Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH:42](OS(C)(=O)=O)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][C@@H:42]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[S:4][CH2:3]2)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 90 °C
Yield: 31.8 %

Procedure:
A mixture of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (2.05 g) and ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (1.5 g) is heated at 90° C. for 1 day. After cooling, ethyl acetate (300 ml) is added to the mixture, and the resulting solution is washed with 5% phosphoric acid solution (30 ml×2) and water (20 ml) successively. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuo to yield an oily residue, which is purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (0.7 g) as a colorless oil. From the subsequent fraction, tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (0.55 g) is obtained as a colorless oil.
Reaction SMILES: [N+:1](=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[N-].[C:14](N)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCCl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Rh+3].[Rh+3]>[C:14]([NH:1][CH:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OC(C)(C)C
Reactant: NC(=O)c1ccccc1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Product: CC(=O)C(NC(=O)c1ccccc1)C(=O)OC(C)(C)C
Yield: 49.5 %

Procedure:
A solution of tert-butyl 2-diazo-3-oxobutanoate (13.1 g, 71.7 mmol) in 1,2-dichloroethane was added over 12 h to a refluxing solution of benzamide (6.16 g, 50.8 mmol) and dirhodium tetraacetate (786 mg, 1.78 mmol) in 1,2-dichloroethane (75 ml). The mixture was evaporated in vacuo and purified by flash chromatography to give tert-butyl 2-benzamido-3-oxobutanoate as a white solid (6.97 g, 51% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([O:10][CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[O:9])[N:4]=[C:3]1[C:24]([O:26]CC)=[O:25].[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([O:10][CH2:11][CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:9])[N:4]=[C:3]1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1nc(NC(=O)OCCSc2ccc(C(F)(F)F)cc2)cn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(NC(=O)OCCSc2ccc(C(F)(F)F)cc2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.9 %

Procedure:
Ethyl 1-methyl-4-[2-(4-trifluoromethyl-phenylsulfanyl)-ethoxycarbonylamino]-1H-imidazole-2-carboxylate (0.69 g, 1.65 mmol) prepared in the capping step was dissolved in THF/H2O (27.40 ml/13.70 ml), 1N LiOH (4.57 ml) was added thereto, and the mixture was stirred at room temperature. After 15 hours have passed, the reaction solution was acidified to pH 2.0 by 1N HCl and then extracted with EA and water. The organic layer was washed with aqueous NaCl solution, dried over anhydrous MgSO4, and concentrated. The residue was recrystallized from EA and n-hexane to give 1-methyl-4-[2-(4-trifluoromethyl-phenylsulfanyl)-ethoxycarbonylamino]-1H-imidazole-2-carboxylic acid (0.52 g, 80.94%) of a white solid.
Reaction SMILES: C([NH:3][C:4](=[O:7])[CH:5]=[CH2:6])O.[C:8]([NH2:12])(=[O:11])[CH:9]=[CH2:10].[CH2:13]([O:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH3:14].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C=O>CC(C)=O>[CH2:8]([C:5](=[CH2:6])[C:4]([NH2:3])=[O:7])[OH:11].[C:8]([NH2:12])(=[O:11])[CH:9]=[CH2:10].[CH2:13]([O:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH3:14]
Reactant: C=CC(=O)NCO
Agent: C=CC(=O)OCC
Agent: C=CC(N)=O
Agent: C=O
Solvent: CC(C)=O
Product: C=C(CO)C(N)=O

Procedure:
36 g of recrystallized N-methylolacrylamide and 20 g of recrystallized acrylamide were dissolved in 1200 ml of acetone, then added with 23 ml of freshly dissolved ethylacrylate and 0.36 g of dibenzoylperoxide and heatedto reflux for 6 hours while stirring under nitrogen atmosphere. After cooling the polymer was filtered, washed with acetone and dried as usual. Yield: 63 g. Analytical results: free CH2O: absent; total CH2O: 16.23%; [η]: 1.20 dl/g in NaNO3 1 N at 30° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:35]2[S:36][C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:35]3[S:36][C:37]4[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=4[N:39]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: c1ccc2sc(N3CCCNCC3)nc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3nc4ccccc4s3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4]diazepan-1-yl-benzothiazole.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([C:18](=[O:20])[CH3:19])=[CH:15][C:14]=3[CH:21]=2)=[CH:6][CH:5]=1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([OH:20])[CH3:19])=[CH:15][C:14]=3[CH:21]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(COc2ccc3oc(C(C)=O)cc3c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOc1ccc(COc2ccc3oc(C(C)O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of the obtained 1-{5-[(4-ethoxybenzyl)oxy]-1-benzofuran-2-yl}ethanone (6.95 g) in methanol (50 mL) was added sodium borohydride (1.04 g, 27.4 mmol) by small portions, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the solvent was evaporated. Ethyl acetate was added thereto, and the mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=3:2) to give the title compound (2.87 g, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.Cl.[CH3:21][C:22]([CH3:26])=[CH:23][CH2:24][NH2:25]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH2:24][CH:23]=[C:22]([CH3:26])[CH3:21])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: CC(C)=CCN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)=CCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To 10 ml of a solution of 438 mg (2.0 mmol) of 2,4-dichloro-7-metylthieno[3,2-d]pyrimidine and 445 mg (4.4 mmol) of triethylamine in DMF was added 243 mg (2.0 mmol) of 3-methyl-2-butenylamine hydrochloride under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 2 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 396 mg (yield: 74.0%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[CH3:40][C:41]([O:44][C:45]([N:47]1[CH2:54][CH2:53][CH2:52][C@H:48]1[C:49](O)=[O:50])=[O:46])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:49]([C@@H:48]2[CH2:52][CH2:53][CH2:54][N:47]2[C:45]([O:44][C:41]([CH3:43])([CH3:42])[CH3:40])=[O:46])=[O:50])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Yield: 51 %

Procedure:
5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol) was treated with 1-{[(1,1-dimethylethyl)oxy]carbonyl}-L-proline (0.022 g, 0.103 mmol), DIPEA (0.090 mL, 0.514 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.079 g, 0.309 mmol) as in the general procedure described herein. The crude product was purified by silica gel chromatography (hexanes/ethyl acetate) to afford the title compound (0.035 g, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.51 (s, 1H), 9.77 (s, 1H), 8.95 (s, 1H), 7.88-7.98 (m, 1H), 7.77 (s, 1H), 7.44 (s, 3H), 7.33-7.40 (m, 1H), 7.27-7.33 (m, 1H), 7.19-7.26 (m, 1H), 7.07 (s, 1H), 4.52 (s, 2H), 4.15 (m, 1H), 3.24-3.45 (m, 2H), 2.14 (m, 1H), 1.62-1.92 (m, 3H), 1.36 (s, 3H), 1.23 (s, 6 H). MS: m/z 666 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[CH3:25])[C:18]([CH3:27])([CH3:26])[CH2:17]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:21]2[CH:20]=[C:19]3[C:24](=[C:23]([CH3:25])[CH:22]=2)[N:16]([CH3:15])[CH2:17][C:18]3([CH3:27])[CH3:26])=[O:9])[CH:3]=1
Reactant: Cc1cccc2c1N(C)CC2(C)C
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1N(C)CC2(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Under an argon atmosphere 0.473 g (2.67 mmol) 6-chloropyrimidine-4-carboxylic acid chloride and 0.427 g (3.20 mmol) aluminium trichloride were stirred in 20 mL DCM for 30 min. Then 0.520 g (2.67 mmol) 1,3,3,7-tetramethyl-2,3-dihydro-1H-indole in DCM were added dropwise to the reaction mixture and it was stirred for 45 min at RT, then for 45 min at 40° C. Next, the reaction mixture was decomposed with ice water/sodium hydroxide solution, extracted with DCM and the organic phase was evaporated down i. vac. The residue was taken up in MeOH and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: I[C:2]1[C:3]([NH2:14])=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:29](=O)([O-])[O-:30].[Cs+].[Cs+]>CO.[Cu]I>[CH3:29][O:30][C:2]1[C:3]([NH2:14])=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(C2CCOCC2)ncc1I
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1cnc(C2CCOCC2)cc1N
Temperature: 130 °C
Yield: 61 %

Procedure:
A stirred suspension of 1.05 g (3.10 mmol) 5-iodo-2-(tetrahydro-pyran-4-yl)-pyridin-4-ylamine, 59 mg (0.31 mmol) copper(I) iodide, 112 mg (0.62 mmol) 1,10-phenanthroline and 2.02 g (6.19 mmol) cesium carbonate in 5 ml methanol was heated at 130° C. for 2×3 min in a microwave oven. The resulting mixture was then cooled to room temperature and concentrated in vacuo. Flash chromatography (methanol/dichloromethane/triethylamine) afforded 394 mg (57%) 5-methoxy-2-(tetrahydro-pyran-4-yl)-pyridin-4-ylamine as a red crystalline solid. ES-MS m/e (%): 209 (M+H+, 100).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([C:33]([OH:35])=O)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:32])[CH3:31].O[NH:37]/[C:38](=[N:55]\[H])/[C:39]1[CH:47]=[C:46]2[C:42]([C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:44][NH:45]2)=[CH:41][CH:40]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:33]2[O:35][N:55]=[C:38]([C:39]3[CH:47]=[C:46]4[C:42]([C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:44][NH:45]4)=[CH:41][CH:40]=3)[N:37]=2)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:31])[CH3:32]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: [H]/N=C(\NO)c1ccc2c(CCC(=O)OCC)c[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc12
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
EDCI (356 mg) and HOBT (306 mg) were added to a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (200 mg) in THF (5 mL) at RT. The resulting solution was stirred for 30 mins. Ethyl 3-{6-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D107) (383 mg) in THF (5 mL) was added and the reaction mixture was stirred at RT for 2 hours. TBAF (970 mg) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 90 mins. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (20% EtOAc in hexane) to afford ethyl 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D108) (310 mg) as a pale yellow solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.46 (6H, d), 2.74 (2H, t), 3.15 (2H, t), 4.15 (2H, q), 5.51 (1H, m), 7.17 (1H, d), 7.72 (1H, d), 7.93 (1H, dd), 8.20 (2H, d), 8.42 (1H, d), 8.89 (1H, d). MS (ES): C23H23ClN4O4 requires 454; found 455.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](F)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([SH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CS(C)=O>[CH2:19]([S:26][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(SCc2ccccc2)cc1Cl
Temperature: 50 °C
Yield: 94.4 %

Procedure:
Methyl 2-chloro-4-fluorobenzoate (1.92 g, 10.2 mmol, 1 eq), cesium carbonate (3.74 g, 11.5 mmol, 0.13 eq) and benzyl mercaptan (1.3 g, 10.5 mmol, 1.03 eq) were combined in dimethyl sulphoxide (20 ml) and the reaction mixture heated at 50° C. for 4 hours. The reaction mixture was poured into ethyl acetate (10 ml) then washed with water (10 ml). The organic phase was dried over sodium sulphate, evaporated to yield the title compound as pink oil (2.82 g, 9.63 mmol, 95%).
Reaction SMILES: [CH2:1]([NH:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:27](Cl)(Cl)=[S:28]>O1CCCC1>[CH2:1]([N:10]1[CH2:11][CH2:12][N:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:27]1=[S:28])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: S=C(Cl)Cl
Reactant: C(=C/c1ccccc1)\CNCCNc1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a solution of 5.37 g of (E)-N-cinnamyl-N'-(3-pyridyl)ethylenediamine dissolved in 100 ml of tetrahydrofuran, 4.5 g of triethylamine was added and the mixture was ice-cooled. To the mixture was added dropwise 20 ml of a tetrahydrofuran solution containing 5.12 g of thiophosgene over 5 minutes, and subsequently the mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 2 hours. The solvent was distilled off, and the residue was dissolved in chloroform, washed with water and dried, followed by distillation of the solvent. The residue was purified by silica gel column chromatorgraphy (solvent: chloroform-methanol=20:1) to give 2.86 g of (E)-1-cinnamyl-3-(3-pyridyl)imidazolidine-2-thione as caramel.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([O:14][CH2:15][CH3:16])[CH:4]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[CH2:15]([O:14][C:5]1[CH:4]=[C:3]([CH2:2][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:16]
Reactant: CCOC(=O)c1ccc(CBr)cc1OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1
Yield: 148.6 %

Procedure:
A mixture ethyl 4-bromomethyl-2-ethoxy-benzoate (4, 1 gm, 3.5 mmol), dichlorobis-(triphenylphosphine)palladium catalyst (0.1 gm), ethyl alcohol (5 ml) was heated to 50° C. with CO for 6-15 hrs. Catalyst was filtered and solvent was removed to yield the product ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate (1, 0.75 gm, 2.6 mmol, 76%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]3[CH:21]=[CH:20][NH:19][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)[CH:2]=1.Cl[C:23]1C2C=CNC=2N=C(C2C=CC=CN=2)N=1.ClC1C2C=CNC=2N=C(C2C=CC=C(C)N=2)N=1>>[CH3:23][C:15]1[N:14]=[C:13]([C:11]2[N:12]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:8]3[CH:21]=[CH:20][NH:19][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(-c2nc(-c3cccnc3)c3cc[nH]c3n2)nc1
Reactant: Clc1nc(-c2ccccn2)nc2[nH]ccc12
Agent: Cc1cccc(-c2nc(Cl)c3cc[nH]c3n2)n1
Product: Cc1cccc(-c2nc(-c3cccnc3)c3cc[nH]c3n2)n1

Procedure:
2-(6-Methyl-pyridin-2-yl)-4-pyridin-3-yl-7H-pyrrolo[2,3-d]pyrimidine is prepared by an analogous method to 4-pyridin-3-yl-2-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine (Example 1) by replacing 4-chloro-2-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 1) with 4-chloro-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH2:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:27]1[N:32]=[C:31]([S:33][C:34]#[N:35])[C:30]([N+:36]([O-:38])=[O:37])=[CH:29][N:28]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[N+:36]([C:30]1[C:31]([S:33][C:34]#[N:35])=[N:32][C:27]([NH:15][C:10]2[CH:9]=[C:8]([NH:7][C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[CH:12][C:11]=2[CH3:14])=[N:28][CH:29]=1)([O-:38])=[O:37]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl(3-amino-4-methylphenyl)carbamate (8.82 g, 39.7 mmol) in tetrahydrofuran (200 mL) were added N-ethyl-N-isopropylpropane-2-amine (10.4 mL, 59.8 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (9.49 g, 43.8 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (200 mL), and the mixture was extracted with ethyl acetate (150 mL, 2×30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl {3-[(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]-4-methylphenyl}carbamate as a yellow amorphous solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C@@:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([F:18])[CH2:17][C@@:11]1([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:12]([OH:24])[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:31][C:32]([F:46])([F:45])[C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:36]Br.C1OCCOCCOCCOCCOCCOC1>CCCC(C)C.C1COCC1>[CH2:3]([N:10]1[C@@H:15]2[C@@:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([F:18])[CH2:17][C@@:11]1([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:12]([O:24][CH2:36][C:35]1[CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=[C:33]([C:32]([F:31])([F:45])[F:46])[CH:34]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)[C@]1(F)C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCCC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)[C@]1(F)C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reaction time: 40 h
Yield: 62.3 %

Procedure:
Sodium hydride (60% in oil, 100 mg, 2.5 mmol) was washed twice with iso-hexane and added as a suspension in THF (3 ml) to a stirred mixture of (1R*,2R*,5S*,6S*)-8-benzyl-6-ethoxycarbonyl-6-fluoro-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 38; 512 mg, 1.3 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (0.5 ml, 2.7 mmol), 18-crown-6 (360 mg, 1.37 mmol) in THF (5 ml) at room temperature. The reaction mixture was stirred for 40 hours, quenched with saturated aqueous NH4Cl and extracted into a 1:1 mixture of iso-hexane:diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound (494 mg, 61%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[OH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:28])[C:19]3[C:24]([S:25][C:26]=2[CH:27]=1)=[CH:23][CH:22]=[CH:21][CH:20]=3.ClCCl.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[OH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:28])[C:19]3[C:24]([S:25](=[O:9])[C:26]=2[CH:27]=1)=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1c2ccccc2Sc2cc(CO)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CN1c2ccccc2S(=O)c2cc(CO)ccc21
Reaction time: 1.5 h
Yield: 94 %

Procedure:
With ice-cooling, m-chloroperbenzoic acid (1.66 g, 9.6 mmol) was added to a mixture of 3-hydroxymethyl-10-methylphenothiazine (1.94 g, 8.0 mmol) and dichloromethane (30 ml), and the mixture was stirred for 1.5 hours and then at room temperature for 1.5 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture and the reaction product was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; methanol:chloroform=3:97 then 10:90) to give the title compound (1.95 g, 7.52 mmol, 94%) as colorless crystals.