Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([C:28]([F:31])([F:30])[F:29])[C:3]([F:27])([F:26])[C:4]([F:25])([F:24])[O:5][C:6]([F:23])([F:22])[C:7]([F:21])([F:20])[O:8][C:9]([F:19])([F:18])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[CH2:33]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C)C=O>[CH2:33]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:21])([F:20])[C:6]([F:23])([F:22])[O:5][C:4]([F:25])([F:24])[C:3]([F:27])([F:26])[C:2]([F:32])([F:1])[C:28]([F:31])([F:30])[F:29])([F:19])[F:18])=[CH:53][CH:54]=2)=[N:47][CH:48]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: FC(F)(COCCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
Using essentially the procedure of Comparative Example A, the title compound was prepared by combining 5-(2-(2 -(nonafluorobutoxy)tetrafluoroethoxy)-2,2 -difluoroethoxy)-l-bromopentane (4.4 g, 7.6 mmol), 5 -decyl-2-(4-hydroxyphenyl)pyrimidine (2.0 g, 6.4 mmol), potassium carbonate (0.5 g, 10 mmol), acetonitrile (20 mL), and dimethyl formamide (20 mL). The resulting crude product was isolated and purified essentially as in Comparative Example A to yield 4.98 g.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.[C:26]([O:30][CH2:31]Cl)(=[O:29])[CH2:27][CH3:28].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:31][O:30][C:26]([CH2:27][CH3:28])=[O:29])=[O:19])(=[O:16])=[O:15]
Reactant: CCC(=O)OCCl
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)OCOC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 13, piretanide can be reacted with chloromethyl propionate, triethylamine and sodium iodide in DMF to yield ethylcarbonyloxymethyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[O:8][C@@H:7]1[C:9]([OH:11])=O)=[O:5])[CH3:2].[NH2:12][C@@H:13]([CH:22]([CH3:25])[CH2:23][CH3:24])[C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15]>>[OH:15][C@@H:14]([C@@H:13]([NH:12][C:9]([C@H:7]1[O:8][C@@H:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[CH:22]([CH3:25])[CH2:23][CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC(C)[C@H](N)[C@H](O)c1ccccc1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](C(C)CC)[C@H](O)c1ccccc1

Procedure:
The procedures of Example 1a were repeated employing (2S,3S)-3-ethoxycarbonyloxirane-2-carboxlic acid and (1R,2S)-2-amino-3-methyl-1-phenyl-1-pentanol (its preparation is described in the after-mentioned Reference Example 1), to prepare the titled compound.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][CH:11]=1)=[O:5])=[N-]>ClCCl.C1(C)C=CC=CC=1>[O:5]=[C:4]1[O:6][CH2:7][C@H:8]2[C@@H:3]1[C@@H:9]2[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][CH:11]=1
Reactant: [N-]=[N+]=CC(=O)OC/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc([C@@H]2[C@H]3COC(=O)[C@H]32)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of (2E)-3-(4-{[(benzyloxy)carbonyl]amino}phenyl)prop-2-enyl diazoacetate (0.7 g, 2.0 mmol) in dichloromethane (20 mL) was added dropwise over 18 h to a refluxing solution of bis-(N-t-butylsalicylaldiminato)copper(II) (0.041 g, 0.01 mmol) in 80 mL of toluene. After the addition was complete, the reaction mixture was heated for another 2 h at reflux and stirred at room temperature for 36 hours. Then the reaction mixture was cooled, filtered and concentrated. The crude oil was purified by silica gel column chromatography (gradient 0-1.5% MeOH-DCM) to provide the title compound and its enantiomer as a racemic mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[NH2:17])=[N:6][CH:7]=1.[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([O:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:23]=1)[CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[NH:17][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([S:21][CH2:19][CH3:20])=[CH:23][C:24]=2[O:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:6][CH:7]=1
Reactant: CCSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Reactant: Nc1cc(F)ccc1C(=O)Nc1ccc(Cl)cn1
Product: CCSc1ccc(C(=O)Nc2cc(F)ccc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1
Yield: 44 %

Procedure:
Using a procedure analogous to Example 4-E, N-(5-chloropyridin-2-yl)-4-fluoro-2-aminobenzamide and 4-(ethylthio)-2-(3-(t-butoxycarbonylamino)propyloxy)benzoic acid gave the title compound as a solid (0.93 g, 44%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.[CH2:35]([OH:39])[CH2:36][C:37]#[CH:38]>COCCOC.O.[Pd].[Cu]I>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([C:38]#[C:37][CH2:36][CH2:35][OH:39])=[CH:28][CH:29]=1)#[N:32]
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#CCCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(C#CCCO)cc1
Temperature: 80 °C

Procedure:
Potassium carbonate (376.7 g, 2.5 mol eq.) was dissolved in a mixture of 1,2-dimethoxyethane (DME, 1.2 L, 6 vol) and water (1.2 L, 6 vol). Palladium on charcoal (20 g, 0.01 mol eq., 10% Johnson Matthey type 87L, 60% water), triphenylphosphine (11.5 g, 0.04 mol eq.) and copper(I) iodide (4.2 g, 0.02 mol eq.) were added. 4-Bromobenzonitrile (200 g, 1 mol eq.) was then added, washing in with a mixture of DME (200 mL, 1 vol) and water (200 mL, 1 vol). This mixture was stirred rapidly under nitrogen for a minimum of thirty minutes. A solution of but-3-yn-1-ol (92.1 mL, 1.1 mol eq) in DME (200 mL, 1 vol) and water (200 mL, 1 vol) was added dropwise over five minutes. The combined mixture was then heated to 80° C. for three hours. The reaction was monitored by HPLC for the disappearance of arylbromide and the formation of sub-title compound. Once all of the starting material had been consumed, the reaction was cooled to 25° C. and filtered through kieselguhr. The filter cake was washed separately with toluene (1.6 L, 8 vol). The DME:water mixture was partially concentrated in vacuo to remove the majority of the DME. This was then partitioned with the toluene wash. The toluene layer was concentrated in vacuo to give sub-title alkyne as a yellow solid, which was dried in a vacuum oven overnight at 40° C. Yield 182.88 g, 97%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4]([N:11]([CH2:16][CH:17]2[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]2)[S:12]([CH3:15])(=[O:14])=[O:13])[N:3]=1.[F:24][C:25]1[CH:46]=[CH:45][C:28]([O:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][C:19]1([CH3:23])[O:18][CH:17]([CH2:16][N:11]([C:4]2[N:3]=[C:2]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[CH:26][C:25]([F:24])=[CH:46][CH:45]=4)=[CH:35][CH:34]=3)[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH2:21][O:20]1
Reactant: CC1(C)OCC(CN(c2cc(C(N)=O)nc(Cl)n2)S(C)(=O)=O)O1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)OCC(CN(c2cc(C(N)=O)nc(-c3ccc(Oc4ccc(F)cc4)cc3)n2)S(C)(=O)=O)O1
Temperature: 80 °C
Yield: 80.5 %

Procedure:
To a mixture of 2-chloro-6-(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methylsulfonamido)pyrimidine-4-carboxamide (0.365 g, 1.00 mmol) in dioxane (5 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.379 g, 1.21 mmol), 2M aqueous Na2CO3 (1.0 mL, 2.0 mmol), and PdCl2(dppf) (0.046 g, 0.056 mmol). The reaction vessel was flushed with argon, sealed, and heated at 80° C. overnight. After cooling, the reaction mixture was evaporated in vacuo to a residue. The residue was chromatographed over silica gel with 30-80% EtOAc in hexanes. The product fractions were evaporated to a residue and triturated with 5 mL 1:1 EtOAc/hexanes. The solid was filtered off, rinsed twice with 1 mL 1:1 EtOAc/hexanes, and dried under vacuum at 40° C. to give 6-(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methylsulfonamido)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as a tan-orange powder (0.416 g, 0.805 mmol, 80% yield). 1H NMR (400 MHz, DMSO-d6): 8.61-8.55 (3H, m), 8.01 (1H, s), 7.94-7.91 (1H, m), 7.33-7.26 (2H, m), 7.23-7.17 (2H, m), 7.10 (2H, d, J=9.0 Hz), 4.44-4.37 (1H, m), 4.35-4.28 (1H, m), 4.22-4.15 (1H, m), 4.07 (1H, dd, J=8.8 Hz, 6.6 Hz), 3.81 (1H, dd, J=8.6 Hz, 5.3 Hz), 3.52 (3H, s), 1.35 (3H, s), 1.23 (3H, s). LC/MS: m/z=517.2 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][O:13][CH2:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1>CN(C)C=O.[I-].[Na+]>[I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:15][CH2:14][O:13][CH3:12]
Reactant: O=[N+]([O-])c1ccc(O)c(I)c1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: COCCOc1ccc([N+](=O)[O-])cc1I
Yield: 39.5 %

Procedure:
A suspension of 2-iodo-4-nitrophenol (15.5 g, 58.7 mmol) [ref: Kometani, T.; Watt, D. S.; Ji, T., Tetrahedron Lett. (1985), 26(17), 2043], 2-chloroethyl methyl ether (10.69 mL, 117 mmols), potassium carbonate (16.8 g, 117 mmol) and sodium iodide (100 mg) in 160 mL of N,N-dimethylformamide was heated at 70-80° C. for 4 hours. An additional 5.35 mL of 2-chloroethyl methyl ether was added and the reaction was heated until thin layer chromatography (TLC) showed the absence of the phenol. The mixture was filtered and the filtrate was concentrated in vacuo. The solid was partitioned between ethyl acetate and 1 N sodium hydroxide. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of hexane to 50% ethyl acetate in hexane. The resultant oil was recrystallized from ether to provide 7.5 g of 2-iodo-1-(2-methoxyethoxy)-4-nitrobenzene as a white solid, mp 35-36° C.; 1H NMR (300 MHz, DMSO-d6) δ 3.37 (s, 3H), 3.74 (t, 2H), 4.33 (t, 2H), 7.20 (d, 1H), 8.26 (d, 1H), 8.56 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:5]2=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:48][C:49]1[CH:50]=[C:51]([NH:56][C:57](=[O:69])[C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([C:67]#[N:68])([CH3:66])[CH3:65])[CH:59]=2)[CH:52]=[CH:53][C:54]=1[CH3:55]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([NH:48][C:49]3[CH:50]=[C:51]([NH:56][C:57](=[O:69])[C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([C:67]#[N:68])([CH3:65])[CH3:66])[CH:59]=4)[CH:52]=[CH:53][C:54]=3[CH3:55])=[O:13])[S:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1cc2nc(Cl)cnc2s1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(Cl)cnc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A solution of 2-chlorothieno[3,2-b]pyrazine-6-carboxylic acid 23 (350 mg, 1.631 mmol), HATU (744 mg, 1.957 mmol) and DIPEA (0.809 mL, 4.89 mmol) in DMF (8 mL) was stirred for 15 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (538 mg, 1.631 mmol) was added and stirred overnight at rt. Quenched in citric acid solution (3%) and the resulting precipitate was collected. Triturating in acetonitrile gave the title compound 2-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 24 (450 mg, 56%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.26 (s, 3H), 7.32 (d, J=8.2 Hz, 1H), 7.58-7.68 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.87 (d, J=1.9, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.49 (s, 1H), 8.89 (s, 1H), 10.38 (s, 1H), 10.59 (s, 1H). (m/z)=490 and 492 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]3([CH3:24])[CH3:23])[CH3:10])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.O.[Fe]>[CH3:21][C:17]1([CH3:22])[CH2:16][CH2:15][C:14]([CH3:23])([CH3:24])[C:13]2[CH:12]=[C:11]([C:9]([CH3:10])=[CH:8][C:7]3[CH:25]=[CH:26][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH:20]=[CH:19][C:18]1=2
Reactant: CC(=Cc1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC(=Cc1ccc(N)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
6 g of 6-[p-nitro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene are dissolved in 200 ml of acetic acid and, after heating to 90°, treated within 2 minutes with 4.5 g of activated iron powder. Thereafter, 60 ml of water are added thereto and, after a further 30 minutes, the mixture is again treated with 60 ml of water. After stirring at 90° for 1 hour the reaction mixture is cooled, diluted with water and extracted with ether. The organic phase is washed with water, dilute soda solution and again with water. After drying with sodium sulphate the organic phase is evaporated and there is obtained a brown oil which is purified by filtration over silica gel (elution agent hexane/acetic acid 4:1). Recrystallization from hexane gives 4.5 g of p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]aniline in colourless crystals, melting point 106°-108°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[CH2:10]([N:17]1[CH2:24][CH:23]2[C:25]([CH3:27])([CH3:26])[CH:19]([CH2:20][NH:21][CH2:22]2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:10]([N:17]1[CH2:18][CH:19]2[C:25]([CH3:27])([CH3:26])[CH:23]([CH2:22][N:21]([S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:8])=[O:7])[CH2:20]2)[CH2:24]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC1(C)C2CNCC1CN(Cc1ccccc1)C2
Solvent: ClCCl
Product: CC1(C)C2CN(Cc3ccccc3)CC1CN(S(=O)(=O)c1cccs1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A solution of 2.87 g (=0.015 mol) thiophene-2-sulfonyl chloride in 20 ml dichloromethane was added dropwise with ice cooling to a solution of 3.5 g (=0.014 mol) 7-benzyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane (=substance No. C8 in the following Table (C)) in 40 ml dichloromethane. Then the ice bath was removed and the reaction mixture stirred further for 3 hours at room temperature. The reaction mixture was then made alkaline by adding aqueous sodium hydroxide solution, the aqueous phase was separated and extracted twice with dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and the solvent was evaporated. 4.0 g of the title compound (base) were thereby obtained as an oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:19][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCC(O)c1ccc(CC(C)C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCC(Br)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.3 %

Procedure:
To a solution of 1-(4-isobutylphenyl)hexan-1-ol (9.15 g) and carbon tetrabromide (25.9 g) in tetrahydrofuran (250 ml) was added triphenylphosphine (20.5 g). The mixture was stirred at room temperature for 6 hours. After the white solid was filtered off, the filtrate was evaporated. n-Hexane (300 ml) was added to the residue and the precipitate was filtered off. The filtrate was evaporated and the residual oil was distilled under reduced pressure to give 1-(1-bromohexyl)-4-isobutylbenzene (3.52 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][C:42]([CH3:46])([CH3:45])[C:43]#[N:44])=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[C:43]([C:42]([CH3:46])([CH3:45])[CH2:41][O:40][C:39]1[CH:38]=[C:37]([CH3:50])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:48]([CH3:49])[CH:47]=1)#[N:44]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OCC(C)(C)C#N)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC(C)(C)C#N)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 3-(4-bromo-3,5-dimethylphenoxy)-2,2-dimethylpropanenitrile following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.89 min; Mass spectrum (ESI+): m/z=544 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH2:20][C:21]#[N:22])=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].I[C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(N)CN>CCOC(C)=O.[Cu](I)I.O1CCOCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH2:20][C:21]#[N:22])=[CH:18][N:17]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1cc2c(CC#N)c[nH]c2cn1
Reactant: CC(C)c1ccc(I)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: NCCN
Product: CCc1cccc(CC)c1-c1cc2c(CC#N)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 60 °C

Procedure:
A mixture of [5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-acetonitrile (800 mg, 3.1 mmol), 1-iodo-4-isopropyl-benzene (1.13 g, 4.6 mmol), copper iodide (874 mg, 4.6 mmol), Cs2CO3 (1.50 g, 4.6 mmol) and ethylenediamine (30 μL, 4.6 mmol), and dioxane (100 mL) is heated to 60° C. under nitrogen for 18 h. The mixture is diluted with EtOAc and filtered over a small pad of silica gel. The obtained solution is concentrated under reduced pressure, and the residue is purified by chromatography on silica gel (hexane-EtOAc, 5:1) to afford [5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-acetonitrile as colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.[F:11][C:12]([F:34])([F:33])[C:13]1[CH:14]=[C:15]([C:23]2[N:27]=[CH:26][N:25](/[CH:28]=[CH:29]\[C:30]([OH:32])=O)[N:24]=2)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>ClCCl.CO>[F:34][C:12]([F:11])([F:33])[C:13]1[CH:14]=[C:15]([C:23]2[N:27]=[CH:26][N:25](/[CH:28]=[CH:29]\[C:30]([N:2]([CH3:1])[CH2:3][C:4]3[CH:5]=[N:6][C:7]([CH3:10])=[N:8][CH:9]=3)=[O:32])[N:24]=2)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1
Reactant: CNCc1cnc(C)nc1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(CN(C)C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)cn1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 4.2 %

Procedure:
In a 25 mL, 3N round-bottomed flask equipped with nitrogen inlet, N-methyl-1-(2-methylpyrimidin-5-yl)methanamine (1) (0.1 g, 1.0 eq.) and (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.178 g, 0.7 eq.) was charged along with dichloromethane (2 mL, 10 V). The reaction mixture was cooled to −20° C. and then added T3P (50% in EtOAc) (0.550 mL, 1.2 eq.) followed by DIPEA (0.250 mL, 2 eq.) was added to reaction mixture. The clear reaction mixture was stirred at −20° C. for 30 min. The progress of the reaction was followed by TLC analysis on silica gel with 5% Methanol in dichloromethane as mobile phase and visualization with UV, which shows that starting material was consumed after 30 min stirring at −30° C. Reaction mixture was diluted by dichloromethane wash with water (2×10 mL), organic layer dried over sodium sulfate and concentrated by rotary evaporation (25° C., 20 mm Hg) to afford crude compound (0.2 g). The crude reaction mixture was purified by column chromatography using 60/120 mesh silica and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner starting with fraction collection (500 mL fractions). The compound started eluting from 2% methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure compound 0.01 g Yield (4.19%).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[C:8]=2[C:25]2[O:29][CH:28]=[N:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C:64]1([C:69]([NH:71][C:72]2[CH:77]=[CH:76][C:75](/[CH:78]=[CH:79]/[C:80]([O:82]CC)=[O:81])=[CH:74][CH:73]=2)=[O:70])[CH2:68][CH2:67][CH2:66][CH2:65]1>CN(C=O)C.C1COCC1.CO>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:63][C:64]4([C:69]([NH:71][C:72]5[CH:73]=[CH:74][C:75](/[CH:78]=[CH:79]/[C:80]([OH:82])=[O:81])=[CH:76][CH:77]=5)=[O:70])[CH2:68][CH2:67][CH2:66][CH2:65]4)=[O:18])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]([CH3:23])[CH3:24])=[O:21])[C:8]=2[C:25]2[O:29][CH:28]=[N:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)Cn1c(-c2cnco2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)C2(N)CCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c(-c2cnco2)c(C2CCCCC2)c2ccc(C(=O)NC3(C(=O)Nc4ccc(/C=C/C(=O)O)cc4)CCCC3)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
A solution (0.04 M) of 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-(1,3-oxazol-5-yl)-1H-indole-6-carboxylic acid (from Step 6) in DMF was treated with DIPEA (3 eq.), HATU (2 eq.) and ethyl (2E)-3-(4-{[(1-aminocyclopentyl)carbonyl]amino}phenyl)acrylate (from Example 1, Step 7, 1.1 eq.). The solution was stirred at 25° C. for 12 h and then evaporated in vacuo. The residual material was purified by chromatography on silica gel (PE:EtOAc, 8:2, then EtOAc:PE 9:1). The product fractions were evaporated and the material obtained was then dissolved in THF/MeOH (1:1). The resulting solution was treated with LiOH monohydrate (3 eq.) and stirred at RT overnight. The product was isolated by preparative HPLC (stationary phase: Waters Xterra C18 19×150 mm, 5 micron; flow 20 mL/min). After lyophilisation the product was obtained as a colourless amorphous solid (98%).