Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]=[N+]=[N-])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[FH:12]>CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[C:7]=1[F:12])[NH2:9]
Reactant: F
Reactant: Cc1cc(C)cc(N=[N+]=[N-])c1
Solvent: CCCCCC
Product: Cc1cc(N)cc(C)c1F
Temperature: 0 °C
Reaction time: 10 h
Yield: 60 %

Procedure:
The 95 ml. hexane solution of 3,5-dimethylphenylazide prepared in Step A above was charged to a rocker bomb and 20 ml. of hydrogen fluoride was added. The reaction mixture was then aged for 10 hours at room temperature with agitation, after which it was cooled, vented, and poured from the bomb, and the bomb rinsed with 40 ml. of water and 40 ml. of dichloromethane. The combined hexane, dichloromethane and hydrogen fluoride were blown down under nitrogen. The resulting residue was combined with the aqueous rinse, cooled to 0° C., and rendered alkaline with KOH pellets. The residue was then extracted three times with 75 ml. of dichloromethane per extraction, and the combined extracts dried over MgSO4 and then concentrated under reduced pressure to yield 7.34g. (66.2%) of a brown-red oil. This oil was then vacuum distilled at 40 mm. Hg to give 6.70g. of a colorless oil, a 60% yield. The final product had a b.p. of 127°-130° C. at 40 mm. Hg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:20])=[O:19]
Reactant: OCCC1CCCCO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1CCCCO1
Temperature: 0 °C
Reaction time: 16 h
Yield: 110 %

Procedure:
2-(Tetrahydro-2H-pyran-2-yl)ethanol (465 mg) was dissolved in dry DCM (10 mL) and triethylamine (996 mg) was added. The stirred solution was cooled in an ice bath under nitrogen and methanesulphonyl chloride (359 mg) was added dropwise over 5 mins. The reaction was allowed to warm to room temperature as the ice bath melted and was left for 16 h. The mixture was then shaken with saturated sodium bicarbonate solution and the aqueous layer was extracted with DCM (×2). The combined organic extracts were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound as a brown oil (718 mg).
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.CS([O-])(=O)=O.[C:19]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[C:27](O)[CH:26]=[CH:25]2)(=[NH:21])[NH2:20].C1CCC(N=C=NC2CCCCC2)CC1>CO.N1C=CC=CC=1>[NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][CH:31]=[C:22]([C:19](=[NH:20])[NH2:21])[CH:23]=3)[C:28]=2[CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[O:10])=[CH:7][CH:6]=1
Reactant: N=C(N)c1ccc2c(CCC(N)=O)c(O)ccc2c1
Reactant: NN=CNc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)[O-]
Solvent: CO
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CCC(N)=O)c(OC(=O)c3ccc(NC=NN)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
100 Milliliters of 20% hydrous pyridine was added to 3.16 g of 4-aminoiminomethylaminobenzoic acid.methanesulfonate, 2.94 g of 6-amidino-1-(2-carbamoylethyl)-2-naphthol and 4.54 g of DCC, followed by stirring for 2 hours under cooling with ice and 24 hours at room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 20 ml of DMF. The resulting solution was added dropwise to 500 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. To the collected precipitate was added 150 ml of methanol to dissolve the precipitate. To the solution was added 3 g of active carbon, followed by stirring for 30 minutes at room temperature. Insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. To the residue was added 30 ml of methanol to dissolve the residue with heating. The resulting solution was added dropwise to 400 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 2.5 g of the desired product.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]1[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]1)=O.[C:18]([NH:26][NH2:27])(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C([O-])(=O)C.[Na+]>[CH3:12][C:11]1([CH3:13])[C:14]([CH3:16])([CH3:15])[O:17][B:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[N:27][NH:26][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[O:10]1
Reactant: CC1(C)OB(c2ccccc2C=O)OC1(C)C
Reactant: NNC(=O)c1ccncc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC1(C)OB(c2ccccc2C=NNC(=O)c2ccncc2)OC1(C)C
Temperature: 100 °C
Reaction time: 0.07 h
Yield: 67 %

Procedure:
A portion of (2-formylphenyl)boronic acid pinacol ester (1 mmol, 0.232 g) was added to a nearly saturated solution of isonicotinic acid hydrazide (1 mmol, 0.137 g) in 0.1 M pH 4.5 sodium acetate buffer. The reaction mixture was stirred over an oil bath at 100° C. in for 4 min. The white insoluble product was collected via vacuum filtration, washed with water, and dried in vacuo to give an off-white powder in 67% yield. Recrystallization by slow evaporation of CH2Cl2 or vapor diffusion of CH2Cl2 and hexanes afforded translucent plates suitable for X-ray diffraction. 1H NMR (DMSO): δ 1.341 (12H, s), 7.447 (2H, td, J=1.20, J=6.47), 7.565 (1H, t, J=7.07), 7.736 (1H, d, J=6.72), 7.818 (2H, dd, J=1.47, J=4.49), 8.029 (1H, d, J=7.68), 8.791 (2H, d, J=5.8), 8.963 (1H, s), 12.20 (1H, s); 13C NMR (DMSO): δ 62.07, 121.45, 138.27, 159.21, 163.11, 166.70, 168.59, 173.04, 176.79, 186.85, 187.74, 187.89; MS (ESI): m/z 352.3 (M+H+), 374.3 (M+Na+), 350.1 (M−H+); IR (neat, cm−1): 3179, 3059, 2974, 1643, 1550, 1479, 1346, 1292, 1141. 1056; UV-vis (MeOH) nm (M−1 cm−1): 208 (20,320), 302 (19,530).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:18]([Cl:29])[CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.O>CN(C)C=O>[Cl:29][C:18]1[CH:17]=[C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:42]4[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]4)=[C:6]([O:30][CH3:31])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)[CH:21]=[CH:20][C:19]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CN1CCNCC1
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCBr)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCN4CCN(C)CC4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A starting compound (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea, 50 mg), potassium carbonate (138 mg), and 1-methylpiperazine (0.055 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 54 mg (yield 100%) of the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[C:14]([CH2:20][CH2:21][CH3:22])[C:13]=1[OH:23])(=[O:11])[CH3:10]>O>[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])=[C:14]([CH2:20][CH2:21][CH3:22])[C:13]=1[OH:23])(=[O:11])[CH3:10]
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCc1c(COCCCCO)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 9.6 g. of a 50% oil dispersion of sodium hydride in 100 ml. of 1,4-butanediol were added 11.3 g. of 4-acetyl-3-hydroxy-2-propylbenzyl chloride. The reaction was stirred overnight at room temperature and then heated to 60° C. for six hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The ethyl acetate solution was evaporated to dryness and the residue was purified by chromatography over silica gel to provide 4.1 g. of the desired title product. NMR.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:26][CH2:25][CH2:24]1.CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:23]2[CH2:26][CH2:25][CH2:24]2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1CNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example B5), azetidine and Et3N in DMSO at 23° C. according to the general procedure C. Obtained as a yellow solid (6.925 g).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:19])[CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:50])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH:40]1[CH:47]2[CH:43]([NH:44][C:45](=[O:48])[NH:46]2)[CH2:42][S:41]1.CCN(CC)CC>CN(C=O)C>[C:15]([O:14][C:12](=[O:13])[NH:11][CH2:10][C:9](=[O:19])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:50])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH:40]1[CH:47]2[CH:43]([NH:44][C:45](=[O:48])[NH:46]2)[CH2:42][S:41]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: NCCCCCCNC(=O)CCCCCNC(=O)CCCCC1SCC2NC(=O)NC21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCCCCCCNC(=O)CCCCCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-Butoxycarbonylamino-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (8b; 0.18 g, 0.69 mmol) dissolved in DMF (5 mL) was added slowly to a DMF solution (3 mL) containing 6-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoylamino]-hexanoic acid (6-amino-hexyl)-amide (7; 0.16 g, 0.27 mmol) and Et3N (0.1 mL, 0.72 mmol) while stirring at room temperature. The reaction was stopped after 3 h by evaporating DMF in vacuo, and the remaining residue was redissolved in a limited volume of a DCM/MeOH (19:1) solution and loaded to a preequilibrated silica column. The products were separated by eluting with mobile phases of 1-6.67% MeOH in DCM to afford 9 (0.10 g; 62.2%) as a yellow solid. 1H NMR (400 MHz) (CD3OD) δ: 4.30 dd, 1H, CHN), 4.15 (dd, 1H, CHN), 3.94 (d, 2H, CH2CO), 3.32 (quin, 4H, CH2NH), 2.99 (q, 2H, CH2N), 2.92 (d, 1H, CHHS), 2.75 (d, 1H, CHHS), 2.20 (t, 4H, CH2CO), 1.44-1.88 (m, 29H). 13C NMR (100.67 MHz) (CD3OD) δ: 175.9 (CO), 63.7 (CHN), 61.6 (CHN), 56.9 (CHS), 49.0 (CH2N), 41.0 (CH2CO), 40.2 (CH2N), 36.9 (CH2S), 30.1 (CH2CO), 28.6 (CH3CO), 26.7 (CH2CH2). HRMS (ESI) calculated for C29H52N6O6S, [M+Na]+ 635.3567 (calcd.), 635.3564 (found).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[S:13](Cl)(=[O:15])=[O:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([CH2:27][NH2:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[S:13](=[O:15])(=[O:14])[NH:28][CH2:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([CH3:17])[CH:19]=[CH:20]2)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cn1ccc2cc(CN)ccc21
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from ethyl 3-chloro-4-(chlorosulfonyl)benzoate and (1-methyl-1H-indol-5-yl)methanamine.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[C:13]([CH3:18])=[C:14]([CH2:16][OH:17])[S:15][C:3]=12.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>Cl>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:8]([C:7]2[C:2]([OH:1])=[C:3]3[S:15][C:14]([CH2:16][OH:17])=[C:13]([CH3:18])[C:4]3=[N:5][CH:6]=2)=[O:10])=[CH:22][CH:21]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1cnc2c(C)c(CO)sc2c1O
Agent: Cl
Product: Cc1c(CO)sc2c(O)c(C(=O)NCc3ccc(F)cc3)cnc12
Temperature: 80 °C
Yield: 85.5 %

Procedure:
A suspension of 140 mg (0.52 mmol) ethyl 7-hydroxy-2-(hydroxymethyl)-3-methylthieno[3,2-b]pyridine-6-carboxylate in 1.28 mL (11.2 mmol) 4-fluorobenzylamine was heated to 80° C. for 24 hours. The mixture was then cooled to room temperature and added to 10 mL of 1N HCl and then cooled in the refrigerator for three hours. The resulting mixture was then filtered and the obtained solid was washed with 1N HCl several times (50 mL total volume) and dried in a vacuum oven at 60° C. over night to provide 154 mg of the title compound as a tan solid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]=[CH2:5].C([Li])CCC.[CH3:11][Si:12]([CH3:15])([CH3:14])Cl>C(OCC)C>[CH3:11][Si:12]([CH:1]=[CH:2][CH2:3][CH:4]=[CH2:5])([CH3:15])[CH3:14]
Reactant: C[Si](C)(C)Cl
Reactant: C=CCC=C
Agent: [Li]CCCC
Solvent: CCOCC
Product: C=CCC=C[Si](C)(C)C
Reaction time: 8 h

Procedure:
A solution containing 1,4-pentadiene (5 g, 73 mol) in diethylether (100 ml) was lowered to −78° C. and n-butyllithium was added dropwise (72 mmol, 1.6M soln. in hexanes, 45 ml). The flask was stirred overnight and the temperature was allowed to warm to ambient. Solvents were removed in vacuo and a bright yellow powder was isolated. The sample was then re-dissolved in fresh diethyl ether (100 ml) and the temperature was lowered to −78° C. Trimethylchlorsilane (7.9 mmol, 10 ml) was added dropwise. The reaction was allowed to slowly warm to ambient and the flask contents stirred overnight. Solvents were removed in vacuo. 1M-NMR: CTHF-d8) d, ppm; 6.25 (m, 2H), 5.9 (m, 2H), 5.65 (m, 2H), 4.95 (s, 1H), 4.90 (s, 1H), 4.80 (s, 1H), 4.75 (s, 1H), 1.5 (d, 2H), 0 (m, 9H).
Reaction SMILES: Br[C:2]1[C:13](=[O:14])[N:12]([CH:15]([CH3:17])[CH3:16])[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29].C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:13](=[O:14])[N:12]([CH:15]([CH3:17])[CH3:16])[C:5]3[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=3[CH:3]=2)=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cc(B(O)O)ccc1F
Reactant: CSc1ncc2cc(Br)c(=O)n(C(C)C)c2n1
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: O
Solvent: COCCOC
Product: CSc1ncc2cc(-c3ccc(F)c([N+](=O)[O-])c3)c(=O)n(C(C)C)c2n1
Temperature: 80 °C
Yield: 109.5 %

Procedure:
To a degassed solution of 6-bromo-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)one (0.78 g, 2 mmol; J. Med. Chem., 48, 2371, 2005) in DME (10 ml) was added Pd(PPh3)4 (0.1 g, 5% mol), 4-fluoro-3-nitrophenylboronic acid (0.5 g, 3 mmol) and 2M Na2CO3 solution (3 ml, 6 mmol) and the mixture was heated to 80° C. for 16 h. The mixture was poured into water (40 mL), and product was extracted with EtOAc (3×25 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo afforded crude product. Purification by silica gel chromatography provided 6-(4-fluoro-3-nitrophenyl)-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as off-white solid (0.82 g, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 8.52 (dd, J=7.2 Hz, 2.4 Hz, 1H), 8.28 (s, 1H), 8.15-8.12 (m, 1H), 7.70 (dd, J=11.6 Hz, 8.8 Hz, 1H), 5.81-5.78 (m, 1H), 2.63 (s, 3H), 1.60 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 375.0 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:43]1([C@H:49]([NH:56][CH3:57])[CH2:50][N:51]2[CH2:54][CH:53]([OH:55])[CH2:52]2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:56]([C@@H:49]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:50][N:51]2[CH2:52][CH:53]([OH:55])[CH2:54]2)[CH3:57])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: CN[C@H](CN1CC(O)C1)C1CCCCC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(C#N)cc1)[C@H](CN1CC(O)C1)C1CCCCC1
Reaction time: 0.17 h
Yield: 49 %

Procedure:
4-cyanobenzoic acid (65.0 mg, 0.44 mmol) in DCM (2 mL) was treated with DIPEA (0.231 mL, 1.32 mmol) and TBTU (142 mg, 0.44 mmol) and the suspension was stirred for 10 min. A 125 mg/mL solution of (S)-1-(2-cyclohexyl-2-(methylamino)ethyl)azetidin-3-ol (Compound G2.3) (125 mg, 0.44 mmol) in DCM (1 mL) was added and the reaction was stirred at ambient temperature overnight. The reaction was washed with 8% aq. sol. of NaHCO3 and concentrated. The residue was dissolved in DMSO (0.4 mL) and filtered through a syringe filter. The residue was purified by HPLC to give the title compound (73.6 mg, 49%). Mixture of rotamers. 1H NMR (600 MHz, DMSO-d6) δ 0.53-0.70, 0.89-1.81, 2.43-2.59, 2.64-2.78, 3.03, 3.28-3.31, 3.43-3.54, 4.11-4.30, 5.23, 5.26, 7.48, 7.61, 7.87-7.94. HRMS (M+H)+: calculated 342.2181. found 342.2193
Reaction SMILES: [N:1]#[N:2].Cl.[C:4]([C:6]1[C:19]2[N:18]([CH:20]([CH3:27])[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[CH:8][C:7]=1[C:28]([NH2:30])=[NH:29])#[N:5].[CH2:31](N)[CH2:32][CH3:33]>C(O)C.C1(C)C=CC=CC=1>[N:1]#[N:2].[C:4]([C:6]1[C:19]2[N:18]([CH:20]([CH3:27])[CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[CH:8][C:7]=1[C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[NH:29])#[N:5]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=N)N)c(C#N)c21
Reactant: CCCN
Agent: Cl
Agent: N#N
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCNC(=N)c1ccc2c(c1C#N)N(C(C)CN1CCCC1)c1ccccc1S2

Procedure:
A solution of N2 -cyano-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamidine hydrochloride (0.93 g) and propylamine (1.86 cc) in ethanol (25 cc) is brought to 100° C. for 16 hours. The reaction mixture is concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is purified by chromatography on a column (height: 13.6 cm; diameter: 2.4 cm) of silica (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a 20:80 (by volume) mixture (750 cc) of cyclohexane and ethyl acetate, then with pure ethyl acetate (750 cc) and finally with a 90:10 (by volume) mixture (750 cc) of ethyl acetate and methanol, while collecting 50-cc fractions. The first 1000 cc are discarded and fractions 5 to 10 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give a solid which is dissolved hot in toluene (4 cc). Crystallization is primed and, after cooling, the crystals are separated by filtration on sintered glass and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 40° C. to give N2 -cyano-N1 -propyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamidine (0.15 g) in the form of yellow crystals, m.p. 154° C.
Reaction SMILES: Br.C(O)(=O)C.[Cl:6][C:7]1[C:8]([F:55])=[C:9]([C@@H:13]2[C@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])([C:18]#[N:19])[C@H:16]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[NH:15][C@H:14]2[C:33]([NH:35][C:36]2[CH:52]=[CH:51][C:39]([C:40]([O:42][CH2:43][C:44]([O:46]C(C)(C)C)=[O:45])=[O:41])=[CH:38][C:37]=2[O:53][CH3:54])=[O:34])[CH:10]=[CH:11][CH:12]=1>>[C:44]([CH2:43][O:42][C:40](=[O:41])[C:39]1[CH:51]=[CH:52][C:36]([NH:35][C:33]([C@H:14]2[C@H:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=3[F:55])[C@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])([C:18]#[N:19])[C@H:16]([CH2:28][C:29]([CH3:31])([CH3:32])[CH3:30])[NH:15]2)=[O:34])=[C:37]([O:53][CH3:54])[CH:38]=1)([OH:46])=[O:45]
Reactant: COc1cc(C(=O)OCC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: Br
Solvent: CC(=O)O
Product: COc1cc(C(=O)OCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 25 mL round-bottomed flask, 45% hydrogen bromide in acetic acid (10 mL, 794 μmol) was added. It was cooled down to 0° C., then 2-tert-butoxy-2-oxoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (580 mg, 794 μmol) was added as solid. After 30 min, the reaction mixture was concentrated, and water (50 mL) was added to the residue. It was extracted with methylene chloride (2×300 mL). The methylene chloride layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by filtering through a short plug of silica gel to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid carboxymethyl ester as an off white solid (530 mg, 99% yield). LCMS (ES+) m/z calcd. for C33H32Cl2F2N3O6 [(M+H)+]: 674. found: 674.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1I.CCCCCC.C([Li])CCC.FC(F)(F)S(O[Si:28]([CH3:31])([CH3:30])[CH3:29])(=O)=O>C(OCC)C>[CH3:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[Si:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1cc(Br)cc(C)c1I
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(Br)cc(C)c1[Si](C)(C)C
Reaction time: 0.75 h
Yield: 84.9 %

Procedure:
2,6-Dimethyl-4-bromoiodobenzene (5.04 g, 16.2 mmol) was dissolved in diethyl ether (50 ml). To the solution was then added dropwise a hexane solution of n-butyl lithium (2.6 M, 6.5 ml) at −50° C. The mixture was then stirred at the same temperature for 45 minutes. To the mixture was then added dropwise trimethylsilyl trifluoromethanesulfonate (3.7 ml, 19.4 mmol). The mixture was then stirred at −30° C. for 30 minutes and at room temperature overnight. After the quenching of the reaction with water, the product was then extracted with diethyl ether. The resulting organic phase was then dried over magnesium sulfate. The solvent was then distilled off. The crude product thus obtained was then distilled under reduced pressure using a glass tube oven so that it was purified to obtain 3,5-dimethyl-4-trimethylsilylbromobenzene (3.54 g; yield: 85%).