Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH3:21])[CH:13]=[CH:12][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[CH2:22]1[C:25]2([CH2:30][CH2:29][O:28][CH:27](O)[CH2:26]2)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:8]1([CH3:21])[CH:9]=[CH:10][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:29][CH2:30][C:25]3([CH2:26][CH2:27][OH:28])[CH2:22][CH2:23][CH2:24]3)[CH2:17][CH2:16]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Reactant: OC1CC2(CCC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC2CCN(CCC3(CCO)CCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.6 %

Procedure:
To a suspension of 4-(p-toluidino)piperidine trifluoroacetate (418 mg) (synthesized in Preparation Example 4-5) in tetrahydrofuran (3 mL) was added triethylamine (0.28 mL). The solution was stirred at room temperature for 5 minutes. Then, 7-oxaspiro[3.5]nonan-6-ol (104 mg) (synthesized in Example 65) in tetrahydrofuran (3 mL) was added to the solution and it was stirred at room temperature for additional 10 minutes. The reaction solution was ice-cooled and sodium triacetoxyborohydride (424 mg) was added thereto. The solution was then 4lowed for its temperature to rise to room temperature. The solution was stirred for additional 4.5 hours. A 3N aqueous sodium hydroxide solution (5 mL) was added to the reaction solution and it was extracted with tert-butyl methyl ether. The resulting residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7:3)] to give the title compound (175 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:9]=3[N:17]=2)[CH:19]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 2,4-dichlorobenzene-1-sulfonyl chloride (0.0460 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 2,4-dichloro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.0340, 41%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.02-2.11 (2H, m), 2.24-2.29 (2H, m), 3.70-3.75 (2H, m), 4.10-4.16 (2H, m), 5.65-5.71 (1H, m), 7.33 (1H, dd, J=1.8, 8.6 Hz), 7.54 (1H, d, J=2.0 Hz), 8.05 (1H, d, J=8.8 Hz), 8.20 (1H, d, J=9.2 Hz), 8.36 (1H, d, J=8.8 Hz), 8.48-8.55 (2H, m), 8.84 (1H, s), 9.15 (1H, d, J=1.6 Hz). m/z=532.0 [M+1]+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)[CH:2]=[CH2:3].[N:25]1C=[CH:29][CH:28]=[CH:27][C:26]=1CCN>>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([NH:4][CH2:1][CH2:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[N:6][C:7]([C:23]#[N:24])=[C:8]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCc1ccccn1
Reactant: C=CCNc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Product: COc1ccc2c(NCCc3ccccn3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (2-pyridin-2-ylethyl)amine in place of allylamine and heating for 35 min instead of 1 h, the title compound was synthesized.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](C(OC(C)C)=O)=[N-])=O)(C)C.[CH3:34][N:35]1[C:43]2[C:38](=[CH:39][C:40]([OH:44])=[CH:41][CH:42]=2)[C:37]([C:45]2[N:53]([S:54]([C:57]3[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[C:48]3=[N:49][CH:50]=[CH:51][CH:52]=[C:47]3[CH:46]=2)=[CH:36]1.[CH3:64][O:65][CH2:66][CH:67](O)[CH3:68]>C1(C)C=CC=CC=1>[CH3:64][O:65][CH2:66][CH:67]([CH3:68])[O:44][C:40]1[CH:39]=[C:38]2[C:43](=[CH:42][CH:41]=1)[N:35]([CH3:34])[CH:36]=[C:37]2[C:45]1[N:53]([S:54]([C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)(=[O:56])=[O:55])[C:48]2=[N:49][CH:50]=[CH:51][CH:52]=[C:47]2[CH:46]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(O)cc34)cc3cccnc32)cc1
Reactant: COCC(C)O
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCC(C)Oc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C

Procedure:
A solution of triphenylphosphine (470 mg) and diisopropyldiazodicarboxylate (350 μl) in dry toluene (15 mL) was treated with 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-ol [150 mg, Reference Example 14(a)] followed by 1-methoxy-2-propanol (150 μl). The resulting mixture was heated under reflux for 5 hours then cooled and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give the title compound (50 mg) as a clear oil. TLC: RF=0.65 (pentane/ethyl acetate: 1/1). MS: 480(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:1][C:2]1[C:3]([C:15](=[O:16])[CH2:14][Cl:13])=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: CC(=O)Nc1cc(Cl)ccc1C
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc(Cl)c(C(=O)CCl)cc1C
Yield: 75.7 %

Procedure:
To N-(5-Chloro-2-methyl-phenyl)-acetamide (30 g, 163.37 mmol) in carbondisulfide (1200 mL) was added chloroacetylchloride (19.50 mL, 245.05 mmol) followed by anhydrous aluminum chloride powder (65.35 g, 490.11 mmol) in one portion at rt. The reaction was heated to reflux for 3 h after which the reaction was cooled and the solvent decanted. The remaining residue was carefully hydrolyzed with cold H2O (500 mL) with vigorous stirring to give a white/gray solid suspension which was collected by filtration and dried in vacuo to give desire product (32.15 g, 123.6 mmol). Yield=76%; 1H NMR (400 MHz, CDCl3) δ 8.28 (bs, 1H, NH), 7.47 (s, 1H), 7.24 (s, 1H), 4.73 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: OC1C=CC([CH:8]2[CH:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20]=4[CH:31]=3)[CH2:12][CH2:11][CH2:10][N:9]2[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=CC=1.C1(C)C=CC(S([O:51][CH2:52][CH2:53][O:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([O:61][CH3:62])[CH:56]=2)(=O)=O)=CC=1>>[CH3:62][O:61][C:57]1[CH:56]=[C:55]([CH:60]=[CH:59][CH:58]=1)[O:54][CH2:53][CH2:52][O:51][C:16]1[CH:17]=[CH:18][C:19]([CH:12]2[CH2:11][CH2:10][N:9]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:8][CH:13]2[O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20]=3[CH:31]=2)=[CH:20][CH:31]=1
Reactant: COc1cccc(OCCOS(=O)(=O)c2ccc(C)cc2)c1
Reactant: COCCCN1C(=O)COc2ccc(COC3CCCN(C(=O)OCc4ccccc4)C3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCOc4cccc(OC)c4)cc3)cc21

Procedure:
Analogously to Method I, 0.500 g of benzyl 4-hydroxyphenyl-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benz[1,4]oxazin-6-ylmethoxy]piperidinecarboxylate and 0.414 g of 2-(3-methoxyphenoxy)ethyl toluene-4-sulphonate are reacted. The title compound is obtained as a colourless oil. Rf=0.31 (2:1 EtOAc-heptane); Rt=5.51.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9]O)[CH:2]=1.[BrH:11]>>[BrH:11].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][Br:11])[CH:2]=1
Reactant: OCCCc1cccnc1
Agent: Br
Product: BrCCCc1cccnc1

Procedure:
A solution of 32.53 g (0.24 mole) of 3-(3-pyridyl)-propan-1-ol in 176 ml of 48% hydrobromic acid is refluxed for 24 h. The reaction mixture is evaporated and the residue is taken up in 500 ml isopropanol and subjected to evaporation again. The evaporation procedure is repeated one more time. The resulting product is then taken up in hot isopropanol and treated with charcoal and filtered. The filtrate is cooled slowly to give 3-(3-pyridyl)propyl bromide hydrobromide, m.p. 103°-105°.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4]P(=O)(OC)OC.[H-].[Na+].[CH:17](=O)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[O:22]1[CH:21]=[CH:20][CH:19]=[C:18]1/[CH:17]=[CH:4]/[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[Br:1]
Reactant: COP(=O)(Cc1ccccc1Br)OC
Reactant: O=Cc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccccc1/C=C/c1ccco1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
A solution of dimethyl 2-bromobenzylphosphonate (10.35 g) in dry DMF (50 ml) was added dropwise at room temperature to a stirred suspension of sodium hydride (0.979 g) in dry DMF (100 ml) (effervescence). After 20 minutes, a solution of furfural (3.56 g) in dry DMF (50 ml) was added (exotherm) and the resulting mixture was stirred at room temperature for 4 hours, then diluted with water and extracted with ether. The extracts were washed with water, treated with magnesium sulphate and charcoal, filtered, concentrated under reduced pressure, and chromatographed using 40°-60° C. petrol as eluant to give E-1-(2-furyl)-2-(2-bromophenyl)-ethylene (3.755 g), a pale yellow liquid (containing about 6% of the corresponding Z-isomer by GC).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.C(O)(=O)C>CO.O>[CH:17]1([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[S:10]([NH2:13])(=[O:11])=[O:12])[CH2:19][CH2:18]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(NC2CC2)c(S(N)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a solution of 2-amino-5-methoxybenzenesulphonamide (4.9 mmol) in methanol (20 mL) there are added (1-ethoxycyclopropyloxy)trimethylsilane (4 mL) and glacial acetic acid (4 mL) and then heating at reflux is carried out for 18 hours. The mixture is then evaporated to dryness under reduced pressure. The oil obtained is taken up in water (30 mL) and extracted with chloroform (3×30 mL). The organic phases are collected and dried over anhydrous MgSO4. After filtration, the filtrate is evaporated to dryness and the residual oil is dissolved in THF (50 mL). Sodium borohydride (2 g) and boron trifluoride etherate (2 mL) are added and then the mixture is heated at reflux for 18 hours. The solvent is then removed by evaporation under reduced pressure and the residue is taken up in water (30 mL), adjusted to slightly acid pH by adding 6N HCl and then extracted with chloroform (3×30 mL). The organic phases are collected and dried over anhydrous MgSO4. After filtration, the filtrate is evaporated to dryness and the expected compound is obtained in the form of an oil used directly in the next Step.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][O:10][C:9]2[CH:8]=[C:7]3[NH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:6]3=[CH:5][C:4]=2[NH:3]1.[CH2:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[CH2:18]([CH:25]1[CH2:30][CH2:29][N:28]([C:15]([C:13]2[NH:12][C:7]3=[CH:8][C:9]4[O:10][CH2:11][C:2](=[O:1])[NH:3][C:4]=4[CH:5]=[C:6]3[CH:14]=2)=[O:17])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C1COc2cc3[nH]c(C(=O)O)cc3cc2N1
Solvent: CCOCC
Product: O=C1COc2cc3[nH]c(C(=O)N4CCC(Cc5ccccc5)CC4)cc3cc2N1

Procedure:
The title compound is prepared from 6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-2-carboxylic acid and 4-benzylpiperidine according to the method described in Example 1/c. Mp.: 225-231° C. (diethyl ether).
Reaction SMILES: CC1[O:6]C(C2C=C(C(N)=O)C=CC=2C2C=CC=CC=2)=NN=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:34])=[N:32][N:33]=2)=[CH:25][C:24]=1[C:35]1[CH:40]=[CH:39][C:38]([C:41](O)=[O:42])=[CH:37][CH:36]=1.[CH3:44][N-:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[CH:49][CH:48]=1>>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:34])=[N:32][N:33]=2)=[CH:25][C:24]=1[C:35]1[CH:40]=[CH:39][C:38]([C:41]([NH:54][CH2:53][C:50]2[CH:51]=[CH:52][C:47]([C:46]([NH:45][CH3:44])=[O:6])=[CH:48][CH:49]=2)=[O:42])=[CH:37][CH:36]=1
Reactant: Cc1nnc(-c2cc(C(N)=O)ccc2-c2ccccc2)o1
Reactant: C[N-]Cc1ccc(CN)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: CNC(=O)c1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
2′-Methyl-N-4-[(methylamino)carbonyl]benzyl)5′-(5-methyl-1,3,4-oxadiazol-2-yl-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-methyl-(4-aminomethylbenzyl)amide using method H. NMR; δH [2H6]—DMSO 9.18,(1H, t), 8.38,(1H, q), 8.01,(2H, d), 7.89, (1H, dd), 7.78,(3H, m), 7.54,(3H, m), 7.40,(2H, d), 4.55,(2H, d), 2.76,(3H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 2.88 min, MH+ 441.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].[Cl:10][C:11]1[C:12]([F:23])=[C:13]([C:17]([CH3:22])=[C:18]([F:21])[C:19]=1[F:20])[C:14](Cl)=[O:15]>>[Cl:10][C:11]1[C:12]([F:23])=[C:13]([C:17]([CH3:22])=[C:18]([F:21])[C:19]=1[F:20])[C:14]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])=[O:15]
Reactant: Cc1c(F)c(F)c(Cl)c(F)c1C(=O)Cl
Reactant: CCOC(=O)CC(=O)O
Product: CCOC(=O)CC(=O)C(=O)c1c(C)c(F)c(F)c(Cl)c1F

Procedure:
The procedure outlined for Example H was used to prepare the title compound from the dianion of malonic acid monoethyl ester and 3-chloro-2,4,5-trifluoro-6-methylbenzoyl chloride. The crude product was also chromatographed on silica gel to give the desired product as an orange oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([C:2]2[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: Clc1ncc(Br)cn1
Product: Brc1cnc(N2CCCC2)nc1

Procedure:
Prepared from 2-chloro-5-bromopyrimidine and pyrrolidine by the method of Example 44 (b).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2/[C:12](=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)/[C:13]#[N:14].C(=O)=O.C(O)C.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2/[C:12](=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)/[C:13]#[N:14]
Reactant: COc1ccc2[nH]cc(/C(C#N)=C/c3cccnc3)c2c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CCO
Product: N#C/C(=C\c1cccnc1)c1c[nH]c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a mixture of (Z)-2-(5-methoxy-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile (compound of example 4) (175 mg, 0.6 mmol, 1.0 eq.) in anhydrous dichloromethane (2 mL) cooled to −78° C. (dry ice/ethanol bath) was added, under an argon atmosphere, a 1M boron tribromide solution in dichloromethane (2 mL, 2.0 mmol, 3.2 eq.). The reaction mixture was stirred at ambient temperature for 18 hours ant then quenched with ethanol. The solvent was removed under reduced pressure and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/MeOH, 95:5 to 93:7) to afford (Z)-2-(5-hydroxy-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile as a yellow powder (150 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:26]=[CH:27]/[C:28]([NH:30][O:31]C2CCCCO2)=[O:29])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[O:15])[CH2:10]1.[ClH:38].C(O)C>CCOC(C)=O>[ClH:1].[ClH:38].[Cl:1][C:2]1[CH:3]=[C:4](/[CH:26]=[CH:27]/[C:28]([NH:30][OH:31])=[O:29])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:20][CH2:21]2)=[O:15])[CH2:10]1
Reactant: CN(C)C[C@H]1CC[C@H](C(=O)N2CC[C@@H](Nc3ncc(/C=C/C(=O)NOC4CCCCO4)cc3Cl)C2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C[C@H]1CC[C@H](C(=O)N2CC[C@@H](Nc3ncc(/C=C/C(=O)NO)cc3Cl)C2)CC1
Reaction time: 3 h

Procedure:
A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino) methyl]cyclohexyl}-carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (530 mg) and 2N HCl/Ethanol (5 ml) was stirred for 3 hrs. EtOAc (10 ml) and IPE (50 ml) was added and stirred. After 1 hour, precipitate was filtered and dried to give 462 mg (89%) of (2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl}carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride.
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].Br[CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=1.CC[O-].[Na+]>CCO>[CH3:17][O:16][C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([CH3:15])[CH:12]=1)[CH:8]=[O:2]
Reactant: COc1cc(C)cc(CBr)c1
Reactant: CC(C)[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C)cc(C=O)c1
Yield: 77.2 %

Procedure:
2-Nitropropane (6.77 ml, 71.3 mmol) and subsequently 1-bromomethyl-3-methoxy-5-methyl-benzene (14.6 g, 67.9 mmol) were added to a solution of NaOEt (4.72 g, 67.9 mmol) in EtOH (60 ml). The mixture was heated for 1.5 h. to 65° C. After cooling the colorless precipitate of filtered off and the filtrate was concentrated. The product was purified by chromatography (SiO2, CH2Cl2/hexane 1:2). There were obtained 7.87 g (77%) of 3-methoxy-5-methyl-benzaldehyde as a colorless liquid.
Reaction SMILES: N1([NH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])CCNCC1.[CH3:18][N:19]([CH3:24])[CH2:20][C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:48]([N:50](CC)[CH2:51][CH3:52])[CH3:49]>O1CCCC1>[CH3:18][N:19]([CH3:24])[CH2:20][C:21]([N:50]1[CH2:51][CH2:52][N:7]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:49][CH2:48]1)=[O:22]
Reactant: CCN(CC)CC
Reactant: CN(C)CC(=O)O
Reactant: O=C(NN1CCNCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 31.2 %

Procedure:
Benzyl piperazine-1-carbamate (2.203 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 ml); 2-dimethylaminoacetic acid (1.24 g, 12.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g, 12.0 mmol), 1-hydroxy-1H-benzotriazole monohydrate (1.84 g, 12.0 mmol) and triethylamine (3.35 ml, 24.0 mmol) were added thereto; and the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine, dried over anhydrous sodium sulfate, and the residue was purified by NH silica gel column chromatography (eluent; ethyl acetate:hexane=3:1) to yield the title compound (954 mg, 3.12 mmol, 31.2%) as a colorless oil.
Reaction SMILES: [N:1]([C:4]1[C:5]([NH:11]C(=O)C(C)(C)C)=[N:6][CH:7]=[C:8]([F:10])[CH:9]=1)=[N+:2]=[N-:3].[ClH:18]>>[N:1]([C:4]1[C:5]([NH2:11])=[N:6][CH:7]=[C:8]([F:10])[CH:9]=1)=[N+:2]=[N-:3].[ClH:18]
Reactant: CC(C)(C)C(=O)Nc1ncc(F)cc1N=[N+]=[N-]
Agent: Cl
Product: [N-]=[N+]=Nc1cc(F)cnc1N
Reaction time: 2 h

Procedure:
N-(3-Azido-5-fluoropyridin-2-yl)-2,2-dimethylpropanamide (275 mg, 1.16 mmol) in 3 N HCl (5 mL) was heated to 100° C. After 2 h, the volatiles were removed in vacuo, to give the title compound as its HCl salt (180 mg). MS154.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-]>C(Cl)CCl.[Cu]Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:19])[C:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cn1cccc1CCNS(=O)(=O)c1ccc(F)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: Cl[Cu]
Solvent: ClCCCl
Product: CCOC(=O)Cc1ccc(CCNS(=O)(=O)c2ccc(F)cc2)n1C
Reaction time: 0.33 h

Procedure:
1.69 g of 2-(2-(4-fluorobenzenesulphonylamino)-ethyl)-1-methylpyrrole are dissolved in 6 ml of ethylene chloride and 0.06 g of copper(I)chloride are added. Under a nitrogen atmosphere the mixture is refluxed and then a solution of 0.34 g of ethyl diazoacetate in 6 ml of ethylene chloride is slowly added dropwise. After 20 minutes the evolution of nitrogen has ended and the suspension is concentrated to dryness by rotary evaporation. Then the residue is chromatographed over a silica gel column (ethylene chloride/ethyl acetate = 100/1).
Reaction SMILES: [C:1]1([N:7]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][S:8]2(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[C:21]([F:27])[CH:20]=1>CN(C=O)C.CCOC(C)=O.O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8]2(=[O:15])=[O:14])=[C:21]([F:27])[CH:20]=1
Reactant: O=S1(=O)NCCCCN1c1ccccc1
Reactant: Fc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)N(Cc2ccc(Br)cc2F)CCCCN1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A solution of 2-phenyl-1λ6,2,7-thiadiazepane-1,1-dione (500 mg, 2.21 mmol) and NaH (214 mg, 6.63 mmol) in DMF (15 mL) was stirred at 0° C. for 10 minutes. To the solution was added a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (881 mg, 3.32 mmol) in DMF (5 mL) and stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc and water, extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-[(4-bromo-2-fluorophenyl)methyl]-7-phenyl-1λ6,2,7-thiadiazepane-1,1-dione as a yellow oil (548 mg, 60%). LCMS (ESI): m/z=413.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](Cl)=[O:5].[CH2:15]([NH2:18])[C:16]#[CH:17]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([NH:18][CH2:15][C:16]#[CH:17])=[O:5]
Reactant: C#CCN
Reactant: C[Si](C)(C)c1cccc(Br)c1C(=O)Cl
Product: C#CCNC(=O)c1c(Br)cccc1[Si](C)(C)C
Yield: 81 %

Procedure:
The compound of Example d was reacted with propargylamine (3 eq) according to General Method E1 and the crude product was recrystallized from hexanes to afford 0.55 g of the title compound as off-white needles in 81% yield. m.p. 120-121° C.