Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[O:15]1[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:3]=3)[NH:8][CH:9]=2)=[CH:12][N:13]=[CH:14]1
Reactant: Brc1cnc2[nH]cc(-c3cnco3)c2c1
Reactant: OB(O)c1ccccc1Oc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccccc2-c2cnc3[nH]cc(-c4cnco4)c3c2)cc1
Temperature: 105 °C
Yield: 46.2 %

Procedure:
A mixture of bromide 22 (300 mg, 1.14 mmol), 2-phenoxyphenylboronic acid (366 mg, 1.71 mmol), PdCl2(PPh3)2 (80.0 mg, 0.114 mmol), LiCl (145 mg, 3.42 mmol) and 1M Na2CO3 (2.85 mL, 2.82 mmol) in toluene (5.4 mL) and EtOH (5.4 mL) was refluxed overnight (105° C. oil bath temp.). The reaction mixture was cooled, and separated between brine (20 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic solutions were dried (MgSO4) and concentrated. The resulting solid was dry loaded on a silicagel column. Fractions containing the product were eluted using ethyl acetate:hexane (1:1) (gradient elution) to give a solid which was triturated with ether to give 23 as a white solid (186 mg, 46%); 1H NMR (400 MHz, CDCl3) δ 6.94 (dd, J=8.8, 1.0 Hz, 2H), 7.05 (t, J=7.4 Hz, 1H), 7.08 (s, 1H), 7.12 (dd, J=8.1, 1.1 Hz, 1H), 7.33-7.20 (m, 3H), 7.38 (dt, J=9.2, 1.7 Hz, 1H), 7.56 (dd, J=7.6, 1.8 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.85 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H), 9.35-9.20 (bs, NH).
Reaction SMILES: ClCl.[Pb]([S:7][C:8]#[N:9])SC#N.[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[CH:14][CH:13]=1>C(O)(=O)C>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][C:23]([S:7][C:8]#[N:9])=[CH:24][C:19]=1[CH2:18][C:15]1[CH:16]=[N:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1
Reactant: N#CS[Pb]SC#N
Reactant: COc1ccc(Cc2ccccc2OC)cn1
Agent: ClCl
Solvent: CC(=O)O
Product: COc1ccc(Cc2cc(SC#N)ccc2OC)cn1
Yield: 123.5 %

Procedure:
To dry acetic acid (250 ml, dried by refluxing with 5% acetic anhydride for 4.5 hours) was added dry chlorine (16.00 g). Lead thiocyanate (36.48 g) was added in portions with rapid stirring then after 40 minutes 2-(6-methoxy-3-pyridylmethyl)-anisole (45.85 g) in dry acetic acid (175 ml) was added slowly from a dropping funnel. The mixture was stirred at room temperature for 20 hours, filtered, poured into water (approximately 2 liters) and extracted with chloroform. The combined chloroform extracts were washed with water, 2N sodium hydroxide, water, then dried with anhydrous magnesium sulphate and evaporated to dryness to give an orange gum which was crystallised from chloroform/petroleum spirit (60-80°) to give 4-methoxy-3-(6-methoxy-3-pyridylmethyl)phenylthiocyanate as a yellow solid (39.89 g, 55%), m.p. 56-58°.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:24]=[C:23]([C:34]([F:37])([F:36])[F:35])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[CH:24]=[C:23]([C:34]([F:36])([F:37])[F:35])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.6 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.38 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.25 g, 78%). MS (ISP) 475.0 [(M+H)+]; mp 239.5° C.
Reaction SMILES: Br[CH:2]1[CH2:17][CH2:16][C:5]2=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:7][C:8]([S:9][CH3:10])=[C:4]2[C:3]1=O.[C:19]([NH2:27])(=[S:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C>O>[CH3:10][S:9][C:8]1[S:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[C:4]=1[C:3]1[N:27]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:26][C:2]=1[CH2:17][CH2:16]2
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(SC)c2c1CCc1sc(-c3ccccc3)nc1-2
Yield: 33.9 %

Procedure:
A mixture of ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (6.99 g), thiobenzamide (5.49 g) and ethanol (150 ml) was refluxed under heating for 3 hours, after which it was poured over water (500 ml) and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-hexane (1:1, v/v) to yield ethyl 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxylate (2.63 g, 33.9%), which was then recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 153-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[NH:12])[NH:6][C:5]2=N.Cl.[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][CH2:29][C:30](=[NH:32])[N:31]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:1].[NH:12]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[C:10]([Cl:11])[CH:9]=2)[C:5](=[C:29]2[S:28][C:27]([NH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:31][C:30]2=[NH:32])[NH:6]1
Reactant: N=C1NC(=N)c2cc(Cl)c(Cl)cc21
Reactant: N=C1CSC(NCCCCCc2ccccc2)=N1
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Product: N=C1N=C(NCCCCCc2ccccc2)SC1=C1NC(=N)c2cc(Cl)c(Cl)cc21

Procedure:
Following the procedure described in Example 9, part B above but using equivalent amounts of 5,6-dichloro-1,3-diiminoisoindoline and 2-(5-phenylpentylamino)-4-imino-2-thiazoline hydrochloride in place of the 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, there is obtained as the product 1-imino-5,6-dichloro-3-[2-(5-phenylpentylamino)-4-imino-2-thiazolin-5-ylidene]isoindoline hydrochloride.
Reaction SMILES: [CH2:1]([Sn:19](Cl)([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N-:57]=[N+:58]=[N-:59].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([Sn:19]([N:57]=[N+:58]=[N-:59])([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCCC[Sn](Cl)(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC[Sn](CCCCCCCCCCCCCCCCCC)(CCCCCCCCCCCCCCCCCC)N=[N+]=[N-]
Temperature: 120 °C
Reaction time: 6 h
Yield: 68.5 %

Procedure:
A mixture of 20.0 g of trioctadecyltin chloride, 3.0 g of sodium azide and 40 ml of toluene was stirred at 120° C. for 6 hours. After cooling, 100 ml of toluene was added to the reaction mixture. The toluene layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 13.8 g of trioctadecyltin azide.
Reaction SMILES: C(OCC)C.[C@@H:6]12[O:13][CH2:12][C@@H:10]([O:11]1)[CH:9]=[CH:8][C:7]2=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[C@@H:6]12[O:13][CH2:12][C@@H:10]([O:11]1)[CH:9]=[CH:8][C@@H:7]2[OH:14]
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
50 ml of a dry diethyl ether solution containing 20 g of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose, was gradually dropwise added to 500 ml of a dry diethyl ether suspension containing 3.0 g of lithium aluminum hydride, at 0° C. under an inert atmosphere of nitrogen gas. After completion of the dropwise addition, the mixture was immediately returned to room temperature, and stirring was continued for 30 minutes. Disappearance of the starting material was confirmed by thin layer chromatography, and then a small amount of water was added to inactivate an excess amount of lithium aluminum hydride. The mixture was further stirred for 30 minutes, and the reaction mixture was filtered through Celite® to remove the precipitate. The precipitate was washed a few times with diethyl ether, and the washing solutions were concentrated under reduced pressure together with the filtrate. Precipitated crude crystals were recrystallized from diethyl ether to obtain 14.5 g of the desired product (Compound No. 1). The NMR analytical data and physical properties of this product were as follows.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.CCCCCC.[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:33]=2)[CH2:28][C:27]1=[O:44])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(I)C.[Cl-].[NH4+]>C1COCC1>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([C:40]([F:42])([F:43])[F:41])[CH:33]=2)[CH:28]([CH2:1][CH3:2])[C:27]1=[O:44])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(N2CCN(Cc3ccccc3)C(=O)C2)cc1C(F)(F)F
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1C(=O)N(Cc2ccccc2)CCN1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A 0.94 ml portion of diisopropylamine was dissolved in 10 ml of anhydrous THF, and the solution was mixed with 4.5 ml of 1.47 M butyl lithium/hexane solution at −20° C., stirred for 10 minutes and then cooled to −78° C. A 20 ml portion of anhydrous THF solution containing 2 g of 4-(4-benzyl-3-oxopiperazin-1-yl)-2-trifluoromethylbenzonitrile synthesized in Reference Example 1-15 was added dropwise thereto, and the mixture was stirred for 20 minutes and then mixed with 0.67 ml of ethyl iodide. After warming up to −10° C., the reaction solution was poured into saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic layer was washed and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by a silica gel column chromatography, and 1.5 g of the title compound was obtained from hexane-ethyl acetate (1:1, v/v) eluate as a white foamy substance.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[N:10]1)#[N:2].S(=O)(=O)(O)[OH:19].[OH-].[NH4+]>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[N:10]1)(=[O:19])[NH2:2]
Reactant: N#Cc1ccccc1-n1nnc2cccnc21
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccccc1-n1nnc2cccnc21
Reaction time: 7 h

Procedure:
The cyano compound (from Example 7) (600 mg.) was dissolved in 8 ml. of concentrated sulfuric acid with ice cooling. After standing at room temperature for 7 hours it was poured onto ice. The cold solution was treated with an excess of ammonium hydroxide. The precipitate was collected, air dried and recrystallized from dimethylformamide and water to give 3-(2-carbamoylphenyl)-3H-1,2,3-triazolo[4,5-b]pyridine, m.p. >340° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[NH:15]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:16]([C:18](O)=[O:19])[CH3:17]>C1COCC1>[NH:15]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[C@H:16]([C:18]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:19])[CH3:17]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Phenylalanine methyl ester hydrochloride (0.5 g, 2.3 mmol) was suspended in 10 mL of dry THF. Et3 n (0.35 mL, 2.5 mol) was added, after which both CBZ-Ala (10, 0.52 g, 100 mol %) and 1 (0.65 g, 104 mol %) were also added. The reaction mixture was stirred for 24 h at room temperature. Following the general procedure gave 21, 0.74 g, 84%, as a crystalline solid. An identical reaction using DMF as the solvent produced 21 in 93% yield: mp 97°-98° C.; [α]25D -8.3° (c 0.3, EtOH); 1H NMR δ 7.42-7.15 (m, 10H), 6.40 (d, 1H, J=4), 5.24-5.21 (m, 1H), 5.10 (s, 2H), 4.88-4.84 (m, 1H), 4.24-4.21 (m, 1H), 3.78 (s, 3H), 3.16-3.13 (m, 2H), 1.38 (d, 3H, J=7). Anal. Calcd for C21H24N3O5 : C, 65.5; H, 6.3,; N, 7.3. Found: C, 65.5; H, 6.3; N, 7.3. Compound 21 was also synthesized from the reaction of 11 and isourea 2 (R=M1) in DMF (82% yield) and was identical to material formed above.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:20][CH2:19][C:14]2(OCC[O:15]2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCCC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(CCOCc2ccccc2)CC1
Reaction time: 10 h

Procedure:
To a mixture of crude 8-[2-(benzyloxy)ethyl]-1,4-dioxaspiro[4.5]decane (227.8 g) in THF (500 mL) is added 5N HCl (600 mL) at room temperature, and the mixture is stirred for 10 hours at the same temperature. After addition of NaHCO3 aq. (300 g in 500 mL water), the mixture is extracted with EtOAc (1500 mL). The water layer is extracted with EtOAc (1000 mL×2), and the combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude mixture is purified by silica gel column chromatography to afford 4-(2-benzyloxyethyl)cyclohexanone.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[NH2:14][C:15]1[N:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][N:16]=1>>[NH2:14][C:15]1[N:20]=[C:19]([C:21]([NH:11][C@@H:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)[CH3:10])=[O:22])[CH:18]=[CH:17][N:16]=1
Reactant: Nc1nccc(C(=O)O)n1
Reactant: C[C@@H](N)c1cccc(C(F)(F)F)c1
Product: C[C@@H](NC(=O)c1ccnc(N)n1)c1cccc(C(F)(F)F)c1
Yield: 72 %

Procedure:
The title compound is prepared in 72% yield (161 mg, a white solid) from (R)-1-(3-(trifluoromethyl)phenyl)ethanamine (136 mg, 0.72 mmol) and 2-aminopyrimidine-4-carboxylic acid (100 mg, 0.72 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[C:12]([CH:20]([OH:43])[C:21]3[CH:22]=[CH:23][C:24]([N:28]([C:36]4[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:25][C:26]=3[F:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:44][NH2:45]>C(O)(C)C.C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:45][CH3:44])[C:13]=3[C:12]([CH:20]([OH:43])[C:21]3[CH:22]=[CH:23][C:24]([N:28]([C:36]4[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:25][C:26]=3[F:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(Cl)c34)c(F)n2)cn1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CNc1ncnc2c1c(C(O)c1ccc(N(C(=O)OC(C)(C)C)c3ccc(C)nc3)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To tert-butyl N-[5-[[7-(benzenesulfonyl)-4-chloro-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-methyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate (85, 75 mg, 0.12 mmol) in Isopropyl alcohol (0.80 mL) was added 2M methylamine in THF (0.6 ml). The resulting solution was stirred at 40° C. for 6 hours. The reaction was concentrated to give product (86, 70 mg, 94.2%). MS (ESI) [M+H+]+=620.
Reaction SMILES: [CH3:1][SiH:2]1[O:9][SiH:8]([CH3:10])[O:7][SiH:6]([CH3:11])[O:5][SiH:4]([CH3:12])[O:3]1.[OH:13][CH2:14][CH2:15][O:16][C:17]([CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH:21]=[CH:22]2)=[O:18].C1C=CC=CC=1>[Zn](OC(C)=O)OC(C)=O.O>[CH:20]12[CH2:25][CH:23]([CH:22]=[CH:21]1)[CH2:24][CH:19]2[C:17]([O:16][CH2:15][CH2:14][O:13][Si:8]1([CH3:10])[O:9][SiH:2]([CH3:1])[O:3][SiH:4]([CH3:12])[O:5][SiH:6]([CH3:11])[O:7]1)=[O:18]
Reactant: O=C(OCCO)C1CC2C=CC1C2
Reactant: C[SiH]1O[SiH](C)O[SiH](C)O[SiH](C)O1
Agent: CC(=O)O[Zn]OC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: C[SiH]1O[SiH](C)O[Si](C)(OCCOC(=O)C2CC3C=CC2C3)O[SiH](C)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution containing 1M of 2,4,6,8-tetramethylcyclotetrasiloxane and 0.01g of (CH3CO2)2Zn was slowly added 1M of 2-hydroxyethyl-5-norbornene-2-carboxylate. The resulting mixture was stirred for 24 hours at a room temperature. Thereafter, 200 mL of benzene and 200 mL of cold water were added. The organic layer was separated, washed with 200 mL of cold water, dried over MgSO4, filtered and concentrated by distillation to provide the title compound of Formula 1A (yield: 97%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1H-indole-5-carboxylic acid (323 mg, 2.0 mmol) in 10 mL of DCM was added DIPEA (1.03 g, 8.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (400 mg, 2.1 mmol). HBTU (1.14 g, 3.0 mmol) was added at 0° C. The resulting mixture was stirred at r.t. for 18 h. TLC indicated that the starting material was gone. The mixture was diluted with DCM (100 mL) and washed with water (30 mL). The organic layer was separated and dried over anhydrous Na2SO4. The solution was concentrated to give a crude product, which was then purified with silica gel column (Hexane/EtOAc=1/1) to give HJC-2-13 (605 mg, 92%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 8.44 (s, 1H), 7.73 (s, 1H), 7.40 (d, 1H, J=8.4 Hz), 7.26-7.27 (m, 2H), 6.59 (s, 1H), 3.56-3.63 (m, 4H), 3.42-3.47 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:7]=[C:8]([C:12]([C:18]2[S:19][C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)([OH:17])[C:13]([F:16])([F:15])[F:14])[S:9][C:10]=1[CH3:11]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:17][C:12]([C:8]1[S:9][C:10]([CH3:11])=[C:6]([CH3:5])[N:7]=1)([C:18]1[S:19][C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=1)[C:13]([F:15])([F:16])[F:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1nc(C(O)(c2nc(C)c(C)s2)C(F)(F)F)sc1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(c1nc(C)c(C)s1)(c1nc(C)c(C)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (0.68 ml) was added to a solution of 1,1-bis (4,5-dimethyl-2-thiazolyl)-2,2,2-trifluoroethanol (1.54 g) and 4-dimethylaminopyridine (2 g) in dry dichloromethane (70 ml). The mixture was stirred at room temperature overnight and was then washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, dried and evaporated and the residue was purified by flash chromatography to give the title compound. M.p. 163°-164° C. Found: C, 45.9; H, 4.0; N, 7.4. C14H15F3N2OS2 requires C, 46.15; H, 4.15; N, 7.7%
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C.[Cl-].[Na+].O>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: OCc1cc(Cl)ccn1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: OCc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Temperature: 160 °C

Procedure:
To a solution of (4-chloropyridin-2-yl)methanol (384 mg, 2.67 mmol) in DMF (12 mL) is added 1H-indol-5-ol (534 mg, 4.01 mmol), and cesium carbonate (1307 mg, 4.01 mmol). The reaction is sealed and heated to 160° C. via microwave irradiation for 30 min. The reaction mixture is then cooled to room temperature and diluted brine and DCM. The resulting layers are separated and the aqueous layer is extracted three additional times with DCM. The organic layers are combined dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue is purified via FCC (0-100% EtOAc/heptane) to give the title compound. MS (ESI) m/z 241.2 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[O:11].[BH4-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: O=Cc1cc2ccccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1cc2ccccc2o1
Yield: 94.5 %

Procedure:
2-Benzofurancarbaldehyde (2.2 g, 15 mmol) was dissolved in 25 mL of methanol. To this solution was added sodium borohydride (0.28 g, 7.5 mmol) in small portions over a period of 20 minutes. Then 2 mL of water were added and the mixture was evaporated. The residue was dissolved in ethyl acetate (75 mL) and washed with water (3×75 mL), dried (MgSO4) and evaporated, providing 2.1 g of benzofuran-2-yl-methanol, in 95% yield; 1H NMR (CDCl3) δ 2.03 (t, J=6.1 Hz, 1H), 4.77 (d, J=6.1 Hz, 214), 6.66 (s, 1H), 7.19-7.32 (m, 2H), 7.45-7.50 (m, 1H), 7.53-7.57 (m, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3C=CC=[CH:17][CH:16]=3)[C:10](=[O:21])C(C#N)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:25]([OH:28])(=[O:27])[CH3:26]>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:21])[C:26]([C:25]([OH:28])=[O:27])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: N#Cc1nn(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Product: CCCCn1c(=O)c(C(=O)O)nn(-c2ccccc2)c1=O
Temperature: 120 °C
Yield: 55 %

Procedure:
Intermediate j (9.2 g, 0.035 mol) was added to a mixed solvent of glacial acetic acid (100 mL) and HCl (72 mL, 0.86 mol). The mixture was warmed up to 120° C. and reacted under reflux for 4 h. The solvent was evaporated off. To the obtained fraction was added water (200 mL). The mixture was filtered by suction and dried to produce Intermediate g (6.5 g) in a yield of 55%.