Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CO[C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([C:20]2[C:21]([CH3:27])=[N:22][N:23]([CH3:26])[C:24]=2[CH3:25])[CH:13]=1.CN(C[N:33]1[C:37]2=[N:38][C:39]([N:42]3[CH2:47][CH2:46][CH:45]([N:48]([CH3:50])[CH3:49])[CH2:44][CH2:43]3)=[CH:40][CH:41]=[C:36]2[N:35]=[CH:34]1)C>>[CH3:49][N:48]([CH3:50])[CH:45]1[CH2:46][CH2:47][N:42]([C:39]2[N:38]=[C:37]3[NH:33][C:34]([C:11]([C:12]4[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([C:20]5[C:21]([CH3:27])=[N:22][N:23]([CH3:26])[C:24]=5[CH3:25])[CH:13]=4)=[O:28])=[N:35][C:36]3=[CH:41][CH:40]=2)[CH2:43][CH2:44]1
Reactant: COC(=O)c1ccc(C#N)c(-c2c(C)nn(C)c2C)c1
Reactant: CN(C)Cn1cnc2ccc(N3CCC(N(C)C)CC3)nc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: Cc1nn(C)c(C)c1-c1cc(C(=O)c2nc3ccc(N4CCC(N(C)C)CC4)nc3[nH]2)ccc1C#N

Procedure:
Following General procedure P (LDA metallation, ketone formation and in situ deprotection) using 4-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzoic acid methyl ester and [1-(3-dimethylaminomethyl-3H-imidazo[4,5-b]pyridin-5-yl)-piperidin-4-yl]-dimethyl-amine to give 4-[5-(4-dimethylamino-piperidin-1-yl)-3H-imidazo[4,5-b]pyridine-2-carbonyl]-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzonitrile. (84%). HRMS m/z 483.2620 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:19])=O>CCCCCC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:19])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cl)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 99 %

Procedure:
13bk) 49.4 g of 4-bromo-2-chloro-benzoic acid were suspended in 60 ml of hexane, treated with 0.2 ml of N,N-dimethylformamide and 18.5 ml of thionyl chloride and boiled at reflux under argon for 15 hrs. The resulting solution was cooled to room temperature, filtered, evaporated and the residue was again evaporated with 60 ml of toluene. There were obtained 53 g (99%) of 4-bromo-2-chloro-benzoylchloride as a crude oil which crystallized upon standing, but which was used directly in the next step without further manipulation.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:5]2[NH:6][CH2:7][CH2:8][S:9][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[N:23]2)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[C:11]([CH2:12][NH:35][CH:32]2[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][S:26][C:22]3[CH:21]=[N:20][C:19]4[C:24](=[CH:25][C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)[N:23]=3)[CH2:34][CH2:33]2)=[CH:10][C:5]2[NH:6][CH2:7][CH2:8][S:9][C:4]=2[CH:3]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=Cc1cc2c(cc1Cl)SCCN2
Product: COc1ccc2ncc(SCCN3CCC(NCc4cc5c(cc4Cl)SCCN5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow waxy solid (23 mg, 34% yield) following Scheme 3 and in analogy to Example 40 using 7-chloro-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (27 mg, 0.12 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40 mg, 0.12 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([CH3:23])=O.CCCBr>O>[CH2:20]([O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:21][CH3:23]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCBr
Solvent: O
Product: CCCOc1cc([N+](=O)[O-])ccc1[N+](=O)[O-]
Reaction time: 96 h

Procedure:
A mixture of 2,5-dinitrophenol (10 g), potassium carbonate (15 g) and acetone (100 ml) is stirred and n-propyl bromide (13.36 g) added to the mixture. The mixture is stirred at room temperature for 3 hours and then heated at reflux for 16 hours. More n-propyl bromide (6.68 g) is then added and refluxing continued for 96 hours. The mixture is filtered and the filtrate evaporated to dryness to afford a dark brown solid. This material is stirred with water (300 ml) and filtered. Recrystallization from methanol yields 8.9 g of 1-n-propoxy-2,5-dinitrobenzene, m.p. 52°-54° C. This compound (8.4 g) is reduced with hydrogen in a pressure vessel in the presence of methanol (250 ml) and 5% Pd/C catalyst (0.85 g); starting pressure: 3.36 kg/cm2, final pressure: 2.52 kg/cm2. The mixture is filtered and evaporated to dryness to afford 6.1 g of oily title compound, which is used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)nc1
Reaction time: 18 h
Yield: 96.4 %

Procedure:
To a solution of 6-chloronicotinic acid (20.0 g, 0.127 mol) in CH2Cl2 (250 mL) was added oxalyl chloride (123.3 mL, 0.15 mol) with 1-5 drops of DMF. The solution was stirred 18 h and concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL) and cooled in an ice bath. To this was added MeOH (20 mL) and the solution was stirred for 15 min while maintaining a temp below 40° C. The solvent was removed in vacuo, and the residue was dissolved in Et2O, washed with H2O and brine, dried with Na2SO4, and filtered through SiO2. The solvent was removed in vacuo to yield 6-chloronicotinic acid, methyl ester (21 g) as an off-white solid: 1H-NMR (300 MHz, CDCl3) δ 9.02 (d, J=13.8 Hz, 1H), 8.51-8.06 (m, 1H), 7.76-7.30 (m, 1H), 4.01 (s, 3H); EIMS m/z 171 ([M]+), which was used in Step 2 without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:16][C:17]1[CH:18]=[C:19]([NH2:25])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].CCN(CC)CC>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:25][C:19]4[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([Br:16])[CH:18]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(N)cc1Br
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reaction time: 16 h

Procedure:
To a Solution of the Crude 1-Benzo[1,3]Dioxol-5-yl-Cyclopropanecarbonyl Chloride (3.0 mmol) in CH2Cl2 (30 mL) at ambient temperature was added a solution of 3-bromo-4-methoxybenzenamine (3.3 mmol), Et3N (15 mmol), and CH2Cl2 (90 mL) dropwise. The mixture was allowed to stir for 16 h before it was diluted with CH2Cl2 (500 mL). The solution was washed with 1N HCl (2×250 mL), sat. aq. NaHCO3 (2×250 mL), then brine (250 mL). The organics were dried over Na2SO4, filtered, and concentrated in vacuo to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methoxyphenyl)cyclopropanecarboxamide (B-10) with suitable purity to be used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:4][C:3]1([CH2:7][OH:8])[CH2:5][O:6][CH:17]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:1][CH2:2]1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(C2OCC(C)(CO)CO2)cc1

Procedure:
1,1,1-tris(Hydroxymethyl)ethane (12.0 g), p-tolualdehyde (12.0 g), benzene (100 ml) and toluene-p-sulphonic acid (100 mg) were heated under reflux in a Dean and Stark water trap until no more water separated. The benzene was removed and the crude product was crystallised from light petroleum (b.p. 60°-80°) ethyl acetate as white needles, m.p. 104.5°-105.5°. (cis:trans isomer ratio 82:18). The following compounds were prepared in a similar manner from 1,1,1-tris(hydroxymethyl)ethane and the corresponding aldehyde R1CHO.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:22])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[C:10]([C:9]1[CH:8]=[C:7]([C:12](=[O:22])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])#[N:11]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)O
Reaction time: 15 h

Procedure:
A mixture of 3-Cyano-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carboxylic acid methyl ester (33 mg, 0.104 mmol), lithium hydroxide monohydrate (44 mg, 1.04 mmol), THF (2 mL) and water (3 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 31.4 mg (100%). MS m/e 302.8 (M+H+).
Reaction SMILES: [C:1]1([S:7](/[CH:10]=[CH:11]/[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1([CH3:31])[O:26][CH:25]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:24]2[O:23]1>C1(C)C=CC=CC=1>[C:1]1([S:7]([CH:10]2[CH:11]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH:30]3[CH:29]=[CH:28][CH:27]2[CH:25]2[CH:24]3[O:23][C:22]([CH3:31])([CH3:21])[O:26]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(/C=C/S(=O)(=O)c1ccccc1)c1ccccc1
Reactant: CC1(C)OC2C=CC=CC2O1
Solvent: Cc1ccccc1
Product: CC1(C)OC2C3C=CC(C2O1)C(S(=O)(=O)c1ccccc1)C3S(=O)(=O)c1ccccc1

Procedure:
Trans-1,2-bis(phenylsulfonyl)ethylene (1.37 g, 4.45 mmol) was added to a solution of the compound obtained in Step (12) in toluene, and air in a vessel containing the mixture was replaced with nitrogen. After having been refluxed for 8 hours, the mixture was concentrated under reduced pressure. The resultant reaction product was purified by silica gel chromatography (50% EtOAc/Hexane), whereby 10,11-bis(phenylsulfonyl)-4,4-dimethyl-3,5-dioxa-tricyclo[5.2.2.02.6]undec-8-ene was obtained (2.0 g, 98%).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([NH:43][CH:44]1[CH2:49][C:48]([CH3:51])([CH3:50])[N:47]([CH3:52])[C:46]([CH3:54])([CH3:53])[CH2:45]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][NH:43][CH:44]2[CH2:49][C:48]([CH3:51])([CH3:50])[N:47]([CH3:52])[C:46]([CH3:54])([CH3:53])[CH2:45]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN1C(C)(C)CC(NC(=O)CCl)CC1(C)C
Product: CCN(Cc1ccc(OCCNC2CC(C)(C)N(C)C(C)(C)C2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 32.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)acetamide (23 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (9.6 mg) was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[S:25]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=[CH:33][C:26]1=2.[O:37]1[C:42]2([CH2:47][CH2:46][N:45]([CH2:48][C:49]3[C:50]([F:58])=[C:51]([CH2:55][CH2:56][OH:57])[CH:52]=[CH:53][CH:54]=3)[CH2:44][CH2:43]2)[CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)CC)C>CN(C=O)C>[S:25]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31]([C:34]([N:40]3[CH2:41][C:42]4([CH2:47][CH2:46][N:45]([CH2:48][C:49]5[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][CH2:56][OH:57])[C:50]=5[F:58])[CH2:44][CH2:43]4)[O:37][CH2:38][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:26]1=2
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: O=C(O)c1ccc2sccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc2sccc2c1)N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.181 g) was added in one portion to a stirred solution at 0° C. of benzo[b]thiophene-5-carboxylic acid (0.065 g) and 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.113 g) and triethylamine (0.153 mL) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.160 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[CH3:11][CH:12]([CH3:16])[CH2:13][CH2:14][NH2:15].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH:15][CH2:14][CH2:13][CH:12]([CH3:16])[CH3:11])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(O)c(Br)c1
Yield: 73.5 %

Procedure:
Combine 3-Bromo-4-hydroxy-benzaldehyde (1.5 g, 7.5 mmol) with 3-methylbutylamine (867 μL, 7.5 mmol), MeOH (25 mL) and molecular sieves 3A (5.8 g) and stir at room temperature overnight. Add NaBH4 (1.4 g, 37.3 mmol) and stir at room temperature for 2 hours. Filtrate over celite with MeOH and eliminate the solvent. Purify by SCX ion-exchange chromatography to afford the title compound (1.5 g, 75%). 1H-NMR (CD3OD, 300 MHz): 7.52 (d, 1H, J=2.0 Hz), 7.17 (dd, 1H, J=2.0 and 8.5 Hz), 6.87 (d, 1H, J=8.5 Hz), 3.80 (s, 2H), 2.79-2.74 (m, 2H), 1.76-1.63 (m, 1H), 1.54 (q, 2H, J=6.8 Hz), 0.99 (d, 6H, J=6.56 Hz). 13C-NMR (CD3OD, 300 MHz): 158.6, 134.9, 130.7, 128.6, 118.8, 112.7, 53.3, 47.9, 38.6, 27.8, 23.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][O:5][CH:4]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[NH:3]1.C([Li])CCC.[CH3:20][S:21]C>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[CH2:6][O:5][CH:4]([C:7]2[S:8][C:9]([S:21][CH3:20])=[CH:10][C:11]=2[O:12][CH3:13])[NH:3]1
Reactant: CSC
Reactant: COc1ccsc1C1NC(C)(C)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(SC)sc1C1NC(C)(C)CO1
Temperature: -45 °C
Reaction time: 1.5 h

Procedure:
27 g (0.128 moles) of 3,4-dihydro-4,4-dimethyl-2-(3-methoxy-2-thienyl)-oxazole are dissolved in 400 ml of absolute tetrahydrofuran, the solution is cooled to -45° C. and 88 ml (0.141 moles) of a 1.6 molar solution of butyllithium in n-hexane is added dropwise such that the temperature in the reaction mixture does not exceed -45° C. After completion of the addition it is stirred further for 1.5 hours at -45° C., a solution of 13.9 g (0.147 moles) of dimethylsulfide in 70 ml of absolute tetrahydrofuran is added and stirring continues for an additional 30 minutes at this temperature. Then it is heated to -20° C., poured onto water and extracted several times with ether. The combined ether phases are dried with sodium sulfate, decolored with activated charcoal, evaporated in vacuo and the crystalline residue is recrystallized from petroleum ether. Yield: 24.7 g (75%), m.p. 56°-58° C.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH3:23])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][N:22]([CH3:23])[C:34]([NH:33][S:30]([C:27]3[CH:26]=[CH:25][C:24]([CH3:36])=[CH:29][CH:28]=3)(=[O:31])=[O:32])=[O:35])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN(C)C(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.6 %

Procedure:
To a solution of N-{2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}-N-methylamine (step 1, 523 mg, 1.7 mmol) in dichloromethane (10 mL) and triethylamine (2 mL) was added p-toluenesulfonyl isocyanate (400 mg, 2.0 mmol). The resulting reaction mixture was stirred at room temperature for 6 h. After removal of solvent, the residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (10:1) to afford 358 mg (42%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.93 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.4 Hz), 6.92 (1H, s), 3.66-3.49 (2H, m), 3.51 (3H, s), 2.93-2.70 (4H, m), 2.65 (3H, s), 2.50 (3H, s), 2.38 (3H, s), 1.24 (3H, t, J=7.2 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([S:18](Cl)(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([S:18]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)N2CCCCC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 1.7 g. (0.02 mole) of piperidine and 5.8 g. (0.02 mole) of 2,4-dichloro-5-chlorosulfonylbenzoic acid (Sturm, et al., Ber., 99, 328 (1966) in 70 ml. of water and cooled to 15° C. is treated dropwise with 50 ml. of 1 N sodium hydroxide. When the addition is complete, the mixture is allowed to warm to room temperature and remain for 1 hr. The hazy suspension is filtered and the clear filtrate acidified with 12 N hydrochloric acid. The precipitated solids are filtered and dried, 7.7 g., m.p. 200°-205° C. A sample is recrystallized from acetonitrile, m.p. 205°-206° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[N:10]=[C:9]([S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][N:7]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][NH:2][C:3]([N:7]1[C:6](=[O:5])[N:10]=[C:9]([S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8]1)=[O:4]
Reactant: CCOC(=O)CSc1nc(O)ns1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CSc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
10 ml of methyl isocyanate were added to a solution of 11 g of 3-hydroxy-5-(ethoxycarbonylmethylthio)-1,2,4-thiadiazole in 100 ml of tetrahydrofuran containing 0.5 ml of triethylamine and the mixture was stirred for 2 hours at 20° C. The mixture was evaporated to dryness under reduced pressure and the residue was empasted with ethyl acetate and vacuum filtered. The crystals were washed with water to obtain 10 g of 2-(N-methylcarbamoyl)-5-(ethoxycarbonylmethylthio)-1,2,4-thiadiazole-3-one which after crystallization from acetone melted at 163° C.
Reaction SMILES: C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([CH:24]1[CH2:28][CH2:27][C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[C:32]([F:39])[C:31]=2[F:40])(O)[CH2:25]1)[CH2:21][CH2:22][CH3:23]>O>[CH2:20]([CH:24]1[CH2:28][CH2:27][C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[C:32]([F:39])[C:31]=2[F:40])=[CH:25]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCC1CCC(O)(c2ccc(OCC)c(F)c2F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC1C=C(c2ccc(OCC)c(F)c2F)CC1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
Toluene (50 ml) and p-toluenesulfonic acid monohydrate (0.14 g) were added to 3-butyl-1-(4-ethoxy-2,3-difluorophenyl)cyclopentanol (2.8 g) obtained in the second step, in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen. The mixture was refluxed for 30 minutes, while forming water was removed with a Dean-Stark apparatus. The reaction solution was cooled to room temperature and was washed with water. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/9 by volume) to give a mixture (2.4 g) of 1-(3-butylcyclopent-1-enyl)-4-ethoxy-2,3-difluorobenzene and 1-(4-butylcyclopent-1-enyl)-4-ethoxy-2,3-difluorobenzene.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.C[Si]([C:30]#[CH:31])(C)C.CCN(CC)CC>CN(C=O)C.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>[C:30]([C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1)#[CH:31]
Reactant: C#C[Si](C)(C)C
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 120 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (1.0 g, 2.8 mmol) in DMF (10 mL) under nitrogen was added trimethylsilylacetylene (2.0 mL, 14 mmol), cupric iodide (0.11 g, 0.58 mmol) and Et3N (1.2 mL, 8.4 mmol). Upon completion of addition, the mixture was degassed with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium (0.20 g, 0.28 mmol) was then added and the resulting mixture was again degassed with nitrogen for 10 min. After this time, the reaction mixture was heated in a sealed tube to 120° C. where it stirred for 16 h. At the conclusion of this period, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was quenched by the addition of water. The resulting reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was dissolved in methanol and saturated with ammonia gas. The saturated solution was stirred for 2 h at 0° C. and then concentrated under reduced pressure to yield a residue. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether to afford 2-ethynyl-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (650 mg). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.15 (d, J=4.0 Hz, 1H), 7.86 (dd, J=8.4, 1.2 Hz, 1H), 7.69 (t, J=8.4 Hz, 1H), 7.56 (dt, J=3.6, 1.6 Hz, 1H), 7.49-7.42 (m, 5H), 7.26-7.23 (m, 1H), 7.13-7.08 (m, 2H), 6.94 (bs, 1H), 4.67 (d, J=10.0 Hz, 2H), 3.02 (s, 1H). LCMS Method O: retention time 1.35 min, [M+1]=337.0.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([Sn]([N:33]=[N+:34]=[N-:35])(CCCC)CCCC)CCC>ClC1C=CC=CC=1Cl.CCOCC>[Br:1][C:2]1[C:3]([C:18]2[NH:35][N:34]=[N:33][N:19]=2)=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(Br)cccc1NS(=O)(=O)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CCOCC
Solvent: Clc1ccccc1Cl
Product: O=S(=O)(Nc1cccc(Br)c1-c1nnn[nH]1)c1ccccc1
Yield: 76.6 %

Procedure:
A solution of N-(3-Bromo-2-cyanophenyl)-benzenesulfonamide (Intermediate 21, 0.22 g) and tributyltin azide (0.43 g) in 1,2-dichlorobenzene (1.5 mL) was heated by microwave irradiation at 130° C. for 2 hours. The mixture was diluted with ether and extracted with aqueous 1M sodium hydroxide. The aqueous solution was acidified with 1N hydrochloric acid to pH 1 and then extracted with ethyl acetate. The organic solution was washed with brine and then dried with sodium sulfate, filtered and the filtrate was evaporated. The residue was triturated with ether and the solid was collected by filtration to give the title compound as a colorless solid (0.19 g).