Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(C2C=C(C3CCNCC3)C=CC=2NC(C2NC=C(C#N)N=2)=O)CCCCC=1.BrCC(OC(C)(C)C)=O.CCN(CC)CC.C([O:56][C:57](=[O:87])[CH2:58][N:59]1[CH2:64][CH2:63][CH:62]([C:65]2[CH:70]=[CH:69][C:68]([NH:71][C:72]([C:74]3[NH:75][CH:76]=[C:77]([C:79]#[N:80])[N:78]=3)=[O:73])=[C:67]([C:81]3[CH2:86][CH2:85][CH2:84][CH2:83][CH:82]=3)[CH:66]=2)[CH2:61][CH2:60]1)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:79]([C:77]1[N:78]=[C:74]([C:72]([NH:71][C:68]2[CH:69]=[CH:70][C:65]([CH:62]3[CH2:61][CH2:60][N:59]([CH2:58][C:57]([OH:87])=[O:56])[CH2:64][CH2:63]3)=[CH:66][C:67]=2[C:81]2[CH2:86][CH2:85][CH2:84][CH2:83][CH:82]=2)=[O:73])[NH:75][CH:76]=1)#[N:80]
Reactant: CC(C)(C)OC(=O)CN1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Agent: CC(C)(C)OC(=O)CBr
Agent: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(CC(=O)O)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 38.9 %

Procedure:
A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (33 mg, 0.067 mmol) (as prepared in Example 14, step (b)), t-butyl bromoacetate (10 μL, 0.067 mmol), NEt3 (20 μL, 0.135 mmol) and 0.25 mL of DCM and stirred for 10 h at 25° C. The reaction mixture was loaded on a 5 g SPE cartridge (silica) and 23 mg (70%) of (4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-acetic acid tert-butyl ester was eluted with 25% EtOAc/DCM. This compound was dissolved in 1 mL of DCM and 20 μL of EtOH and 1 mL of TFA were added and the reaction stirred for 3 h at 25° C. The title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA/H2O over 12 min to give 10 mg (40%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.16 (d, 1H), 8.02 (s, 1H), 7.22 (dd, 1H), 7.10 (d, 1H), 5.72 (m, 1H), 4.04 (s, 2H), 3.76 (m, 2H), 3.22 (m, 2H), 2.90 (m, 1H), 2.29 (m, 4H), 2.10 (m, 4H), 1.82 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C24H27N5O3, 434.2 (M+H). found 434.2.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH3:20])[C:15]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:14]([O:29][CH2:30][C:31]3(/[CH:34]=[CH:35]/[C:36]#[N:37])[CH2:33][CH2:32]3)[CH:13]=2)=[CH:6][N:5]=1>C(O)(C)C>[NH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH3:20])[C:15]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:14]([O:29][CH2:30][C:31]3([CH2:34][CH2:35][C:36]#[N:37])[CH2:33][CH2:32]3)[CH:13]=2)=[CH:6][N:5]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2(/C=C/C#N)CC2)c1-c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2(CCC#N)CC2)c1-c1ccc(OC)cc1
Reaction time: 19 h
Yield: 33.9 %

Procedure:
Sodium borohydride (45 mg; 1.2 mmol) is added to (E)-3-[1-[4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-4′-methoxy-biphenyl-2-yloxymethyl]-cyclopropyl]-acrylonitrile (220 mg; 0.467 mmol) in isopropanol (25 ml) and the mixture is stirred for 19 hours under reflux. The reaction mixture is concentrated, the residue is stirred with water (15 ml), the mixture is adjusted to pH 2 with 1 N aqueous hydrochloric acid and back to pH 9 with conc. NH4OH and filtered with suction and the residue is dried under a high vacuum. The crude product is chromatographed over silica gel (20 g) with methylene chloride/methanol/NH4OH conc. (19/1/0.05). The pure fractions are concentrated together and the residue is stirred with diethyl ether, filtered off with suction and dried under a high vacuum. 75 mg (34%) 3-{1-[4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-4′-methoxy-biphenyl-2-yloxymethyl]-cyclopropyl}-propionitrile are obtained as a colourless powder.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=3[F:26])=[CH:13][C:12](=[O:27])[N:11]([CH3:28])[C:10]=2[N:9]([CH3:29])[CH:8]=1)=[O:6]>CO>[F:26][C:20]1[CH:21]=[C:22]([I:25])[CH:23]=[CH:24][C:19]=1[NH:18][C:14]1[C:15]2[C:16](=[O:17])[C:7]([C:5]([OH:6])=[O:4])=[CH:8][N:9]([CH3:29])[C:10]=2[N:11]([CH3:28])[C:12](=[O:27])[CH:13]=1
Reactant: COC(=O)c1cn(C)c2c(c(Nc3ccc(I)cc3F)cc(=O)n2C)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C(=O)O)c(=O)c2c(Nc3ccc(I)cc3F)cc(=O)n(C)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.1 %

Procedure:
An aqueous LiOH solution (2N, 0.08 mL) was added to a stirring solution of example 31 (10 mg, 0.021 mmol) in MeOH (0.15 mL). The reaction mixture was stirred at r.t. for 2 h. Purification by preparative HPLC mass triggered gave 0.4 mg (4%) of the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 14.29 (s, 1H), 11.06 (s, 1H), 8.47 (s, 1H), 7.51-7.56 (m, 2H), 7.17 (t, 1H, J=8.4 Hz), 5.73 (s, 1H), 3.95 (s, 3H), 3.63 (s, 3H). MS (ES) [m+H] calc'd for C17H13FIN3O4, 470; found 470.
Reaction SMILES: [ClH:1].[CH3:2][O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[N:13]=[CH:12][N:11]=[C:10]2[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[C:30][Si](C)(C)C)[CH:24]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)C>O1CCCC1>[ClH:1].[C:29]([C:25]1[CH:24]=[C:23]([NH:22][C:10]2[C:9]3[C:14](=[CH:15][C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:7]([O:6][CH2:5][CH2:4][O:3][CH3:2])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:28]=[CH:27][CH:26]=1)#[CH:30]
Reactant: COCCOc1cc2ncnc(Nc3cccc(C#C[Si](C)(C)C)c3)c2cc1OCCOC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A slurry of the silyl compound, 6,7-bis(2-methoxyethoxy)-N-[3-[(trimethylsilyl)ethynyl]phenyl]-4-quinazolinamine monohydrochloride, prepared above (1.22 g, 2.43 mmol) in tetrahydrofuran (6.1 mL) was treated with a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (2.6 mL, 2.55 mmol) and stirred at room temperature for 1 hour. The solution was treated with 2-propanol (12.2 mL) and concentrated by evaporation. The oil in 2-propanol (20 mL) was treated with concentrated hydrochloric acid (0.2 mL) giving a precipitate. The mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with 2-propanol (2 mL) and dried in vacuo to afford the title product (747 mg, 72%) as an off white solid (mp 226-229° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[N:7]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])([CH3:4])([CH3:3])[CH3:2].[O:50](C(OC(C)(C)C)=O)[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=O.O>C1COCC1>[C:54]([O:53][C:51](=[O:50])[N:16]([CH2:15][CH2:14][CH2:13][N:12]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:49])[CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:17][CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]1=[O:29])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCNCCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCN(CCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 56 %

Procedure:
The compound obtained in Stage 1 above (2.31 g, 3.3 mmol, 1 eq) is dissolved in 50 mL of THF with stirring. A solution of BOC2O (0.8 g, 3.7 mmol, 1.1 eq) in 10 mL of THF is then added dropwise at room temperature. Stirring is continued for 4 hrs and then the medium is poured into water and extracted with AcOEt (3×100 mL), dried (Na2SO4), filtered, and evaporated. The residue is flash chromatographed with a gradient from pure heptane to pure AcOEt. 1.49 g (Yield 56%) is obtained after evaporation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]2[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl[C:14]1[N:19]=[C:18]([OH:20])[C:17]([Cl:21])=[CH:16][N:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:21][C:17]1[C:18]([OH:20])=[N:19][C:14]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:10]3[CH2:11][CH2:12]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:15][CH:16]=1
Reactant: N#Cc1cc(N)ccc1C1CC1
Reactant: Oc1nc(Cl)ncc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: N#Cc1cc(Nc2ncc(Cl)c(O)n2)ccc1C1CC1
Temperature: 110 °C

Procedure:
5-amino-2-cyclopropylbenzonitrile (25.4 mmol; from the previous reaction) was transferred to a large reaction tube with magnetic stir bar in 250 mL isopropyl alcohol. 2,5-dichloropyrimidin-4-ol (4.20 g, 25.5 mmol) and p-toluenesulfonic acid monohydrate (14.50 g, 76.2 mmol) were weighed out and added. This was heated overnight at 110° C. After that time, it was allowed to cool to room temperature and an orange precipitate was filtered off. The filtrate was concentrated to half volume, and a second precipitate crashed out which was filtered off. Again, the filtrate was concentrated to half volume and a third precipitate crashed out which was filtered off. Finally, further concentration crashed out a fourth precipitate which was collected and washed with hexane. This was dried on high vacuum to give 5.63 g of 5-(5-chloro-4-hydroxypyrimidin-2-ylamino)-2-cyclopropylbenzonitrile as a tosylate salt, containing 1.2 equivalents of p-toluenesulfonic acid (45% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1.Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1
Reactant: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2O)c1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OC(CC)C(=O)OCC)c1

Procedure:
A mixture of 4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenol (Intermediate 267; 110 mg; 0.32 mmol) and ethyl 2-bromobutyrate (50 μl; 0.35 mmol) in DME (2 mL) was treated with K2CO3 (250 mg, 1.81 mmol) and refluxed for 18 hours. Water was added and the reaction mixture was extracted with EtOAc. The organic phase was dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica), eluting with heptane containing increasing amounts of EtOAc. The title compound was obtained as a colorless sticky solid which was not further purified before use.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[S:15][C:14]([NH:16][C:17](=[O:37])[CH:18]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:33])=[O:32])=[CH:27][CH:26]=3)[O:19][C@@H:20]3[CH2:24][CH2:23][O:22][CH2:21]3)=[N:13][CH:12]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO.O>[CH:34]1([S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH:18]([O:19][C@@H:20]3[CH2:24][CH2:23][O:22][CH2:21]3)[C:17]([NH:16][C:14]3[S:15][C:11]([O:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][CH:6]=4)=[CH:12][N:13]=3)=[O:37])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:36][CH2:35]1
Reactant: COC(=O)c1ccc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Yield: 0.1 %

Procedure:
The compound of example B30 was obtained by similar method described in example B28 using 4-(2-{2-(4-Cyclopropanesulfonyl-phenyl)-2-[(R)-(tetrahydro-furan-3-yl)oxy]-acetylamino}-thiazol-5-yloxy)-benzoic acid methyl ester (0.180 g, 0.32mmol), LiOH (0.067 g, 1.61 mmol) in THF: MeOH: Water (1:1:1, 9 mL) to provide the title compound (0.160 mg, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]1([CH2:26]O)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1>CO>[N:17]1([CH2:26][NH:13][C:12]2[CH:14]=[CH:15][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[F:16])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: Nc1ccc(OCc2ccccc2)cc1F
Reactant: OCn1nnc2ccccc21
Solvent: CO
Product: Fc1cc(OCc2ccccc2)ccc1NCn1nnc2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 66.6 %

Procedure:
After dissolving 4-benzyloxy-2-fluoroaniline (11.25 g, 51.78 mmol) in methanol (300 ml), 1H-benzotriazole-1-methanol (8.11 g, 54.37 mmol) was added and the mixture was stirred for 10 hours at room temperature. The precipitated crystals were filtered out, washed with ethanol and dried by aspiration to obtain the title compound (12.01 g, 34.47 mmol, 66.57%) as colorless crystals.
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:25])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH:23]=O)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.Cl.[NH2:33]O>CN1CCCC1=O>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:25])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[C:23]#[N:33])[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: NO
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(C=O)c2c(=O)n1-c1ccccc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(C#N)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinoline-8-carbaldehyde (15) (50 mg, 0.12 mmol) in anhydrous 1-methyl-2-pyrrolidinone (3 mL), hydroxylamine hydrochloride (17 mg, 0.24 mmol) was added and the resulting mixture was stirred at 120° C. for 16 h. The mixture was allowed to cool to RT, partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinoline-8-carbonitrile (16) (14 mg, 28% yield) as a while solid. ESI-MS m/z: 408.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1.[CH:22](=O)[C:23]1[O:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(N(CC)CC)C>[O:27]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:22][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1
Reactant: NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: O=Cc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=S(=O)(c1cccc2cncc(Br)c12)N1CCC(NCc2ccco2)C1
Temperature: 25 °C
Reaction time: 30 h
Yield: 27.3 %

Procedure:
A suspension of 3-amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine hydrochloride (172 mg) obtained in Example 1 in 1,2-dichloroethane (10 ml) is added with triethylamine (0.28 ml, Wako Pure Chemical Industries), and then with furfural (42 mg, Aldrich), and the mixture is stirred at room temperature for 30 minutes, then added with sodium triacetoxyborohydride (170 mg, Aldrich), and further stirred at room temperature for 30 hours. The reaction mixture is added with saturated aqueous sodium hydrogencarbonate (15 ml), and the organic layer is separated. The aqueous layer is extracted 3 times with chloroform (10 ml for each time), and the combined organic layer is washed with saturated brine (30 ml). The organic layer is dried over anhydrous magnesium sulfate, and then the solvent is evaporated under reduced pressure. The residue is purified by silica gel chromatography (chloroform:methanol=30:1) to obtain the title compound (52 mg (predictive yield)).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:34])[C:5]([C:35](O)=[O:36])=[CH:4]1)[CH3:2].ClC(OCC(C)C)=O.CC(C[AlH]CC(C)C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6](=[O:34])[C:5]([CH2:35][OH:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCn1cc(CO)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
To a suspension of 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (40 g, 79 mmol) in Tetrahydrofuran (THF) (300 mL) was added TEA (12.08 mL, 87 mmol) and isobutyl chloroformate (11.39 mL, 87 mmol). The resulting mixture was stirred at r.t. for 1 h. LCMS showed completion of the reaction. Then the mixture was cooled down to −78° C. and a solution of DIBAL-H (158 mL, 236 mmol) in toluene (1.5 M) was added. The mixture was stirred at the same temperature for 1.5 h, LCMS indicated completion of the reaction. The reaction was quenched with sat. NH4Cl (aq.), warmed up to r.t., concentrated, diluted with sat. NH4Cl and extracted with dichloromethane twice. The organic mixture was filtered through Celite to remove any solids. The combined organic solution was then washed with brine and dried over sodium sulfate, filtered and the resulting filtrate was concentrated in vacuo to afford 1-ethyl-6-fluoro-3-(hydroxymethyl)-7,8-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one (33 g, 51.5 mmol, 65.3% yield) as yellow solid, which was used in the next oxidation step without further purification. LCMS: (M+H)+: 494.3.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccccc1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
An oven-dried test tube was charged with tris(dibenzylideneacetone)dipalladium (4.6 mg, 0.005 mmol) and bis(2-(diphenylphosphino)phenyl)ether [DPE-phos] (8.2 mg, 0.015 mmol), capped with a rubber septum, evacuated and refilled with argon. Benzophenone imine (190 mg, 1.05 mmol), 2-bromoanisole (187 mg, 1.0 mmol) and toluene (2 mL) were added via syringe. The resulting solution was stirred at rt for 5 minutes. The tube was opened and sodium tert-butoxide (135 mg, 1.4 mmol) was added. The tube was again capped with the septum, and additional toluene (2 mL) was added via syringe to wash the solid from the test tube wall into the solution. The solution was stirred at room temperature with a gentle argon purge for 23 minutes, then heated at 80° C. for 2 hours and 10 minutes. The reaction mixture was cooled to room temperature and 1 mL ether was added. This solution was washed with saturated aqueous sodium chloride (2 mL) and the organic layer was concentrated in vacuo. The product was isolated as a yellow oil (216 mg, 75%) by flash chromatography on silica gel using 10% ethyl acetate in hexanes as eluent.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:23])([C:19]([F:22])([F:21])[F:20])[CH2:5][CH2:6][CH2:7][CH:8](C(OCC)=O)[C:9](OCC)=[O:10].Cl.B.CSC>O.C(O)C.CO>[F:3][C:4]([F:23])([C:19]([F:20])([F:21])[F:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10]
Reactant: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: B
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CSC
Solvent: O
Product: OCCCCCC(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
A solution of potassium hydroxide (370 g, 6.6 mol) in water (500 ml) was added to a solution of diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (105.3 g, 0.33 mol) in ethanol (1000 ml), followed by stirring for 16 hours at 60° C. The reaction mixture was adjusted to pH 5 by slowly adding 1N hydrochloric acid dropwise, and then extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was dissolved in dimethyl sulfoxide (500 ml) and stirred for 18 hours at 170° C. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was dissolved in anhydrous tetrahydrofuran (300 ml) and cooled to −30° C. Borane-methyl sulfide complex (10 M in THF, 55 ml, 0.55 mol) was slowly added dropwise to the solution, followed by stirring for 3 hours at room temperature. After treatment with methanol at 0° C., water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/20) to give 6,6,7,7,7-pentafluoroheptan-1-ol (39 g, Yield 57%).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[C:6]([NH:16][C:17]([NH:19][CH2:20][C@H:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)=[O:18])[CH:7]=[C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:9]=1)[CH3:3].Cl[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:30]>C(N(CC)CC)C>[CH2:2]([C:4]1[CH:5]=[C:6]([NH:16][C:17]([NH:19][CH2:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[O:30])[CH2:22]2)=[O:18])[CH:7]=[C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:9]=1)[CH3:3]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CCc1cc(NC(=O)NC[C@H]2CCCNC2)cc(-c2nnnn2C)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1cc(NC(=O)NC[C@@H]2CCCN(CC(=O)c3ccc(F)cc3)C2)cc(-c2nnnn2C)c1
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of (S)-1-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-piperidin-3-ylmethyl-ureahydrochloride (50 with 2-chloro-4′-fluoroacetophenone (27 mg, 158 μmol) and minutes. Additional triethylamine (73 μL, 526 μμmol) and 2-chloro-4′-fluoroacetophenone (ca. 5 mg) were added and stirring was continued for 60 minutes more. The mixture was concentrated under vacuum, and the residue was purified by flash chromatography, eluting with 3% methanol in dichloromethane, containing 0.3% aqueous ammonia, to provide a tan glassy solid (51 mg, 81%). 1H NMR (300 MHz, CDCl3) δ8.02 (m, 3H), 7.70 (s, 1H), 7.59 (s, 1H), 7.13 (m, 3H), 6.64 (bs, 1H), 4.20 (s, 3H), 3.85 (ab, J=18 Hz, 2H), 3.30 (m, 2H), 2.9-2.6 (m, 4H), 2.37 (m, 2H), 2.0-1.6 (m, 5H), 1.25 (t, J=8 Hz, 3H). Mass spec (ES+) m/z 480.4 (M+H+).