Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:31][C:32]([O:34]CC3C=CC=CC=3)=[O:33])[N:27]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:31][C:32]([OH:34])=[O:33])[N:27]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3cccc(F)c3)n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 4.100 g 4-((S)-2-{[5-Benzyloxycarbonylmethoxy-1-(3-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester in 30 ml ethyl acetate were added under argon 0.5 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 16 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was dried under vacuo. Yield: 3.17 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC(C)(O)[C:9]#[N:10].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:18](=[O:28])/[C:17]/2=[C:29](/[C:34]#[N:35])\[C:30]([O:32][CH3:33])=[O:31]>O.O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:18](=[O:28])[C:17]2([CH:29]([C:34]#[N:35])[C:30]([O:32][CH3:33])=[O:31])[C:9]#[N:10]
Reactant: COC(=O)CN1C(=O)/C(=C(/C#N)C(=O)OC)c2cc(Cl)ccc21
Reactant: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CN1C(=O)C(C#N)(C(C#N)C(=O)OC)c2cc(Cl)ccc21
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A solution of potassium carbonate (1.39 g, 10.03 mmol) in water (8.2 ml) was treated with acetone cyanohydrine (4.0 ml, 43.5 mmol) at ambient temperature and continuously stirred for 15 min. A fine suspension of methyl (2Z)-[5-chloro-1-(2-methoxy-2-oxoethyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene](cyano)acetate, intermediate 45, (11.19 g, 33.43 mmol) in tetrahydrofuran (500 ml) was added dropwise and the resulting suspension was heated to reflux for 3 hours. The solid was filtered off, the residue was washed with tetrahydrofuran (3×40 ml) and the collected filtrates were evaporated to dryness. The solid was dissolved in dichloromethane (250 ml), washed with saturated NaHCO3 (2×100 ml), water (100 ml) and dried (MgSO4) to obtain the title compound (10.82 g, 89%) as red-brown solid (HPLC purity: 91%). MS (ESI+): 362.2; MS (ESI−): 360.2
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH:12][CH2:13][CH:14]([CH2:16][OH:17])[OH:15]>N1C=CC=CC=1>[C:1]([O:12][CH2:13][CH:14]([OH:15])[CH2:16][O:17][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)Cl
Reactant: OCC(O)CO
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
n-Nonanoyl chloride (23 g) was dropwise added to a stirred solution of glycerin (6.0 g) in dry pyridine (60 ml) at 0° to 5° C. over 30 minutes. The mixture was stirred at the same temperature for an hour, and then allowed to stand at room temperature overnight. The resultant mixture was poured into ice water (300 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with water (10 ml), 10% aqueous hydrochloric acid and a saturated aqueous solution of sodium chloride (40 ml) in turn, and then dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo, and the residue was subjected to column chromatography on silica gel (636 g) with a mixture of chloroform and acetone (30:1). The eluate was evaporated in vacuo to give 1,3-di-n-nonanoyloxy-2-propanol, mp 30°-31° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCCC[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 19 h
Yield: 73.8 %

Procedure:
To a stirred solution of 30.1 (0.054 g, 0.11 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting mixture was stirred for 19 hours. The reaction was then concentrated in vacuo, and 1 N HCl was added to bring the pH to 1. The resulting mixture was extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The resulting product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 30 (40 mg, 76% yield) as a colorless oil. MS ESI (neg.) m/e: 983.5 (2M−H)+, 491.2 (M−H)+.
Reaction SMILES: [I:1][C:2]1[C:3](C)=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:13]C1C=CC(C(O)=O)=C(C)C=1>>[Cl:13][C:3]1[C:2]([I:1])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:11])[CH:4]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Product: Cc1cc(Cl)c(I)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 2.1, except 4-chloro-2-methylbenzoic acid was used in place of 2,4-dimethylbenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([NH2:8])=O)=[C:4]([F:12])[CH:3]=1.N1C(Cl)=NC(Cl)=NC=1Cl.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([C:6]#[N:8])=[C:9]([F:11])[CH:10]=1
Reactant: NC(=O)c1c(F)cc(Br)cc1F
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(F)cc(Br)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a stirred solution of the above benzamide intermediate (9.4 g, 40 mmol) in DMF (15 mL) was added cyanuric chloride (7.24 g, 40 mL) at 0° C. The reaction was stirred at 0° C. for 3 h. Water was added slowly to the reaction and it was extracted with CH2Cl2 (3×100 mL). The solvent was washed with brine and dried over Na2SO4. The solvent was removed to give 4-bromo-2,6-difluorobenzonitrile (7.57 g, 86.9%).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11]Br)=[C:6](CCC)[C:5]=1O)(=[O:3])[CH3:2].[Br:19][C:20]1[CH:30]=[CH:29][C:23]([O:24]CCCBr)=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH2:2][CH2:2][CH2:1][C:4]3[CH:14]=[CH:13][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[CH:29][CH:30]=1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: BrCCCOc1ccc(Br)cc1
Product: OC(CCCc1ccccc1)c1ccc(OCCCOc2ccc(Br)cc2)cc1

Procedure:
Following the procedure of Step 2 of Example 1, but substituting 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl bromide for the bromide from Step 2, the title compound was prepared.
Reaction SMILES: [CH:1]([N:4]([C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]3[N:21]([CH:23]=[C:24]([C:26](=[O:29])[NH:27][CH3:28])[N:25]=3)[CH:22]=2)=[CH:15][N:16]=1)C(=O)OC(C)(C)C)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]3[N:21]([CH:23]=[C:24]([C:26]([NH:27][CH3:28])=[O:29])[N:25]=3)[CH:22]=2)=[CH:15][N:16]=1)([CH3:3])[CH3:2]
Reactant: CNC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cn2cc(-c3cnc(NC(C)C)s3)cc(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A solution of tert-butyl isopropyl(5-(2-(methylcarbamoyl)-8-phenylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl)carbamate (30 mg) in methylenechloride (2 ml) was treated with TFA (4 ml) and stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue chromatographed on silica gel using ethyl acetate as eluent to give 15 mg of 6-(2-(isopropylamino)thiazol-5-yl)-N-methyl-8-phenylimidazo[1,2-a]pyridine-2-carboxamide as a tan solid. LCMS (Conditions C): 2.62 min (RT); (M+H)+=392.14 (100%). 1H NMR, 500 MHz, CDCl3/CD3OD: δ 8.20 (s, 1 H), 8.19 (d, J=1.65 Hz, 1 H), 7.89 (d, J=1.37 Hz, 1 H), 7.88 (s, 1 H), 7.42-7.53 (m, 3 H), 7.36 (d, J=1.92 Hz, 1 H), 7.34 (s, 1 H), 3.55-3.64 (m, 1 H), 1.34 (d, J=6.32 Hz, 6 H).
Reaction SMILES: NC1C2C(=CC(OC)=C(OC)C=2)N=C([NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])N=1.C(N)CN.C(C1C=CC=CC=1S(Cl)(=O)=O)(C)(C)C>CO>[NH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: COc1cc2nc(NCCNS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(N)c2cc1OC
Agent: CC(C)(C)c1ccccc1S(=O)(=O)Cl
Solvent: NCCN
Solvent: CO
Product: CC(C)(C)c1ccc(S(=O)(=O)NCCN)cc1
Reaction time: 3 h

Procedure:
General Procedure for the Synthesis of Sulfonamides (Scheme 3). N-[2-(4-Amino-6,7-dimethoxy-quinazolin-2-ylamino)-ethyl]-4-tert-butyl-benzene sulfonamide (41): A mixture of ethylenediamine (0.36 g, 6.0 mmol) and t-butylbenzenesulfonyl chloride (0.464 g, 2.0 mmol) in methanol (15 mL) was stirred for 3 h, concentrated, and purified by silica gel chromatography to yield N-(2-amino-ethyl)-4-t-butyl-benzenesulfonamide. Following the procedure for the synthesis of compound 14, compound 42 was obtained. 1HNMR (DMSO-d6) δ 1.17 (s, 9H), 3.11 (s, 2H), 3.48 (s, 2H), 3.86 (s, 3H), 3.93 (s, 3H), 6.90 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.70 (d, J=8.4 Hz, 2H). HRMS (M+H)+ calcd for C22H30N5O4S 460.2013, found 460.2010. Anal. (C22H29N5O4S.HCl) C, H, N.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][CH2:14][CH2:15][C:16]#[N:17].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](O)=[O:25]>>[C:16]([CH2:15][CH2:14][N:13]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:18])[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=1)#[N:17]
Reactant: Cc1ccccc1-c1ccncc1NCCC#N
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(CCC#N)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from 3-(4-o-tolyl-pyridin-3-ylamino)-propionitrile and 3,5-bis(trifluoromethyl)benzoic acid (CAS RN 725-89-3) after a reaction time of 19 hours. The compound was purified by two silica gel chromatographies (10 g and 5 g column, respectively) using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Colorless solid (2%). MS (ESI): m/z=478.13 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](I)=[C:7]([CH:34]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:15][CH:14]=1)#[N:2].[NH:36]([C:40](=[CH2:45])[C:41]([O:43][CH3:44])=[O:42])[C:37]([CH3:39])=[O:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:37]([NH:36][C:40](=[CH:45][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:34][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)=[CH:15][CH:14]=1)[C:41]([O:43][CH3:44])=[O:42])(=[O:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)NCCOc3cc(C#N)ccc3I)cc2)CC1
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)C(=Cc1ccc(C#N)cc1OCCNC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1)NC(C)=O

Procedure:
2.72 g (4.60 mmol) of N-[2-(5-cyano-2-iodophenoxy)ethyl]-4-(1-t-butoxycarbonyl-4-piperidyloxy)benzamide and 1.32 g (9.22 mmol) of methyl 2-acetaminoacrylate were dissolved in 80 ml of acetonitrile. 272 mg (1.21 mmol) of palladium (II) acetate, 630 mg (2.07 mmol) of tri-o-tolylphosphine and 1.71 g (9.23 mmol) of tributylamine were added to the solution, and they were heated under reflux for 3 days. The solvent was evaporated, and the residue was treated with ethyl acetate as the extractant in an ordinary manner to obtain the crude product, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:48])=[C:6]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[S:31](=[O:43])(=[O:42])[NH:32][C:33](=[O:41])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])=[CH:21][CH:20]=3)[C:10]([CH2:44][CH2:45][CH2:46][CH3:47])=[N:9]2)[CH:7]=1.[C:49](Cl)(=[O:54])[CH2:50][CH2:51][CH2:52][CH3:53]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:44]([C:10]1[C:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31](=[O:42])(=[O:43])[NH:32][C:33](=[O:41])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])=[CH:23][CH:24]=2)=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:49](=[O:54])[CH2:50][CH2:51][CH2:52][CH3:53])[CH:3]=[CH:4][C:5]=2[Cl:48])[N:9]=1)[CH2:45][CH2:46][CH3:47]
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Reactant: CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc(Cl)c(-n2nc(CCCC)c(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3)c2C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a mixture of 150 mg (0.213 mmol) of ethyl 1-(5-amino-2-chlorophenyl)-3-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]-biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylate (from Step I), 26 mg (0.213 mmol) of 4-(dimethylamino)pyridine (DMAP), and 1.75 mL of dry pyridine was added 126 μL (128 mg, 1.06 mmol) of valeryl chloride. The mixture was stirred under N2 at room temperature overnight and then partitioned between H2O and ethyl acetate. The organic layer was washed twice with H2O and then with brine. Next, the ethyl acetate phase was dried over Na2SO4, filtered, and rotary-evaporated in vacuo. The yellow-orange residual oil was flash chromatographed on silica gel (gradient elution with 0.5-3% MeOH in CH2Cl2) to give 123 mg (72%) of the title compound as a slightly yellow solid, mp>95° C. (gradual); homogeneous by TLC in 95:5 CH2Cl2 -- MeOH; mass spectrum (FAB) m/e 827 (M+K)+. 400 MHz 1H NMR (CDCl3) δ0.87 (t, J=7.3 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H), 1.02 (t, J=7.1 Hz, 3H), 1.29-1.40 (m, 4H), 1.57 (m, 2H), 1.67 (m, 2H), 2.32 (t, J=7.6 Hz, 2H), 2.53 (t, J=7.8 Hz, 2H), 4.05-4.15 (m, 4H), 7.06 (d, J=8.2 Hz, 2H), 7.21-7.66 (m, 10H), 7.75 (d, J=2.4 Hz, 1H), 8.27 (s, 1H), 8.34 (dd, J=8.0, 1.3 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([NH2:18])[N:3]=1.[Br:19]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([Br:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([NH2:18])[N:3]=1
Reactant: BrBr
Reactant: Nc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47 %

Procedure:
2,6-Diamino-9-benzylpurine (1.00 g, 4.16 mmol) and bromine (1 ml) were dissolved in 100 ml of methylene chloride and the solution was stirred at room temperature for 5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (0.62 g, yield 47%).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:3]=1[CH:25]=[O:26].ClC1C2C([C:37]3[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=3)[C:40]#[N:41])=C(C)N(COCC[Si](C)(C)C)C=2N=CN=1>>[CH:25]([C:3]1[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2[N:6]=[CH:7][N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:10]=2[C:2]=1[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[C:40]#[N:41])=[O:26]
Reactant: C[Si](C)(C)CCOCn1c(C=O)c(I)c2c(N3CCOCC3)ncnc21
Reactant: Cc1c(-c2cccc(C#N)c2)c2c(Cl)ncnc2n1COCC[Si](C)(C)C
Product: C[Si](C)(C)CCOCn1c(C=O)c(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc21

Procedure:
5-Iodo-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (C29) was converted to the product using the method described for synthesis of 3-(4-chloro-6-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C7) in Example 2. The product was obtained as a yellow solid. Yield: 1.5 g, 3.2 mmol, 78%. 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 8.60 (s, 1H), 7.77-7.83 (m, 2H), 7.72-7.76 (m, 1H), 7.67 (br dd, J=8, 8 Hz, 1H), 6.09 (s, 2H), 3.66-3.71 (m, 2H), 3.38-3.44 (m, 4H), 3.23-3.28 (m, 4H), 0.94-1.01 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][C:14]=1[CH3:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2.[CH2:30]([Sn](CCCC)(CCCC)C#C)[CH2:31]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:30]#[CH:31])=[CH:15][C:14]=1[CH3:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(I)cc3C)cc2OC1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C#Cc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)OCC)C(C(F)(F)F)O3)c(C)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of 0.28 g (0.52 mmol) of ethyl 6-chloro-7-(2-methyl-4-iodophenoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate and 12 mg (0.0104 mmol) of tetrakistriphenylphosphine-palladium in 3.5 mL of anhydrous toluene was added 168 uL (0.586 mmol) of tributyl(ethynyl)tin. The resulting solution was heated to 110° C. and shaken for three hrs. LC-MS indicated that the reaction was complete. After cooling to room temperature, the reaction was quenched with addition of 20% aqueous ammonium fluoride. The product was extracted with ethyl acetate. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate. After removing the volatiles, the residues were purified by silica gel chromatography with EtOAc/hexane (1:9). The product was carried on to the next step.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[C:12]([NH:13][C:14](=[O:24])[CH2:15][CH2:16][S:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:11][N:10]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[N:9]=1.CN(C)C=O.I[CH2:37][CH3:38]>O.C(OCC)(=O)C>[Cl:7][C:8]1[C:12]([N:13]([CH2:37][CH3:38])[C:14](=[O:24])[CH2:15][CH2:16][S:17][CH2:18][CH2:19][C:20]([F:22])([F:21])[F:23])=[CH:11][N:10]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[N:9]=1
Reactant: O=C(CCSCCC(F)(F)F)Nc1cn(-c2cccnc2)nc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A 100 mL, 3-neck round bottom flask, equipped with mechanical stirrer, temperature probe and nitrogen inlet was charged with cesium carbonate (654 mg, 2.01 mmol), N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide (380 mg, 1.00 mmol) and N,N-dimethylformamide, (5 mL). Iodoethane (0.089 mL, 1.10 mmol) was added dropwise. The reaction was stirred at 40° C. for 2 hours, at which point thin layer chromatography analysis [((Eluent: ethyl acetate] indicated that only a trace of starting material remained. The reaction mixture was cooled to 20° C. and water (20 mL) was added. It was extracted with ethyl acetate (2×20 mL) and the combined organic layers were concentrated to dryness at <40° C. The residue was purified by flash column chromatography using 0-100% ethyl acetate/hexane as eluent. The fractions containing pure product were concentrated to dryness to afford a colorless oil (270 mg, 66%): 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J=2.7 Hz, 1H), 8.97 (s, 1H), 8.60 (dd, J=4.8, 1.4 Hz, 1H), 8.24 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.60 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.62 (q, J=7.1 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.66-2.57 (m, 2H), 2.57-2.44 (m, 2H), 2.41 (t, J=7.0 Hz, 2H), 1.08 (t, J=7.1 Hz, 3H); EIMS m/z 406 ([M]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26].[CH3:36][Zn]C.C1(C)C=CC=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:36])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Reactant: C[Zn]C
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (200 mg, 0.360 mmol) and dimethyl zinc in toluene (0.360 mL, 0.720 mmol), the title compound was obtained as a yellow solid (161 mg, 84% yield). MS (ESI): 535.0 [M+H]+.