Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:10][C:9](=[O:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.BrC1[CH:21]=[C:22]2[O:28]C(=O)N(C)C2=NC=1>>[CH2:12]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:22](=[O:28])[CH3:21])[CH:3]=[C:4]2[O:10][C:9]1=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1oc2cc(Br)cnc2n1Cc1ccccc1
Reactant: Cn1c(=O)oc2cc(Br)cnc21
Product: CC(=O)c1cnc2c(c1)oc(=O)n2Cc1ccccc1

Procedure:
The method of operation is the same as that used for the synthesis of the compound of Example 1 (coupling with 1-ethoxy-1-(trimethylstannyl)ethylene), 6-bromo-3-benzyloxazolo[4,5-b]pyridin-2(3H)-one from Preparation 13 being used instead of 6-bromo-3-methyloxazolo[4,5-b]pyridin-2(3H)-one. The yield obtained is 75%. ##STR47##
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=O)[C:20]12OCCC[O:27]1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:33][C:34]1([C:38]#[N:39])[CH2:37][CH2:36][CH2:35]1>>[O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:25]=[CH:24][C:23]2[N:22]3[CH2:33][C:34]4([CH2:37][CH2:36][CH2:35]4)[CH2:38][N:39]=[C:21]3[C:20](=[O:27])[C:19]=2[CH:18]=1)(=[O:15])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C12OCCCO2
Reactant: N#CC1(CCl)CCC1
Product: O=C1C2=NCC3(CCC3)CN2c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc21

Procedure:
The title compound was prepared as a yellow foam from 5′-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cyclobutanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 464 [M−H].
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: Cc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1

Procedure:
Using cyclohexyl{3-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.75 g) synthesized in Example 1(6) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.80 g) synthesized in Example 2(2) and in the same manner as in Example 1 (7), the title object compound (0.74 g, 65%) was obtained as a white solid.
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:28])[C@@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C@H:17]1[C:25](Cl)=[O:26].N1C=CC=CC=1.Cl>C1C=CC=CC=1>[CH3:15][C:16]1([CH3:28])[C@@H:18]([CH:19]=[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C@H:17]1[C:25]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:26]
Reactant: OCc1cnc(Oc2ccccc2)s1
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C1CCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)OCc2cnc(Oc3ccccc3)s2)[C@@H]1C=C1CCCC1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
3.1 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of (1R,3S) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-1-carboxylic acid chloride prepared from 2.9 g of the corresponding acid [described in French Pat. No. 70-00265 published under No. 2.076.204] in 45 ml of benzene and 1.2 ml of pyridine were added dropwise thereto at 10° C. The mixture was stirred at 20° C. for 17 hours and was poured into dilute aqueous hydrochloric acid solution. The decanted aqueous phasewas extracted with ether and the combined organic phases were washed with water, dried and evaporated to dryness under reduced pressure. The residuewas chromatographed over silica gel and was eluted with a 7-3 hexane-isopropyl ether mixture to obtain 1.3 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-1-carboxylate meltingat less than 50° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:9]2([OH:17])[O:14][CH2:13][C@@H:12]([CH3:15])[NH:11][C@H:10]2[CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[NH2:25][S:26]([C:29]1[C:30]([Cl:47])=[CH:31][C:32]([NH:40][CH2:41][C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[C:33]([CH:39]=1)[C:34]([O:36][CH2:37]Cl)=[O:35])(=[O:28])=[O:27]>C(#N)C>[NH2:25][S:26]([C:29]1[C:30]([Cl:47])=[CH:31][C:32]([NH:40][CH2:41][C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[C:33]([CH:39]=1)[C:34]([O:36][CH2:37][N:11]1[C@H:12]([CH3:15])[CH2:13][O:14][C@:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)([OH:17])[C@@H:10]1[CH3:16])=[O:35])(=[O:27])=[O:28]
Reactant: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1
Reactant: NS(=O)(=O)c1cc(C(=O)OCCl)c(NCc2ccco2)cc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1COC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1

Procedure:
A solution of free base of (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (20a) (0.023 mole) (U.S. Pat. No. 5,104,870), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate (15) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give (2S,3S,5R)-4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (520). See eg., U.S. Pat. No. 5,104,870) and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.Br[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: c1ccc(Cc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 60 °C
Yield: 14 %

Procedure:
(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidine (200 mg, 0.658 mmol) was taken into DMF (2 mL), and methyl 3-bromopropionate (121 mg, 0.724 mmol) was added, followed by potassium carbonate (182 mg, 1.317 mmol). The mixture was heated to 60° C. and left to react overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The compound was then purified by flash chromatography (eluted with 1% methanol in dichloromethane with a 30:1 silica ratio) to obtain the title product (32.6 mg, 0.092 mmol, 14% yield); LCMS; m/z 353.47, found 354.3 (M+1); 1H NMR (400 MHz, CDCL3) δ 3.92 (s, 1H), 1.59 (s, 2H), 1.76-1.78 (m, 1H), 1.93-2.00 (m, 1H), 2.28-2.30 (m, 1H), 2.52-2.55 (m, 2H), 2.67-2.74 (m, 1H), 2.84-2.91 (m, 1H), 3.11-3.15 (m, 1H), 3.20-3.27 (m, 1H), 3.66 (s, 3H), 3.73-3.77 (m, 1H), 3.91-3.92 (m, 2H), 6.81-6.84 (m, 2H), 7.07-7.09 (m, 2H), 7.16-7.29 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:23][OH:24])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:23][O:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCNC(=O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: COC(=O)CCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(3-methoxycarbonylpropyl)propanamide (504 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(3-methoxycarbonylpropyl)propanamide (497.8 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]3)[N:9]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C>[F:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:13]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[N:11]=[C:10]([NH:20][CH:21]4[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]4)[N:9]=3)=[CH:4][CH:3]=2)=[O:41])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)C1
Reactant: O=C=Nc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)nc(N3CCOCC3)n2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (100 mg, 0.23 mmol), 4-fluorophenylisocyanate (63 mg, 0.46 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; Yield 40 mg (30%); (M+H) 565.6
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.CCN(C(C)C)C(C)C.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>C1COCC1>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:38][CH2:37][CH2:36][CH2:35][N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)N1CCN(CCCN)CC1
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCN(CCCNc2ccnc(Nc3cccc(Cl)c3)n2)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
To 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (0.2 g, 0.837 mmol) in THF (10 mL) is added DIPEA (0.29 mL, 1.67 mmol) followed by 3-(4-(methylsulfonyl)piperazin-1-yl)propan-1-amine, 25, (0.0.369 g, 1.67 mmol). The resulting mixture is refluxed for 12 hours after which the reaction mixture is cooled to room temperature and the solvent removed in vacuo. To the resulting residue is added water (50 mL) and the solution is washed with EtOAc (3×100 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue which is obtained is purified over silica (10% MeOH in CH2Cl2) to afford 0.129 g (50% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz) δ1.71 (m, 2H), 2.39-2.45 (m, 6H), 2.84 (s, 3H), 3.08 (m, 4H), 3.38 (m, 2H), 5.96 (d, J=5.7 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 7.18-7.27 (m, 2H), 7.58 (d, J=7.5 Hz, 1H), 7.81 (bs, 1H), 8.12 (bs, 1H), 9.18 (s, 1H). MS (ESI, pos. ion) m/z: 425 (M+1). HRMS calcd for C18H25ClN6O2S, 425.1526 m/z (M+H)+; observed 425.1512 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[C:3]=1[C:4]#[N:5].[Br:12]Br>C(Cl)(Cl)(Cl)Cl.ClCCl.[Fe].II>[Br:12][C:9]1[C:2]([Cl:1])=[C:3]([C:6]([S:10][CH3:11])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: CSc1cccc(Cl)c1C#N
Reactant: BrBr
Agent: [Fe]
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CSc1ccc(Br)c(Cl)c1C#N
Temperature: 30 °C
Yield: 45.5 %

Procedure:
Iron powder (0.5 g) and iodine (0.05 g) were added to a solution of 2-chloro-6-(methylsulphenyl)benzonitrile (10.0 g) in a mixture of carbon tetrachloride and dichloromethane. The mixture was warmed to 30° C. and bromine (9.5 g) was added. The mixture was heated at 55° C. for 5 hours. It was cooled, washed with aqueous sodium bisulphite, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was redissolved in a mixture of carbon tetrachloride and dichloromethane and treated with iron powder (0.5 g) and iodine (0.05 g). Bromine (6.5 g) was added and the mixture was heated at 55° C. for 5 hours. It was cooled and washed with sodium bisulphite, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography eluted with a mixture of ethyl acetate and n-hexane to give 3-bromo-2-chloro-6-(methylsulphenyl)benzonitrile (6.51 g) as an orange solid NMR (CDCl3) 2.5(s,3H) 7.0(d, 1H) 7.65(d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:23]([NH2:25])[CH3:24]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH2:23][CH3:24])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: FC(F)(F)Oc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CCN
Solvent: CO
Product: CCNc1nc(Cl)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Yield: 92.7 %

Procedure:
A solution of 2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.573 mmol), and ethanamine (0.286 mL, 0.573 mmol) in MeOH (2 mL) was stirred at rt for 1 h. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 2-chloro-N-ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (190 mg, 0.531 mmol, 93% yield). LC-MS (M+H)+=358.2.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([NH:7][S:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(OCC)(=O)C>[C:3]([NH:7][S:8]([C:11]1[CH:12]=[C:13]([S:17]([NH2:2])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [NH4+]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1cccc(S(N)(=O)=O)c1
Reaction time: 8 h

Procedure:
20 ml of concentrated ammonium hydroxide was added to a solution of 1 gram (3.2 mmole) 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. It was stirred vigorously for 8 hours. The ethyl acetate layer was separated dried over magnesium sulfate in vacuo to give 320 mg of the titled compound as a white solid. m.p. 151-154° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[CH2:15](Br)[CH:16]=[CH2:17].O>CN(C=O)C>[CH2:17]([C:12]1[C:11]([OH:14])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([F:3])[CH:13]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Oc1ccc(F)c2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1cc(F)c2cccnc2c1O
Temperature: 0 °C
Yield: 96.1 %

Procedure:
After a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel was replaced with Ar, 5 mL of DMF and NaH (0.88 g, 60 mass % article, 22.0 mmol) were placed therein and the temperature of the mixture was cooled to 0° C. or lower in an ice bath, followed by stirring of the mixture. 5-Fluoro-8-quinolinol (3.42 g, 21.0 mmol) dissolved in 30.0 mL of DMF was added dropwise to this over 1 hour. After the mixture was stirred at the same temperature for 30 minutes, allyl bromide (2.54 g, 21.0 mmol) was added dropwise thereto. Further, the mixture was stirred at the same temperature for 30 minutes, and then the internal temperature was slowly raised to 150° C. and the mixture was heated and stirred for 2 hours. This was cooled to room temperature, and then the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. Then, ethyl acetate was removed under reduced pressure and the resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) using silica gel, followed by drying under reduced pressure to give 4.10 g of 7-allyl-5-fluoro-8-quinolinol as a white solid (yield: 96.0%).
Reaction SMILES: [C-]#[C-].[Na+].[Na+].COC1C=CC([C:13]2C=CS[C:14]=2[C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=O)=CC=1.CS(C)=[O:35]>>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([C:20]2[S:21][CH:13]=[CH:14][CH:18]=2)([OH:35])[C:23]#[CH:22])=[CH:30][CH:29]=1
Reactant: CS(C)=O
Reactant: COc1ccc(-c2ccsc2C(=O)c2sccc2-c2ccc(OC)cc2)cc1
Agent: [C-]#[C-]
Agent: [Na+]
Product: C#CC(O)(c1ccc(OC)cc1)c1cccs1

Procedure:
Sodium acetylide (1.37 g, 33.5 mmol) suspended in dry DMSO (25 ml) was added to p-methoxyphenyl-thiophene-2-yl-ketone (4.8 g, 22 mmol) in portions with stirring under water bath cooling while bubbling acetylene gas. After addition, the reaction mixture was stirred at room temperature for 2 hours, poured onto crushed ice, acidified with 4 M hydrochloric acid until the pH was approximately 6. After extraction with methylene chloride (20 ml, then 2×10 ml), the mixture was dried over anhydrous sodium sulfate and filtered. Evaporation of the solvent gave an oil that was purified by flush chromatography on neutral alumina (activity III) using hexane/methylene chloride (2:1) as eluent. De-coloration with a small amount of charcoal followed by removal of solvent afforded the relatively clean 1-(4methoxyphenyl)-1-(thiophene-2-yl)prop-2-yn-1-ol as yellow-brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](Cl)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([CH:24]=[N+:25]=[N-:26])(C)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:18])[CH:24]=[N+:25]=[N-:26])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Product: [N-]=[N+]=CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.1 %

Procedure:
4-Chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (43 g, 0.15 mol) in dichloromethane (300 mL) was treated with (trimethylsilyl)diazomethane (2.0 M in hexanes, 150 mL, 0.31 mol) over 15 min. The reaction mixture was stirred at ambient temperature for 18 hours and the mixture was concentrated to afford crude 4-(2-diazo-acetyl)-piperidine-1-carboxylic acid benzyl ester (44 g), which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].NC([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)CNC(=O)OC(C)(C)C.N1CCC[C@@H]1CNC(C1SC=CC=1NC1C=CN=C2NC=CC=12)=O>>[NH2:1][CH2:2][CH:3]([NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)NCC(N)c1cccc(F)c1
Agent: O=C(NC[C@H]1CCCN1)c1sccc1Nc1ccnc2[nH]ccc12
Product: NCC(NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1cccc(F)c1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using tert-butyl [2-amino-2-(3-fluorophenyl)ethyl]carbamate instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 496 (M+H) followed by deprotection in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid ((R)-1-pyrrolidin-2-ylmethyl)-amide. LCMS (ESI) 396 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.42 (1H, br. s.) 10.87 (1H, s) 9.24 (1H, d, J=8.59 Hz) 8.20 (1H, br. s.) 8.01 (1H, d, J=6.78 Hz) 7.95 (1H, d, J=5.22 Hz) 7.41 (1H, dd, J=3.51, 2.59 Hz) 7.32 (1H, d, J=5.22 Hz) 7.18-7.27 (1H, m) 7.13-7.17 (1H, m) 7.10 (1H, dd, J=12.89, 1.61 Hz) 7.04 (1H, td, J=8.90, 3.29 Hz) 6.94 (1H, br. s.) 6.58 (1H, d, J=6.93 Hz) 5.32 (1H, dd, J=18.28, 4.32 Hz) 3.18 (1H, dd, J=11.86, 5.12 Hz)
Reaction SMILES: N[C:2]1[CH:7]=[C:6](OC)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2.Cl.[N:25]([O-:27])=[O:26].[Na+].O>C(O)(=O)C>[N+:25]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2)([O-:27])=[O:26]
Reactant: COc1ccc(-c2ccc3cc(OC)c(OC)cc3c2)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2ccc(-c3ccccc3[N+](=O)[O-])cc2cc1OC
Reaction time: 8 h
Yield: 41.4 %

Procedure:
6-(2-Amino-4-methoxyphenyl)-2,3-dimethoxynaphthalene (32) (12 mg, 0.039 mmol) was dissolved in acetic acid (0.6 mL) and concentrated hydrochloric acid (0.06 mL). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.026 g in 0.5 mL water). The resulting diazonium solution was allowed to rise to room temperature slowly and left overnight. To the resulting red solution which contained some precipitate was added 30 mL water and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. The ethyl acetate extracts were dried with anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 40:60 hexanes:ethyl acetate to give the pure 4 (5 mg) in 40% yield; mp 244-246° C.; IR (KBr) 2919, 1619, 1507, 1388, 1292, 1277, 1204 cm−1; UV (MeOH) 292, 266, 216 nm; 1H NMR (CDCl3) δ4.10 (6H, s), 4.22 (3H, s), 7.32 (1H, s), 7.54 (1H, dd, J1=9.1, J2=2.6), 8.04-8.08 (2H, m), 8.28 (1H, d, J=8.9), 8.49 (1H, d, J=9.1), 9.16 (1H, s); 13C NMR δ56.33, 56.52, 56.92, 104.36, 107.93, 108.92, 116.88, 117.08, 119.48, 123.51, 124.54, 127.14, 128.42, 132.46, 141.77, 148.52, 151.12, 151.40, 160.45; HRMS (EI) calcd for C19H16N2O3 m/z: 320.1161; found: 320.0384.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])[CH:19]=[C:18]([Cl:28])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])[CH:19]=[C:18]([Cl:28])[C:17]=1[O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:12][CH2:13][CH3:14]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CCOC(COCCCCO)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)OCC
Yield: 92.1 %

Procedure:
To a mixture of 2.30 g of 4-(2,2-diethoxyethoxy)butanol, 2.94 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 2.94 g of triphenylphosphine, and 30 ml of tetrahydrofuran was slowly added dropwise 2.48 g of diisopropylazodicarboxylate with stirring in a stream of nitrogen gas under ice cooling. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to give a residue. This residue was subjected to silica gel chromatography, which afforded 4.48 g (yield, 73%) of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene.