionate was added to the solution to make a clear solution. A solution of 270 g of 3-methoxy-4-methoxymethoxy-5-propyl-1-naphthalenecarbaldehyde in N,N-dimethylformamide (250 ml) was dropped in the solution and stirred at room temperature for 1 hour. The reaction mixture was poured into brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (8% ethyl acetate/hexane) to obtain 325.3 g of the titled compound as a pale yellow oil (containing a small amount of Z isomer).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:29][C@@H:30]1[O:32][CH2:31]1)(=O)=O.CN(C=O)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][CH2:29][C@H:30]1[CH2:31][O:32]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(OCc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
A 500 mL round bottomed flask equipped with a nitrogen inlet and a magnetic stir bar is charged with: 2-(benzyloxy)-4-nitrophenol (10.00 g, 40.8 mmol), potassium carbonate (7.05 g, 51.0 mmol), (R)-(−)-glycidyl tosylate (10.00 g, 43.8 mmol) and DMF (65 mL). The mixture is immersed in an oil bath heated to 60° C. and stirred for 18 h. The solution is allowed to cool to rt, then water (200 mL) is slowly added. The resulting suspension is stirred for 2 h, the precipitate is collected by vacuum filtration and the filter cake is washed with water (25 mL). The cake is dried under suction to yield 10.70 g (87%) of the title compound as a light yellow powder. LCMS (Standard Method): 2.74 min, 302 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J=2.6, 9.0 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.48-7.34 (m, 5H), 6.98 (d, J=8.8 Hz, 1H), 5.19 (s, 2H), 4.43 (dd, J=2.7, 11.5 Hz, 1H), 4.08 (dd, J=5.8, 11.5 Hz, 1H), 3.43-3.39 (m, 1H), 2.95-2.91 (m, 1H), 2.81-2.78 (m, 1H).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[CH:32]([NH2:34])[CH2:31][CH2:30][CH2:29]2>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[CH:32]([NH:34][C:20]1[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=1)[CH2:31][CH2:30][CH2:29]2
Reactant: COc1cccc2c1C(N)CCC2
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Product: COc1cccc2c1C(NC1=Nc3ccc([N+](=O)[O-])cc3CO1)CCC2
Yield: 79.2 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (2.76 g, 8.5 mmol; HPLC: 4.446 min) and rac-8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamine (CAS 535935-61-6) (1.51 g, 8.5 mmol; HPLC 0.403 min) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (2.38 g, 79%, HPLC 1.805 min), MS (ISP) m/e=354.2 [(M+H)+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7]([NH:11][C:12]([C:14]1[S:36][C:17]2[N:18]=[C:19]([S:34][CH3:35])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:29]([CH:32]=[CH2:33])(=[O:31])=[O:30])[CH:23]=3)[C:16]=2[C:15]=1[NH2:37])=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([NH:11][C:12]([C:14]1[S:36][C:17]2[N:18]=[C:19]([S:34][CH3:35])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:29]([CH2:32][CH2:33][N:1]4[CH2:6][CH2:5][S:4][CH2:3][CH2:2]4)(=[O:31])=[O:30])[CH:23]=3)[C:16]=2[C:15]=1[NH2:37])=[O:13])([CH3:9])([CH3:8])[CH3:10]
Reactant: C=CS(=O)(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reactant: C1CSCCN1
Product: CSc1nc(-c2cccc(NS(=O)(=O)CCN3CCSCC3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
Reaction of thiomorpholine (184 μl) with tert-butyl 5-amino-2-methylthio-4-(3-(vinylsulfonamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 10, 87 mg) was performed according to the method described in example 11. The title compound was first purified by chromatography on silica gel with hept/EtOAc=3/2 (v/v) as eluent and then by HPLC using a Luna C-18 column with the following gradient: CH3CN/0.1% aq. TFA=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4dioxane and 0.1 % aq TFA.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[C:13][CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18])[C:7]([O:10][CH3:11])=[N:8][CH:9]=1)(=O)[CH3:2].[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[CH:20]1([NH:23][CH:1]([C:4]2[CH:5]=[C:6]([C:12]#[C:13][CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18])[C:7]([O:10][CH3:11])=[N:8][CH:9]=2)[CH3:2])[CH2:22][CH2:21]1
Reactant: COC(=O)NCC#Cc1cc(C(C)=O)cnc1OC
Reactant: NC1CC1
Product: COC(=O)NCC#Cc1cc(C(C)NC2CC2)cnc1OC

Procedure:
Methyl [3-(5-acetyl-2-methoxypyridin-3-yl)prop-2-yn-1-yl]carbamate and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give methyl (3-{5-[1-(cyclopropylamino)ethyl]-2-methoxypyridin-3-yl}prop-2-yn-1-yl)carbamate [Ex(296-3)] as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[N:4][CH:5]=[C:6]([O:16]CC2C=CC=CC=2)[C:7]=1[O:8]CC1C=CC=CC=1>C1(SC)C=CC=CC=1.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:7](=[O:8])[C:6]([OH:16])=[CH:5][NH:4][C:3]=1[C:24]([OH:26])=[O:25]
Reactant: O=C(O)c1ncc(OCc2ccccc2)c(OCc2ccccc2)c1Br
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1[nH]cc(O)c(=O)c1Br

Procedure:
3.24 g of the title compound of Example 8 were stirred in a mixture of 20 ml thioanisole and 30 ml TFA at room temperature for 16 hours. The solvents were distilled off in vacuo and the residue stirred with 50 ml ice water at pH 5.5 (NaHCO3 were added). Solid title compound, beige crystals, were isolated by filtration after washing with water and drying over P2O5 ; yield: 2.2 g title compound. Title compound was also obtained by hydrogenation of the title compound of Example 8 in DMF, Pd/C (10%) as catalyst.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[I:15]N1C(=O)CCC1=O.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[I:15]
Reactant: O=C1CCC(=O)N1I
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c(-c2ccccc2F)c1I
Reaction time: 12 h
Yield: 13.5 %

Procedure:
5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (2.0 g) was dissolved in N,N-dimethylformamide (60 mL), N-iodosuccinimide (2.38 g) was added and the mixture was stirred at for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate solution, a 3% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a pale-brown powder (yield 450 mg, 14%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5].[Cl:12][CH:13]([Cl:17])[C:14](Cl)=[O:15]>C(Cl)Cl>[Cl:12][CH:13]([Cl:17])[C:14]([O:1][N:2]=[C:3]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(O)C(=NO)c1ccco1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccco1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
2-Hydroxyimino-2-(fur-2-yl)acetic acid (1.38g) mixture was added portionwise to an ice cold solution of dichloroacetyl chloride (2.8 mls.) in dry methylene chloride (14 mls.). After 15 mins stirring a white precipitate was formed which was collected, washed successively with cold dry methylene chloride and petrol (b.p. 40°-60°) and dried to yield 2-dichloroacetoxyimino-2-(fur-2-yl)acetic acid (syn-isomer) (1.5 g, 63%).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]([NH2:27])([CH3:26])[CH3:25]>>[C:24]([NH:27][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:26])([CH3:25])[CH3:23]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(C)(C)N
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 100 °C
Yield: 32 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 63 mg, 0.213 mmol) and 2-methylpropan-2-amine (44.9 μl, 0.425 mmol, Aldrich), heating at 100° C. for 3 h. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (32% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 9H) 2.57 (s, 3H) 2.88 (t, J=6.94 Hz, 2H) 3.45 (td, J=6.80, 2.45 Hz, 2H) 6.03 (s, 1H) 6.95 (br. s., 1H) 7.04 (d, J=2.15 Hz, 1H) 7.35 (t, J=7.82 Hz, 1H) 7.59 (dd, J=8.02, 1.37 Hz, 1H) 7.84 (dd, J=7.53, 1.27 Hz, 1H) 12.01 (br. s., 1H). MS (ESI, pos. ion) m/z: 350.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=S)c1cc(Br)c(C)s1
Product: COC(=S)c1cc(Nc2cccc(Cl)c2)c(C)s1
Yield: 52.8 %

Procedure:
A stirred suspension of 80 mg (0.299 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate and 41 μL (0.389 mol, 1.3 eq) of 3-chloroaniline (Aldrich, Milwaukee, Wis.) was treated in a manner similar to Example 241, step (b) to give 47 mg of the title compound (50%) as a yellow oil. 1H-NMR (CDCl3, 400 MHz) δ7.75 (s, 1H), 7.23-6.89 (m, 4H), 6.10 (s, 1H), 3.89 (s, 3H), 2.42 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C13H2NO12S2Cl, 314.0 (M+H), found 314.1.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F.C(N(C(C)C)CC)(C)C>CS(C)=O>[Cl:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C

Procedure:
A solution of t-butyl 1-piperazinecarboxylate 38 (1.0 g., 5.37 mmole), 3-chloro-4-fluoronitrobenzene (0.94 g., 5.37 mmole) and diisopropylethylamine (0.70 g., 5.4 mmole) in DMSO (30 mL.) was heated 16 hours at 100°, cooled to r.t. and poured into ice water (300 mL.). The suspension was extracted with ethyl acetate (2×60 mL.). The combined organic layers were washed with water (3×40 mL.), dried over Na2SO4 and evaporated to dryness to give an orange solid which was recrystallized twice from methanol to give the title compound, 1.2 g. MS (M+H)+ 342.0
Reaction SMILES: C([C:3]([N:17]1CCOCC1)([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH2:4][CH:5]([CH3:10])[C:6]([O:8]C)=O)#N.CC(CC(=O)C1C=C[N:34]=[CH:33]C=1)C(OC)=O>>[CH3:33][N:34]1[C:6](=[O:8])[CH:5]([CH3:10])[CH2:4][C:3]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[N:17]1
Reactant: COC(=O)C(C)CC(=O)c1ccncc1
Reactant: COC(=O)C(C)CC(C#N)(c1ccncc1)N1CCOCC1
Product: CC1CC(c2ccncc2)=NN(C)C1=O

Procedure:
Following the procedure described in Example A-16 but using in place of methyl 4-cyano-4-(4-morpholinyl)-4-(4-pyridinyl)-2-methylbutanoate a molar equivalent quantity of methyl 2-methyl-4-oxo-4-(4-pyridinyl)butanoate, it is contemplated that there can be obtained 4,5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3(2H)-pyridazinone. Also, this same compound can be obtained following the procedure described in Example A-1 but using in place of 4-oxo-4-(4-pyridinyl)butanenitrile a molar equivalent quantity of 2-methyl-4-oxo-4-(4-pyridinyl)butanenitrile.
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 72.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S,2R)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (130 mg, 0.20 mmol) prepared in Example 102d, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (70 mg, 99%) as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C1CCCCN1
Reactant: COc1cccc(CCl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCCN1Cc1cccc(OC)c1

Procedure:
A solution of ethyl 2-piperidinecarboxylate (10.0 ml), 3-methoxybenzyl chloride (9.2 ml), and triethylamine (26.6 ml) in N,N-dimethylformamide (64.0 ml) was stirred at room temperature overnight and partitioned between ethyl acetate and water. The organic layer was separated, washed with water (four times) and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford ethyl 1-(3-methoxybenzyl)-2-piperidinecarboxylate (12.06 g) as a colorless oil.
Reaction SMILES: B1([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)OC(C)(C)C(C)(C)O1.I[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[N:27][C:28]=2[NH2:30])[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=[C:21]([C:10]3[CH:11]=[CH:12][C:13]([S:16]([NH2:19])(=[O:17])=[O:18])=[CH:14][CH:15]=3)[C:29]=12
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc(S(N)(=O)=O)cc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 9.5 %

Procedure:
A solution of benzenesulfonamide-4-boronic acid pinacol ester (23 mg, 0.08 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA14 (2.2 mg, 10% yield). ESI-MS (M+H)+ m/z calcd 333.1, found 333.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:24]([C:33]([F:36])([F:35])[F:34])[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:28]1([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][O:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6]5[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=5[C:4]=4[CH:3]=3)=[CH:23][C:24]=2[C:33]([F:34])([F:35])[F:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (50.0 mg, 0.193 mmol) and 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (152.0 mg, 0.578 mmol) in DMF (3 mL) was added cesium carbonate (75.0 mg, 0.231 mmol). The mixture was stirred at room temperature overnight, filtered through Celite®, and concentrated under reduced pressure. The residue was purified by HPLC to give the title compound as a light pink oil (38.7 mg). LCMS m/z=486.5 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(Br)cn1
Reactant: C1CNCCN1
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A mixture of 5-bromo-2-chloropyridine (110 g, 573 mmol) and piperazine (99.1 g, 1.15 mol) was stirred overnight at 130° C. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (200 mL) and then extracted with DCM (3×200 mL). The combined organic layers were concentrated under reduced pressure to obtain compound 90a as a white solid (105 g, 76% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C9H12BrN3: 242.0 (M+H). found 242.0.