Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:5]=1[C:6]1[C:7]([CH2:18][CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=[CH:10][C:11]=1[NH:12]2.[CH3:27]I>CN(C)C=O>[CH3:3][C:4]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:5]=1[C:6]1[C:7]([CH2:18][CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=[CH:10][C:11]=1[N:12]2[CH3:27]
Reactant: CCCN(CCC)CCc1cccc2[nH]c3c(C)ccc(C)c3c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)CCc1cccc2c1c1c(C)ccc(C)c1n2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a Suspension of 0.25 ml of 60% sodium hydride (in an oil) in 5 ml of dry N,N-dimethylformamide was added dropwise a solution of 2 g of 5,8-dimethyl-4-(2-di-n-propylaminoethyl)carbazole in 10 ml of dry N,N-dimethyl-formamide, and the mixture was stirred for 30 minutes. To the mixture was added dropwise 1.0 g of methyl iodide, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and extracted with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was chromato-graphed on silica gel column with hexane - acetone (1 : 3) to give 5,8,9-trimethyl-4-(2-di-n-propylaminoethyl)-carbazole, to which a 4N hydrochloric acid - ethyl acetate solution was added. The formed crystals were collected by filtration to give 1.7 g of 5,8,9-trimethyl-4-(2-di-n-propylaminoethyl)carbazole hydrochloride.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].[H-].[Na+].Cl[C:13]1[C:14]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:15][S:16][N:17]=1.O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:13]1[C:14]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:15][S:16][N:17]=1)[CH3:2]
Reactant: CCOCCOCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-ethoxyethoxy)ethanol (1.21 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:25][C:26]([CH3:37])=[C:27]([CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[CH3:36])[N:28]=2)=[CH:20][CH:19]=1>>[CH3:37][C:26]1[O:25][C:24]([C:21]2[CH:22]=[CH:23][C:18]([C:11]3[CH:12]=[CH:13][C:8]([C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:7])=[CH:9][CH:10]=3)=[CH:19][CH:20]=2)=[N:28][C:27]=1[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[CH3:36]
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: Cc1oc(-c2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 4-pyrrolidine-1-carbonyl phenyl boronic acid (314 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 55 mg (43%). MS (m/e) 444.4 (M+1)
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=1>ClC(Cl)C.C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8]2)[CH3:21])=[CH:16][CH:15]=1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: CC(=O)c1ccc(Br)cc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(c1ccc(Br)cc1)N1CCOC(c2ccccc2)C1

Procedure:
The above compound could be made the following way: 1 eq. of 2-Phenylmorpholine (Array) in dichloroethane could be combined with 1.2 eq. 4′-Bromoacetophenone (Aldrich) and stirred overnight at room temperature. 1.5 eq. borane-pyridine complex could be added and the reaction stirred for several hours. The reaction mixture could be diluted with methylene chloride and washed with water and brine. The organics could be dried over sodium sulfate and purified by column chromatography.
Reaction SMILES: [S:1]([O-:6])(O[O-])(=O)=[O:2].[K+].[K+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([C:26]([C:28]3[C:36]4[CH:35]=[N:34][CH:33]=[N:32][C:31]=4[N:30]([CH2:37]SC)[CH:29]=3)=[O:27])[CH:25]=2)=[O:18])=[CH:12][CH:11]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[CH3:49]O>O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([C:26]([C:28]3[C:36]4[CH:35]=[N:34][CH:33]=[N:32][C:31]=4[N:30]([CH2:37][S:1]([CH3:49])(=[O:6])=[O:2])[CH:29]=3)=[O:27])[CH:25]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CO
Reactant: CSCn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)Cn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
Potassium peroxomonosulfate (Oxone, 67.2 mg, 0.110 mmol) was added to a stirring solution of 2-(4-chlorophenyl)-N-[5-({7-[(methylthio)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]acetamide (Example 313, 25.0 mg, 0.055 mmol) in methanol (1.0 mL) and water (0.25 mL) at 0° C. After 1 hour, the reaction was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was cooled to 0° C. and sodium metabisulfite (0.5M, 1 ml) was added. The reaction mixture was evaporated under reduced pressure to remove the methanol. Water (3 mL) was added to the mixture and it was extracted with EtOAc (3×5 mL). The combined organic fractions were washed with water (5 mL), brine (5 mL), dried over magnesium sulfate the solvent was removed under reduced pressure to give the crude product as an off-white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:24]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]([C:32](O)=[O:33])=[N:25]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[Cl:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:32]([C:26]3[NH:25][N:24]=[C:28]([C:29]([OH:31])=[O:30])[CH:27]=3)=[O:33])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(C(=O)O)n[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of Intermediate 8-1 (130 mg, 0.367 mmol), 1H-pyrazole-3,5-dicarboxylic acid (74.5 mg, 0.477 mmol), EDCl (91 mg, 0.477 mmol) and HOBt (64.5 mg, 0.477 mmol) in DMF (3 mL) is added triethylamine (149 mg, 0.203 mmol) and the mixture is stirred at room temperature for 18 hours. Any insoluble material is removed by filtration and the filtrate is chromatographed by HPLC using a gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA). Lyophilization of the proper fractions gives the title compound; HPLC Retention time 1.31 minutes (condition C); MS 456.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.07 Hz, 3H), 2.54-2.67 (m, 2H), 2.84-2.97 (m, 2H), 4.02 (q, J=7.07 Hz, 2H), 4.54 (m, 1H), 7.11 (s, broad, 1H), 7.32 (d, J=8.08 Hz, 2H), 7.39 (m, 1H), 7.46 (t, 1H), 7.62 (d, J=8.08 Hz, 3H), 7.69 (s, 1H), 8.41 (s, broad, 1H).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1O)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:25])=O.O>CN(C=O)C>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[Br:25])=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1c(Cc2ccccc2)nnc2c(C(F)(F)F)cccc12
Reactant: O=P(Br)(Br)Br
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc2c(Br)c(Cc3ccccc3)nnc12
Reaction time: 1 h
Yield: 105.2 %

Procedure:
A solution of 3-benzyl-8-trifluoromethyl-cinnolin-4-ol (1.6 g, 4.4 mmol) and POBr3 (2.5 g, 8.7 mmol) in DMF (30 ml) was heated to 75° C. After 1 hr, the reaction was cooled and poured into water. The aqueous layer was extracted with EtOAc which was dried (MgSO4) and concentrated to give a solid. The solid was triturated with MeOH and filtered to give 3-benzyl-4-bromo-8-trifluoromethyl-cinnoline (1.7 g). MS (ES) m/z 366.7.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[OH:21])[O:17][C:16](=[O:22])[C:15]([C:23]([OH:25])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12>CN(C=O)C>[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:15]3[C:16](=[O:22])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([OH:10])=[C:20]([OH:21])[CH:19]=4)=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cc(O)c(O)cc2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(O)c(O)cc2oc1=O
Temperature: 25 °C

Procedure:
DIEA (43.1 μL, 0.25 mmol) was added to 6,7-dihydroxy-3-carboxy-coumarin (50.0 mg, 0.23 mmol) and HATU (94.1 mg, 0.25 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (47.1 mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give the final product: LCMS (ESI) m/z 413 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C([C:9]1[CH:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)[CH:12]=[CH:13][CH:14]=1)#N.C[N:21]([CH:23]=[O:24])C>ClCCl>[CH2:15]([C@H:16]1[CH2:17][O:19][C:23](=[O:24])[NH:21]1)[C:11]1[CH:10]=[CH:9][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: N#Cc1cccc(/C=C/C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C1N[C@@H](Cc2ccccc2)CO1
Reaction time: 0.5 h

Procedure:
Oxalyl chloride was slowly added at room temperature to a mixture of (2E)-3-(3-cyanophenyl)acrylic acid, DMF and dichloromethane and stirred for 30 minutes. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was dissolved in THF and again concentrated under a reduced pressure. By repeating this operation, excess hydrogen chloride and oxalyl chloride were removed and crude (2E)-3-(3-cyanophenyl)acrylic acid chloride was obtained. The thus obtained crude product and (S)-4-benzyl-2-oxazolidinone were subjected to condensation reaction in the same manner as in Reference Example 1 to obtain 3-{(1E)-3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxoprop-1-en-1-yl}benzonitrile. FP: 333, NMR 1: 3.02 (1H, dd, J=7.0, 13.5 Hz), 3.10 (1H, dd, J=3.5, 13.5 Hz), 4.25 (1H, dd, J=3.0, 8.5 Hz), 4.41 (1H, t, J=8.5 Hz), 4.75-4.85 (1H, m), 7.20-7.37 (5H, m), 7.68 (1H, t, J=8.0 Hz), 7.85 (2H, br.s), 7.90-7.95 (1H, m), 8.01-8.06 (1H, m), 8.20 (1H, br.s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)[CH2:14][CH2:13]2)[CH2:2]1.[Cl:27][CH2:28][C:29]([NH2:31])=[O:30]>CS(C)=O>[ClH:27].[ClH:27].[NH:23]1[C:24]2[C:20](=[CH:19][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C@@H:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[N:1]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:2]4)[CH2:17][CH2:16]3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: NC(=O)CCl
Reactant: c1ccc2c(c1)NC[C@@H]2CCN1CCN(c2ccc3[nH]ccc3c2)CC1
Solvent: CS(C)=O
Product: Cl
Product: NC(=O)CN1C[C@H](CCN2CCN(c3ccc4[nH]ccc4c3)CC2)c2ccccc21

Procedure:
from 5-{4-[(R)-2-(2,3-dihydro-1H-indol-3-yl)-ethyl]-piperazin-1-yl}-1H-indole and 2-chloroacetamide. Assignment of the optical rotation was done in dimethyl sulfoxide.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:17])[NH:13][N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:5]=1.Cl.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](NN)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:13]2[C:12](=[O:17])[C:11]3[O:10][C:9]4[C:4]([O:3][CH:2]([F:1])[F:23])=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]=4[C:16]=3[CH:15]=[N:14]2)=[CH:28][CH:27]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(OC(F)F)c2oc3c(=O)[nH]ncc3c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(OC(F)F)c2oc3c(=O)n(-c4ccc(Cl)cc4)ncc3c12
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of ethyl 6-difluoromethoxy-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylate (from step 6 of example 4) (168 mg, 0.4 mmol) in ethanol (20 ml), p-chloro phenylhydrazine hydrochloride (72 mg, 0.4 mol) and sodium carbonate (43 mg, 0.4 mmol) was added at room temp. The reaction mixture was stirred at room temp. for 4 hrs. Ethanol was distilled out under vacuum. The concentrated mass was heated to reflux temperature in acetic acid. Progress of reaction was monitored by TLC. At the end, water was added, the solid obtained was filtered and suck dried. The solid was dried in oven. White colored solid (160 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]([CH3:17])[CH2:14][N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:11]=2[CH:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]=O.Cl.CNC.O.[C:38]([OH:41])(=[O:40])[CH3:39]>>[C:38]([O:41][CH2:31][C:10]1[C:11]2[CH2:12][N:13]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH:15]([CH3:17])[C:16]=2[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:40])[CH3:39]
Reactant: C=O
Reactant: CC1CN(Cc2ccccc2)Cc2cc(-c3ccccc3)n(Cc3ccccc3)c21
Reactant: CC(=O)O
Agent: CNC
Agent: Cl
Solvent: O
Product: CC(=O)OCc1c2c(n(Cc3ccccc3)c1-c1ccccc1)C(C)CN(Cc1ccccc1)C2
Reaction time: 72 h

Procedure:
A mixture of 1,5-dibenzyl-4,5,6,7-tetrahydro-7-methyl-2-phenyl-1H-pyrrolo[3,2-c]pyridine (2 g), formaldehyde (1 ml 40% aqueous solution) and dimethylamine hydrochloride (1 g) in glacial acetic acid (20 ml) was kept at room temperature for 3 days and then poured into water (150 ml). The mixture was extracted with ether (2 × 100 ml), the ether extracts washed with saturated sodium carbonate solution (3 × 100 ml), dried over magnesium sulphate and evaporated. Trituration of the resulting oil with ether gave the title compound as white needles. 0.82 g M.pt. 126° C(Found: C, 79.8; H, 7.1; N, 6.0. C31H30N2O2 requires: C, 80.1; H, 6.9; N, 6.0.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:4]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Chloroacetyl chloride (0.37 ml, 4.6 mmol) was added to a solution of indoline (0.47 ml, 4.19 mmol) and triethylamine (TEA; 0.70 ml, 5.03 mmol) in dichloromethane (DCM; 15 ml). The mixture was stirred for 3 hrs at room temperature (RT) and then quenched with water (5 ml). The phases were separated and the aqueous layer was extracted with DCM (3×5 ml). The combined organic layers were dried over MgSO4 and concentrated to a dark brown residue, 1 g (quantitative), which was used for the next step without further purification.
Reaction SMILES: CO.C([Cl:6])(=O)C.C(=O)([S:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)C>CO.ClCCl>[ClH:6].[NH:14]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:20]2[C:12]([CH2:11][CH2:10][SH:9])=[CH:13]1.[ClH:6]
Reactant: CC(=O)Cl
Reactant: CC(=O)SCCc1c[nH]c2ncccc12
Solvent: CO
Solvent: ClCCl
Product: Cl
Product: SCCc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanol (20 ml) was cooled to below 0° C. under argon. Acetyl chloride (3 ml, 42 mmole) was then slowly added dropwise. The reaction was exothermic. The temperature was maintained below 15° C. during the dropwise addition. The reaction mixture was stirred for 1 hour at room temperature. S-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl ethanethioate (600 mg, 2.724 mmole) was dissolved in methanol/dichloromethane 1:1 (10 ml) and then added dropwise within 10 minutes. The reaction mixture was stirred for 18 hours at 23° C. The solvent was distilled off. The orange residue was suspended in cyclohexane (5 ml), filtered and washed with cyclohexane (3×1 ml). The beige-coloured Ind-4 was presumably obtained as hydrochloride (578 mg, 99%, melting point 138-150° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[S:16]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)=[CH:17]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:29]2[CH2:28][CH2:27][N:26]([C:24]3[S:23][N:22]=[C:21]([C:18]4[CH:19]=[CH:20][S:16][CH:17]=4)[N:25]=3)[CH2:31][CH2:30]2)=[O:15])[CH:2]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: c1cc(-c2nsc(N3CCNCC3)n2)cs1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccsc3)ns2)CC1
Yield: 33.2 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (235 mg, 0.872 mmol), 1-[3-(3-thienyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.793 mmol) and diisopropylethylamine (0.152 ml, 0.872 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 98.2 mg (33.3%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[C:46]([NH:50][C:51]([CH:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[O:52])[CH:47]=[CH:48][CH:49]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][C:51]([CH:53]5[CH2:54][CH2:55][O:56][CH2:57][CH2:58]5)=[O:52])[CH:45]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Reactant: CC1(C)OB(c2cccc(NC(=O)C3CCOCC3)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NC(=O)C6CCOCC6)c5)nc43)cc2)CCC1
Temperature: 80 °C
Yield: 50.6 %

Procedure:
To a suspension of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50 mg) and N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]tetrahydro-2H-pyran-4-carboxamide (67 mg) and potassium phosphate (65 mg) and PdCl2(dppf)CH2Cl2 (8 mg) in dioxane (2 mL) and H2O (0.2 mL) was degassed for 5 minutes and then heated to 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (2 times: 0-10% methanol in chloroform then 0-10% methanol in ethyl acetate) gave the product (34 mg, 51%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](Cl)[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O-:29])(=[S:28])[CH3:27].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:28][C:26](=[O:29])[CH3:27])[CH2:10][C@@H:9]1[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Cl)C[C@H]1COCc1cc(F)c(F)cc1F
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@H](COCc2cc(F)c(F)cc2F)N(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 88.8 %

Procedure:
A solution of 0.873 mg (2 mmol) (2S,4S)-4-chloro-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 20 ml DMF and after the addition of 0.343 mg (3 mmol) potassium thioacetate heated for 2.5 h at 100° C. Evaporation and flash-chromatography on silica gel (toluene/CH3CN 95:5) gave 0.745 g (89%) of (2R,4S)-4-acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 420 (MH+).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1C(=O)C2=CC=CC=C2C1=O.[SH:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.O.NN.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2[Cl:55])(=O)C.C[O-].[Na+]>CO>[ClH:55].[ClH:55].[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[S:15][CH2:2][CH2:3][NH2:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Sc1nc2ccccc2s1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: C[O-]
Agent: NN
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cl
Product: NCCSc1nc2ccccc2s1

Procedure:
2-(2-Benzothiazolylthio)ethylamine dihydrochloride was prepared by standard synthetic steps with a by Mitsunobu reaction between N-(2-hydroxyethyl)phthalimide and 2-mercaptobenzothiazole, followed by reaction with hydrazine hydrate. This amine dihydrochloride (0.52 g, 2.11 mmol) was reacted with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (0.79 g, 1.7 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-N-[(R)-2(2-benzothiazolylthio)-1-ethyl]-2-chloroadenosine using sodium methoxide in methanol to provide the title N-[(R)-2-(2-benzothiazolylthio)-1-ethyl]-2-chloroadenosine as a foam after column chromatography, 1H NMR (DMSO-D6) δ3.54-3.60 and 3.64-3.71 (4H, m, H-5'a and H-5'b and --CH2 --), 3.42, (2H, q, --CH2 --), 3.96 (1H, d, H-4'), 4.15 (1H, q, H-3'), 4.52 (1H, q, H-2'), 5.08 (1H, t, 5'-OH), 5.22, 5.51 (2H, 2d, 2'- and 3'-OH), 5.85 (1H, d, H-1'), 7.38, 7.48 (2H, 2t, Ar--H), 7.85, 8.02 (2H, 2d, Ar--H), 8.43 (1H, s, H-8), 8.68 (1H, t, N--H). HPLC retention time 18.5 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].