Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][C@@H:4]([C:13]([OH:15])=O)[NH:5][C:6]([O:8][C:9]([CH3:12])(C)C)=[O:7].[CH2:16]([N:18](CC)CC)[CH3:17].ClC(O[CH2:27][CH:28](C)C)=O.C(N)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:16]([NH:18][C:13](=[O:15])[C@H:4]([CH2:3][S:2][CH3:1])[NH:5][C:6]([O:8][CH2:9][CH2:12][CH2:27][CH3:28])=[O:7])[CH3:17]
Reactant: CCN(CC)CC
Reactant: CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)N[C@@H](CSC)C(=O)NCC
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 69.9 %

Procedure:
S-Methyl-N-t-butyloxycarbonyl-L-cysteine (6.63 g, 28.2 mmole) was dissolved in 70 ml of tetrahydrofuran and 4.18 ml (30 mmole) of triethylamine was added to the solution. To the resulting mixture was added dropwise 3.94 ml (30 mmole) of isobutyl chloroformate under cooling at -15° C. and the mixture was stirred at that temperature for 20 minutes. After cooling to -40° C., 3.9 g (60 mmole) of aqueous 70% ethylamine solution was added in a portion and the mixture was stirred for 3 hours under ice cooling. Thereafter, 30 ml of aqueous 5% sodium bicarbonate was added and the organic layer was separated. The aqueous layer was then extracted with 50 ml of ethyl acetate and the combined organic layers were washed successively with 30 ml of aqueous 5% sodium bicarbonate, 30 ml of aqueous saturated sodium chloride, 30 ml of aqueous 10% citric acid, 30 ml of aqueous 5% sodium bicarbonate and 30 ml of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate. The solution was then concentrated in vacuo, resulting in formation of crystals, which were collected and recrystallized from ethyl acetate-n-hexane to give 5.17 g of S-methyl-N-butyloxycarbonyl-L-cysteine ethylamide (70% yield), m.p. 106°-7° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24]O)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:28][CH:27]=2)=[N:4]1)[CH3:2].[CH3:38][CH2:39][N:40](CC)[CH2:41][CH3:42].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][N:40]5[CH2:41][CH2:42][CH2:38][CH2:39]5)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:30][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CCO)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CCN5CCCC5)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a stirred solution of N′-[4-(1-ethyl-4-{2-[3-(2-hydroxyethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea (210 mg, 0.42 mMol) in CH2Cl2 (15 mL) was added at 0° C. Et3N (120 uL, 0.86 mmol) and methanesulfonyl chloride (40 uL, 0.52 mmol). After stirring for 3 h, pyrrolidine (2 mL, 24 mmol) was added. The reaction was allowed to warm to RT, stirred for 18 h, and evaporated to dryness under vacuum. Purification by Gilson HPLC provided the title compound (25%) as a pale yellow solid. ESMS [M+H]+: 548.4.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[C@@H:4]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][C@H:22]2[CH2:26][CH2:25][O:24][CH2:23]2)[CH2:3]1.[CH3:27]N(C(OC)OC)C.[CH2:35]([O:37][C:38](=[O:41])[CH2:39]Br)[CH3:36].CO>C1(C)C=CC=CC=1>[CH2:35]([O:37][C:38]([C:39]1[N:11]2[CH:12]=[C:7]([N:5]3[CH2:6][C@@H:2]([F:1])[CH2:3][C@@H:4]3[C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:26][CH2:25][O:24][CH2:23]3)[CH:8]=[CH:9][C:10]2=[N:13][CH:27]=1)=[O:41])[CH3:36]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(N2C[C@@H](F)C[C@@H]2c2cc(F)ccc2O[C@H]2CCOC2)cn1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1cnc2ccc(N3C[C@@H](F)C[C@@H]3c3cc(F)ccc3O[C@H]3CCOC3)cn12
Temperature: 120 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
To a stirred solution of 5-((2R,4S)-4-fluoro-2-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)pyridin-2-amine (4.2 g, 11.63 mmol) in dry toluene (11 ml) was added DMF-DMA (2.9 g, 24.43 mmol) under N2 atm and stirred for 2 h at 120° C. during which complete consumption of starting material was observed by TLC, cooled it to 10° C. then added Ethylbromoacetate (4.27 g, 25.59 mmol) drop wise and methanol (4 ml) was added under N2 atm then stirred for 16 h at 120° C. Reaction mixture was cooled to room temperature and solvent was removed in vacuo and residue was dissolved in DCM (200 ml), washed with water and brine, dried over anhydrous Na2SO4 and concentrated under vacuum to get crude product. Crude was purified by column chromatography (eluted with 30-40% ethyl acetate/Hexane) to afford pale green solid (1.3 g, yield: 30%), MS (ESI): 458.2 (M+H)
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([NH:28][C:29]2[N:34]=[CH:33][C:32]3=[CH:35][CH:36]=[C:37]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:39]=4)[N:31]3[N:30]=2)[CH:25]=[CH:24][C:23]=1[Cl:48])=O)(C)(C)C>>[Cl:48][C:23]1[CH:24]=[CH:25][C:26]([NH:28][C:29]2[N:34]=[CH:33][C:32]3=[CH:35][CH:36]=[C:37]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([CH3:47])(=[O:45])=[O:46])[CH:39]=4)[N:31]3[N:30]=2)=[CH:27][C:22]=1[O:21][CH2:20][C@H:16]1[CH2:17][CH2:18][CH2:19][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(Nc2ncc3ccc(-c4cccc(S(C)(=O)=O)c4)n3n2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(Cl)c(OC[C@H]5CCCN5)c4)nn23)c1

Procedure:
This example was made by TFA deprotection of (R)-2-{2-Chloro-5-[7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenoxymethyl}-pyrrolidine-1-carboxylic acid tert-butyl ester as described in Example 1223. 1H-NMR (DMSO) δ 9.7 (s, 1H), 9.5 (brs, 1H), 9.0 (s, 1H), 8.7 (brs, 1H), 8.6 (s, 1H), 8.4 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.8 (t, 1H), 7.6 (d, J=8.7 Hz, 1H), 7.4 (m, 2H), 7.3 (d, J=4.7 Hz, 1H), 7.0 (d, J=4.7 Hz, 1H), 4.1 (m, 1H), 3.95 (m, 2H), 3.3 (s, 3H), 3.2 (m, 2H), 2.0 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H); LC/MS (ESI+): 498 (M+H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.CCOCC>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([O:5][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: O=C(O)[C@@H](O)CC1CCCC1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(OCc1ccccc1)[C@@H](O)CC1CCCC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 287 mg (1.81 mmol) of 2-(S)-hydroxy-3-(cyclopentyl)propanoic acid (from Step F) in 8 mL of DMF was treated with 0.38 mL (2.72 mmol) of TEA and 0.33 mL (2.77 mmol) of benzyl bromide and stirred at rt for 22 h. The reaction was diluted with 200 ml of ether and washed with 200 mL of H2O, 200 mL of 2.0 N HCl, 200 mL of 1.0 N NaHCO3, 200 mL of H2O and 200 mL of sat'd NaCl. The organic layer was dried over MgSO4 and concentrated. Flash chromatography on silica gel using 17:3 v/v hexanes/EtOAc afforded 102 mg (22%, 95.5% ee) of the title compound: RF: 0.40 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz): δ 1.04-1.17 (m, 2H), 1.46-1.87 (m, 8H), 1.99 (m, 1H), 2.65 (m, 1H), 4.22 (dd, J=7.8, 4.8, 1H), 5.23 (ABq, J=12.3, 2H), 7.32-7.41 (m, 5H). HPLC: Chirapak AS 4.6×250 mm column, 17:3 v/v hexanes/iPrOH, 0.5 mL/min, 220 nm. Retention times: (S)-Enantiomer, 12.2 min; (R)-enantiomer, 15.3 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:16]=3[S:17][C:18]=2Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:46])(=O)=O)=CC=1.[Na+].[Cl-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:16]=3[S:17][C:18]=2[F:46])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Br)sc3cc(F)ccc23)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)sc3cc(F)ccc23)CC1
Temperature: -65 °C
Yield: 82.7 %

Procedure:
At a temperature of −65° C. stir, under nitrogen, a solution of the 4-(2-bromo-6-fluoro-benzo[b]thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 28b) (15.59 g, 37.55 mmol) in anhydrous THF (247 mL) and add, dropwise, n-butyllithium in hexane (2.5M, 19.53 mL, 48.82 mmol). Stir for 30 min and then add, dropwise, N-fluorobenzenesulfonimide (17.76 g, 56.33 mmol) dissolved in anhydrous THF. Stir overnight at ambient temperature, cool the reaction to 0° C., add saturated NaCl solution and then water. Extract the mixture with EtOAc (3×'s), combine the extracts and wash with water and brine. Dry the extract (MgSO4), and concentrate to obtain 11.0 g of oil. Chromatograph the oil over silica gel (ether/pet. ether, 9:1) and obtain 6.28 g (52%) of red oil, MS, m/z, 354 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][CH:4]=1)#[CH:2].I[C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:42])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[C:26]([C:38]([F:41])([F:40])[F:39])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH:6]=[N:5][CH:4]=[C:3]2[C:1]#[C:2][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:42])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]3)=[C:26]([C:38]([F:39])([F:40])[F:41])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cncc2c(N)cccc12
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cncc2c(N)cccc12

Procedure:
The title compound can be synthesized from 4-ethynylisoquinolin-8-amine and N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide in a manner similar to that described for Example 1. 4-ethynylisoquinolin-8-amine is prepared from 4-bromoisoquinolin-8-amine and ethynyltrimethylsilane according to the 2 steps procedure described in example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([Cl:33])=[O:32])=[CH:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[CH3:36][NH2:37]>C1COCC1>[ClH:33].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([NH:37][CH3:36])=[O:32])=[CH:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1ncnc(N2CCOc3ccc(-c4ccc(C(=O)Cl)cc4)cc3C2)c1Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2ccc3c(c2)CN(c2ncnc(C)c2Cc2ccc(F)cc2)CCO3)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of 4-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoyl chloride (30.0 mg, 62 μmol) in THF (5 mL) was added drop wise 40% aqueous methylamine (0.25 mL, 2.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h, at which time it was concentrated. The resulting solid was dissolved in chloroform (30 mL), washed with water (20 mL), and dried over sodium sulfate then filtered. To the solution was then added drop wise 4N hydrogen chloride in dioxane (0.25 mL) and the mixture concentrated. The residue was taken up in 4:1 water and acetonitrile (2 mL) and lyophilized to give 4-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-N-methylbenzamide hydrochloride salt (16.5 mg, 53% yield) as a white powder. 1H NMR (400 MHZ, DMSO-d6): 8.79 (s, 1H), 8.53 (dd, 1H), 7.97 (d, 2H), 7.65 (d, 2H), 7.57 (d, 1H), 7.30-7.13 (m, 5H), 6.97 (d, 1H), 4.92 (s, 1H), 4.35 (br 2H), 4.04-3.97 (m, 4H), 3.83 (d, 3H), 2.24 (s, 3H); MS (EI) for C29H27FN4O2: 483 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl.[Cl:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1.Cl.CN(C)CCCCl>>[ClH:18].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:16][CH2:15][N:14]([CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:30]2)[CH2:13][CH2:12]1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: ClCCCN1Cc2ccccc2C1
Agent: CN(C)CCCCl
Agent: Cl
Product: c1ccc2c(c1)CN(CCCN1CCC(c3ccc4ccccc4c3)CC1)C2
Yield: 48.7 %

Procedure:
Using 4-(2-naphthyl)piperidine (149 mg, 0.60 mmol) and 2-(3-chloropropyl)isoindoline hydrochloride (209 mg, 0.90 mmol) instead of 4-(3-indolyl)piperidine and 3-dimethylaminopropyl chloride hydrochloride respectively, reaction, extraction, and concentration were carried out in the same procedure as Example 4. The resulting crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform) to afford a free form (119 mg) of the title compound as a colorless viscous oil. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then recrystallized from ethanol/ethyl acetate to afford the title compound (110 mg, yield: 41%) as white crystals.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:30][C:31]1[CH:38]=[C:37]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])[CH:36]=[CH:35][C:32]=1[CH2:33][NH2:34].[N:47]1[CH:52]=[C:51]([C:53]([NH:55][C:56]2([C:59](O)=[O:60])[CH2:58][CH2:57]2)=[O:54])[CH:50]=[N:49][CH:48]=1>O1CCCC1.CN(C=O)C>[Cl:30][C:31]1[CH:38]=[C:37]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])[CH:36]=[CH:35][C:32]=1[CH2:33][NH:34][C:59]([C:56]1([NH:55][C:53]([C:51]2[CH:50]=[N:49][CH:48]=[N:47][CH:52]=2)=[O:54])[CH2:58][CH2:57]1)=[O:60]
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Reactant: NCc1ccc(Oc2ccccc2Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)NCc2ccc(Oc3ccccc3Cl)cc2Cl)CC1)c1cncnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
85 mg (0.84 mmol) of triethylamine, 130 mg (0.40 mmol) of TBTU and 100 mg (0.37 mmol) of 2-chloro-4-(2-chloro-phenoxy)-benzylamine were added to a solution of 80 mg (0.38 mmol) of 1-[(pyrimidin-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1 b) in 30 mL tetrahydrofuran and 5 mL DMF and the mixture was stirred overnight at ambient temperature. Then the mixture was evaporated to dryness and the residue was combined with 2 M potassium carbonate solution. It was extracted with ethyl acetate and the organic phase was washed with water and saturated sodium chloride solution, dried and evaporated down. The crude product thus obtained was purified by reversed-phase chromatography. The fractions were evaporated down to the aqueous phase, made basic with ammonia and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried and evaporated down. The residue was evaporated out with ether and dried.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:52][C:53]1[S:54][CH:55]=[N:56][N:57]=1>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:52][C:53]2[S:54][CH:55]=[N:56][N:57]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nncs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nncs1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 76.1 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 200.0 mg, 0.70 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (316.9 mg, 0.84 mmol), N,N-diisopropylethylamine (365 mL, 2.09 mmol), and 2-amino-1,3,4-thiadiazole (140.8 mg, 1.39 mmol) in dry N,N-dimethylformamide (2 mL) was stirred at 25° C. under nitrogen for 20 h. The reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (100 mL). The organic layer was washed sequentially with a saturated aqueous sodium bicarbonate solution (1×50 mL), a 10% aqueous hydrochloric acid solution (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide (197.3 mg, 77%) as a white foam: mp 90-91° C.; EI-HRMS m/e calcd for C16H17Cl2N3OS (M+) 369.0469, found 369.0476.
Reaction SMILES: [F:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].[Cl:11][S:12](O)(=[O:14])=[O:13].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[F:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH3:4]
Reactant: O=S(=O)(O)Cl
Reactant: C[C@@H](CF)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: C[C@@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 11.7 %

Procedure:
1.3 g of ((R)-2-fluoro-1-methyl-ethyl)-benzene (9.4 mmol) were dissolved in 50 ml of dichloromethane. At 0-5° C., 1.1 g of chlorosulfonic acid (9.4 mmol), dissolved in 10 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 20 min at 0-5° C. and then added to a solution of 2.15 g of phosphorous pentachloride dissolved in 40 ml of dichloromethane. The reaction mixture was stirred for 30 min at 0-5° C. and 1 h at room temperature. The solvent was evaporated, 100 ml of diethyl ether were added, the mixture was washed once with 150 ml of water, and the organic layer dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with n-heptane-dichloromethane (1:1) as eluent to give 0.261 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](Cl)=[N:8][OH:9])=[N:4][O:5][N:6]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[F:19])[NH2:15].C(=O)(O)[O-].[Na+]>O>[NH2:1][C:2]1[C:3]([C:7](=[N:8][OH:9])[NH:15][C:14]2[CH:16]=[CH:17][C:18]([F:19])=[C:12]([Br:11])[CH:13]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(Cl)=NO
Reactant: Nc1ccc(F)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
4-Amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride (33.8 g, 208 mmol) was mixed with water (300 mL). At 60° C., 3-bromo-4-fluoroaniline (Sigma-Aldrich) (43.6 g, 229 mmol, 1.1 equiv.) was added to the suspension with stirring for 10 min. A solution of sodium bicarbonate (26.3 g, 313 mmol, 1.5 equiv.) in water (300 mL) was added over 15 min with stirring at 60° C. After stirring 20 min, LCMS indicated reaction completion. The reaction mixture was then cooled to room temperature and extracted with ethyl acetate (2×300 mL). The combined ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to give the desired product (65 g, 99%) as an off-white solid, which was used in the subsequent reaction without further purification. C9H7BrFN5O2 (MW 316.09), LCMS (EI) m/e 316/318 (M++H).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Br:13][C:14]1[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:13][C:14]1[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[O:22][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: CCc1cccc(O)c1Br
Reactant: COC(=O)c1ccc(F)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cccc(Oc2ccc(C(=O)OC)cc2C)c1Br
Temperature: 130 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of methyl 4-fluoro-3-methylbenzoate (1.7 g, 10 mmol) and 2-bromo-3-ethylphenol (2.0 g, 10 mmol) in dimethyl sulfoxide (10 mL) was added potassium carbonate (2.8 g, 20 mmol). The reaction mixture was stirred at 130° C. for 3 hours. After the reaction, the mixture was poured into water (50 mL) and the solution was extracted with ethyl acetate (50 mL), washed with water (50 mL). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure to give the pure product methyl 4-(2-bromo-3-ethylphenoxy)-3-methylbenzoate as colorless oil (2.10 g, 60%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:5][CH:4]=1.C1(=O)[NH:21]C(=O)C2=CC=CC=C12.[K].O.O.NN>CN(C=O)C.CO>[NH2:21][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: NN
Agent: [K]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: N#Cc1ccccc1-c1ccc(CN)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 154.6 %

Procedure:
A mixture of 2-(4-bromomethylphenyl)benzonitrile (12 g) and potassium phtalimide (15 g) in DMF (200 ml) was stirred at 70° C. for 5 hours. After addition of water, the mixture was extracted with methylene chloride. The extract was washed with water, dried and concentrated to dryness to give crystals. Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals. To a suspension of the crystals in methanol (500 ml) was added hydrazine hydrate (10 ml) and the mixture was refluxed for 12 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate and the solution was washed with 1N-NaOH and water. The organic layer was dried and concentrated to dryness to give crystals (14.2 g, 93%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[CH3:10][N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO.O>[CH3:10][N:11]1[CH:15]=[C:14]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)[CH:13]=[N:12]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CSc1nccc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1nccc(-c2cnn(C)c2)n1
Temperature: 100 °C

Procedure:
4-Chloro-2-methylsulfanyl-pyrimidine (1.4 g, 8.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 1.1 eq), Na2CO3 (2.8 g, 3 eq) and Pd(PPh3)4 (500 mg, 0.43 mmol) were combined in a solvent comprised of toluene/EtOH/H2O (4/4/1, 20 mL). The reaction mixture was purged with argon and heated to 100° C. overnight. The reaction was filtered to remove insolubles and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to provide 4-(1-methyl-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine contaminated with triphenylphoshine oxide (2.0 g, >100% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.49 (d, J=5.1 Hz, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 7.38 (d, J=5.1 Hz, 1H), 3.89 (s, 3H), 2.52 (s, 3H).