Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=[O:4].[O:15]=[C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH2:5]([C@H:2]1[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:3]1=[O:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)/C=C/C(=O)c1ccccc1
Reactant: CCCCCCCCCCC(Cl)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC[C@@H]1C(=O)OC(c2ccccc2)=C[C@@H]1C(=O)OC
Yield: 90 %

Procedure:
Prepared according to the general procedure from 2-chlorododecanal and (E)-methyl 4-oxo-4-phenylbut-2-enoate using 0.5 mol % 1 as the catalyst in 90% yield as a single diastereomer (white solid). [α]r)20 (c 1.15, CHCl3)=+154.3; mp=108-111° C.; 1H NMR (400 MHz, CDCl3) δ 7.66-7.63 (m, 2H), 7.40-7.37 (m, 3H), 5.89 (d, 1H, J=6.4 Hz), 3.73 (s, 3H), 3.57 (t, 1H, J=6.3 Hz), 2.76 (q, 1H, J=6.3 Hz), 2.04 (t, 1H, J=7.0 Hz), 1.47-1.26 (m, 18H), 0.88 (t, 3H, J=6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 171.0, 169.5, 152.4, 132.0, 129.8, 128.8, 125.0, 97.9, 52.7, 41.9, 40.7, 32.1, 29.8, 29.8, 29.6, 29.6, 27.4, 27.3, 22.9, 14.4; IR (thin film) ν 3062, 2916, 2846, 1758, 1722, 1464, 1339, 1176, 1115 cm−1; HRMS (ESI) calcd for C23H32O4 [M+Na]+ 395.2192, found 395.2192; 99% ee (3S,4S)-isomer as determined by HPLC (AD-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=7.2 min, tr (3R,4R)=10.3 min.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:17]=2[C:15](=[O:16])[O:14][CH2:13][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N)C1C=CC=CC=1.Cl>>[CH2:19]([NH:26][C:15]([C:17]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][OH:14])=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: O=C1OCCc2cccc(-c3ccccc3)c21
Agent: Br
Agent: Cl
Product: O=C(NCc1ccccc1)c1c(CCO)cccc1-c1ccccc1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A mixture of 7.84 parts of 3,4-dihydro-8-phenylisocoumarin and 8 parts of benzylamine hydrobromide in 40 parts by volume of benzylamine is stirred at about 160° C. for about 4 hours. The reaction solution is then cooled and poured into 500 parts by volume of 5% hydrochloric acid. The oil which separates is extracted into methylene chloride and the extracts are washed with several portions of 5% hydrochloric acid, water, dried over anhydrous magnesium sulfate and the solvent removed to give, as a solid, N-benzyl-3-(2-hydroxyethyl)-2-biphenylcarboxamide. The solid is recrystallized from a mixture of chloroform and hexane to give white flocculant crystals melting at about 129°-130° C. This compound has the following formula ##STR13##
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH2:17]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[CH3:18].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1>ClCCl>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([C:13]([NH:22][CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:23])=[O:15])[C@@H:10]([CH3:12])[OH:11]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Yield: 85.4 %

Procedure:
Boc-threonine (produced by Wako Pure Chemical Industries Ltd.) (11.0 g, 50 mmol) and glycine ethyl ester hydrochloride (produced by Wako Pure Chemical Industries Ltd.) (8.4 g, 60 mmol) were dissolved in dichloromethane (250 mL). After triethylamine (8.4 mL, 60 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 12.4 g, 60 mmol) and hydroxybenzotriazole (9.2 g, 60 mmol) were further added thereto, the mixture was reacted at room temperature for overnight with stirring. After completion of the reaction, reaction mixture was filtered, and then the filtrate was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the product was crystallized from hexane, to obtain Boc-Thr-Gly-OEt (1) (13.0 g) (yield; 85.1%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:8]=23)=[CH:3][CH:2]=1.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:8]1=[C:7]2[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc2c(c1)c(-c1ccncc1)c1n2CCCCC1
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c1n2CCCCC1

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 7,8,9,10-tetrahydro-11-(4-pyridyl)-6H-azepino[1,2-a]indole-2-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)=[CH:6][CH:7]=[N:8]2.[Cl-].[NH4+]>CO.[Zn]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[CH:6][CH:7]=[N:8]2
Reactant: COc1cc(OC)c2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COc1cc(OC)c2c(Oc3ccc(N)cc3)ccnc2c1

Procedure:
A mixture of 5,7-dimethoxy-4-(4-nitrophenoxyl)quinoline (50 mg, 0.15 mmol), Zn dust (100 mg, 1.50 mmol) and ammonium chloride (32 mg, 0.60 mmol) in methanol (3 mL) was heated at reflux for 1 h. The mixture was filtered through celite and washed with CHCl3. The organic layer was washed with 10% NaOH solution and brine, dried over Na2SO4, and concentrated to afford 4-(5,7-dimethoxyquinolin-4-yloxy)phenylamine as an off white solid. LCMS m/z=298 (M+1); 1H NMR (CDCl3) δ: 8.44 (d, 1H, J=4.8 Hz), 7.00 (s, 1H), 6.83 (d, 2H, J=8.8 Hz), 6.65-6.63 (m, 3H), 6.32 (d, 1H, J=4.8 Hz), 5.11 (br s, 2H), 3.89 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[CH:11][CH:10]=1.[C:23]([NH2:27])(=[O:26])[CH:24]=[CH2:25]>CN(C)C=O.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(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:16][O:15][C:13]1[N:14]=[C:9](/[CH:25]=[CH:24]/[C:23]([NH2:27])=[O:26])[CH:10]=[CH:11][C:12]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1nc(Br)ccc1-n1cnc(C)c1
Reactant: C=CC(N)=O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nc(/C=C/C(N)=O)ccc1-n1cnc(C)c1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 89.5 %

Procedure:
Triethylamine (52 ml) was added to a suspension of 6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (49.8 g), tris(dibenzylideneacetone)dipalladium (0) (5.11 g), tri-o-tolylphosphine (3.41 g) and acrylamide (14.5 g) in N,N-dimethyl formamide (260 ml). The reaction solution was stirred at 100° C. for 50 minutes. The reaction solution was returned to room temperature and then filtered through celite. The filter cake was sequentially washed with N,N-dimethylformamide, methanol, a 50% N,N-dimethylformamide solution and N,N-dimethylformamide. The resulting filtrate was filtered through celite again, and the filtrate was concentrated under reduced pressure. Toluene was added to the residue, and the reaction solution was concentrated again. Toluene and a saturated sodium bicarbonate solution were added to the resulting residue, and the insoluble matter was collected by filtration. The resulting powder was dried under reduced pressure to obtain 42.96 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1
Reactant: NCCCCl
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.43 g (49 mmol) 3-chloropropylamine and 13.6 ml (98 mmol) triethylamine in 220 ml methylene chloride was cooled by an ice bath and 9 g (48.5 mmol) 4-nitrobenzoyl chloride were added fractionwise. After one hour stirring at room temperature the organic phase was washed twice with water, dried over MgSO4 and concentrated in vacuo to afford 10.68 g (91%). of beige crystals. 1H NMR was consistent with the desired structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]Cl.CN(C)C=O>C(OCC)(=O)C>[CH2:32]1[C:27]2[C:26](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:1]1[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Reactant: ClCc1ccccc1CCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1cn2cc(Oc3cccc(N4Cc5ccccc5C4)c3)ccc2n1)C1CC1
Temperature: 50 °C
Reaction time: 14 h
Yield: 34 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (19.4 mg, 0.063 mmol), 1,2-bis(chloromethyl)benzene (13.5 mg, 0.077 mmol) and N,N-dimethylformamide (2.0 mL) was stirred at 50° C. for 14 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (8.8 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1>CC(O)=O.CCOC(C)=O.[Fe]>[Cl:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Temperature: 70 °C
Yield: 97.3 %

Procedure:
A mixture of 12A (95.5 mg, 0.30 mmol) and Fe powder (135 mg, 2.4 mmol) in HOAc/EtOAc (1/1) (2 ml) was heated at 70° C. for 3.5 h. The mixture was cooled to rt, filtered through an 1″ celite pad and rinsed with HOAc/EtOAc (1/1) (4×8 ml). The filtrate was concentrated in vacuo. The residue was diluted with 1N NaOH (40 ml), extracted with EtOAc (2×60 ml) and the combined EtOAc extracts were washed with brine (1×20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 12B (83.1 mg, 79% pure) which was used in next step without further purification. Analytical HPLC retention time=2.08 min. (YMC Xterra S7 C18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[F:19][C:20]([F:28])([F:27])[C:21]1([CH3:26])[CH2:25][CH2:24][CH2:23][NH:22]1.Cl>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:22]1[CH2:23][CH2:24][CH2:25][C:21]1([C:20]([F:28])([F:27])[F:19])[CH3:26])=[O:5]
Reactant: CC1(C(F)(F)F)CCCN1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C(F)(F)F)CCCN1C(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of 8.83 g (0.05 mol) of 2,6-difluorobenzoyl chloride in 10 ml of tetrahydrofuran (THF), to which 5.6 g (0.055 mol) of triethylamine had been added, was added dropwise to a solution of 7.65 g (0.05 mol) of 2-trifluoromethyl-2-methylpyrrolidine in 25 ml of tetrahydrofuran (THF). The reaction is exothermic, and slow dropwise addition prevented the temperature from rising above +35° C. Stirring was continued for one hour at room temperature, and the mixture was then poured into 250 ml of ice-water and acidified using dilute hydrochloric acid, and the precipitate obtained was filtered off with suction, washed thoroughly with water and dried. 9.96 g (68% yield of theory) of N-(2,6-difluorobenzoyl)-2-trifluoromethyl-2-methyl-pyrrolidine of melting point 119°-120° C. are obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][C@H:16]3[NH:27][CH2:26][CH2:25][C@@:22]4([C:23]=2[CH:24]=1)[C@H:17]3[CH2:18][CH2:19][CH2:20][CH2:21]4.C(N(CC)CC)C>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][C@H:16]3[N:27]([C:1](=[O:3])[CH3:2])[CH2:26][CH2:25][C@@:22]4([C:23]=2[CH:24]=1)[C@H:17]3[CH2:18][CH2:19][CH2:20][CH2:21]4
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(C)=O)CC3
Temperature: 60 °C
Yield: 81.9 %

Procedure:
Acetic anhydride (3.14 g, 30.76 mmol) was added to a solution of (+)-3-methoxy-morphinan hydrochloride (1.5 g, 5.1 mmol) in THF (30 ml) and triethylamine (8.7 g, 85.98 mmol) in the presence of nitrogen. The resulting solution was heated at 60° C. for 15 hr. The reaction mixture was cooled to room temperature and evaporated under vacuum. The residue was dissolved in methylene chloride (50 ml), washed with water (40 ml×2) and dried (MgSO4). Evaporation of the dried solution gave a tan viscous oil (1.25 g, 81% yield); ms (ESI+): m/z 300 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]([CH:19]=O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([C:27]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCC1>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](/[CH:19]=[C:32]2\[CH2:33][N:28]([C:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:29][CH2:30][C:31]\2=[O:34])=[N:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)Cc1cc(C=O)nn1C(=O)OC(C)(C)C
Solvent: C1CCNC1
Solvent: c1ccccc1
Product: CCOC(=O)Cc1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)nn1C(=O)OC(C)(C)C
Yield: 57 %

Procedure:
Following a procedure similar to that described in Example 132-(c), ethyl [1-(t-butoxycarbonyl)-3-formyl-1H-pyrazol-5-yl]acetate (7.84 g) was subjected to the reaction with 1-(triphenylmethyl)piperidin-4-one in benzene using pyrrolidine. The crude product thus obtained was purified by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (3:1:1) as an eluent to afford the title compound (9.64 g, yield: 57%) as a yellow amorphous solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23][CH3:24])=[C:18](Br)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH2:27]([S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:28].COCCOC.[F-].[Cs+]>CN(C=O)C.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>[CH2:27]([S:29]([C:32]1[CH:37]=[C:36]([C:18]2[C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=[C:16]([C:15]([NH:14][C:5]3([C:3]([OH:2])=[O:4])[CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6]3)=[O:26])[CH:17]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:30])=[O:31])[CH3:28]
Reactant: COC(=O)C1(NC(=O)c2cc(F)c(OC)c(Br)c2)Cc2ccccc2C1
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)cc(F)c2OC)c1
Temperature: 130 °C

Procedure:
300 mg (0.71 mmol) of the compound of step 4 and 175 mg (1.07 mmol) of 3-ethanesulfonylphenylboronic acid were dissolved in 4 ml of DMF and 4 ml of 1,2-dimethoxyethane under an argon atmosphere. 216 mg (1.42 mmol) of cesium fluoride and 41.08 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium(0) were added, and the mixture was heated to 130° C. in a microwave reactor for 15 min. After cooling, the solvent was evaporated and the residue purified by preparative RP HPLC (water/ACN gradient) to yield the methyl ester of the title compound. 135.1 mg (0.26 mmol) methyl ester were dissolved in 5 ml of a mixture of THF and water (9:1), 12.65 mg (0.53 mmol) of lithium hydroxide were added and the mixture was stirred for 3 days. The solvent was evaporated and the residue was purified by preparative RP HPLC (water/ACN gradient). 123 mg of the title compound were obtained.
Reaction SMILES: [ClH:1].[C:2](=[NH:7])(OCC)[CH3:3].[OH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>C(O)C>[ClH:1].[NH:7]=[C:2]([N:12]1[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]1)[CH3:3]
Reactant: CCOC(C)=N
Reactant: OC1CCNCC1
Agent: Cl
Solvent: CCO
Product: CC(=N)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.46 g of ethyl acetoimidate hydrochloride was added to a solution of 4-hydroxy-piperidine (1.0 g) in 10 ml of absolute ethanol. The resulting mixture was stirred at room temperature for 6 hours and then allowed to stand for 7 days. After concentration to dryness the obtained oil spontaneously solidified. After crystallization from acetone 0.7 g of the desired product were obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.C([Li])CCC.[C:25]1([CH:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:32]2[CH2:35][C:34](=[O:36])[CH2:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CCOCC>[C:37]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:32]2[CH2:35][C:34]([C:2]3[C:11]4[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=4)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=3)([OH:36])[CH2:33]2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: FC(F)(F)c1cc(Br)c2cccc(C(F)(F)F)c2n1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: OC1(c2cc(C(F)(F)F)nc3c(C(F)(F)F)cccc23)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
To a solution of 4-bromo-2,8-bis(trifluoromethyl)quinoline (500 mg, 1.45 mmol) in dry ether (10 mL) at −78° C. under argon was added n-butyllithium (0.64 mL of 2.5-M, 1.6 mmol). After 20 min a solution of N-diphenylmethyl-3-azetidinone (345 mg, 1.45 mmol) in ether (5 mL) was added dropwise, the mixture stirred for 20 min, water was added and the mixture allowed to warm slowly to room temperature. The mixture was extracted with ether (3×20 mL), the combined extracts dried (MgSO4), concentrated in vacuo and the residue purified by chromatography [SiO2; heptane-EtOAc (3:1)] to give the product (738 mg, 100%) as a pale yellow foam: IR νmax (Nujol)/cm−1 3378, 2924, 1456, 1377, 1311, 1145 and 702; NMR δH (400 MHz, CDCl3) 3.74-3.79 (4H, m), 4.45 (1H, s), 7.21-7.37 (6H, m), 7.41-7.46 (4H, m), 7.65-7.69 (2H, m), 8.15 (1H, d, J 7.1 Hz) and 8.35 (1H, d, J 8.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C@H:10]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[O:13][CH2:12][CH2:11]2)[C:3]=1[NH2:21].[C:22](Cl)(Cl)=[O:23]>C1COCC1.C1(C)C=CC=CC=1>[NH2:8][C:6]1[N:5]=[C:4]2[C:3]([NH:21][C:22](=[O:23])[N:9]2[C@H:10]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[O:13][CH2:12][CH2:11]2)=[C:2]([Cl:1])[N:7]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc(Cl)c(N)c(N[C@@H]2CCOc3c(F)cccc32)n1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1nc(Cl)c2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of (R)-6-chloro-N4-(8-fluorochroman-4-yl)pyrimidine-2,4,5-triamine (0.9 g, 2.91 mmol) in 900 mL of anhydrous THF at −78° C. under Ar was added dropwise, over 20 min, a solution of phosgene in THF (2.6 mL of a 20% solution of phosgene in toluene, 4.94 mmol, 1.7 equiv., diluted with 26 mL of anhydrous THF). The reaction mixture was left to gradually warm up to room temperature over 16 h. It was purged with air for 30 min. The solvent was then removed in vacuo, and the residue was taken in ethyl acetate/saturated aqueous NaHCO3. The layers were separated, and the aqueous layer extracted with ethyl acetate three times. The combined organic extracts were put together, dried (anhydrous Na2SO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (silica gel, gradual elution with 6/1 to 4/1 methylene chloride/ethyl acetate) to give 0.78 g (80% yield) of the desired product as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ, ppm: 7.13-7.06 (m, 1H), 6.90-6.82 (m, 1H), 6.75-6.72 (m, 1H), 5.92-5.82 (m, 1H), 4.80-4.73 (m, 1H), 4.50-4.42 (m, 1H), 3.20-3.05 (m, 1H), 2.42-2.30 (m, 1H); MS (EI) m/z 336.3 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8](B(O)O)=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1)[CH3:2].[OH:21]O>C(OCC)(=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:21])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1)[CH3:2]
Reactant: OO
Reactant: CCc1nn(-c2ccccc2)c2cc(B(O)O)ccc12
Solvent: CCOC(C)=O
Product: CCc1nn(-c2ccccc2)c2cc(O)ccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-ethyl-1-phenyl-1H-indazol-6-ylboronic acid (1.4 g, 5.26 mmol, 1.00 equiv) in ethyl acetate (10 mL). To the resulting mixture was then added H2O2 (2 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 0° C. in a water/ice bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield 3-ethyl-1-phenyl-1H-indazol-6-ol as a white solid. MS: 239 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:16].[CH3:17][OH:18]>>[ClH:16].[ClH:16].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:15])[O:18][CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1CCN(Cc2ccccc2)CC1
Reactant: CO
Agent: Cl
Product: COC(=N)C1CCN(Cc2ccccc2)CC1
Reaction time: 4 h

Procedure:
A solution of 20 g of 1-benzylpiperidine-4-carbonitrile in a mixture of dry dichlolomethane (200 ml) with methanol (30 ml) was cooled and saturated with a hydrogen chloride gas while maintaining the reaction system at 0° C. or below. After allowing to stand for 4 hours at 0° C., the solvent was distilled off under reduced pressure at room temperature or below and the residue was diluted with ethyl acetate. The colorless crystals thus obtained were ground, filtered and washed with ethyl acetate to thereby give 23.6 g of the title compound.