Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:19])[CH3:18].[C-:20]#[N:21].[Na+]>CN1CCCC1=O.C(OCC)(=O)C.[Ni](Br)Br>[C:20]([C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:19])[CH3:18])#[N:21]
Reactant: CC(=O)NCC1CC1c1c(Br)ccc2nn(C)cc12
Reactant: [C-]#N
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)NCC1CC1c1c(C#N)ccc2nn(C)cc12
Temperature: 180 °C
Reaction time: 0.67 h
Yield: 31.2 %

Procedure:
To a solution of N-{[2-(5-bromo-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (200 mg, 0.621 mmol) obtained in Example 29 in N-methylpyrrolidinone (3 mL) were added nickel(II) bromide (136 mg, 0.621 mmol) and sodium cyanide (61 mg, 1.241 mmol), and the mixture was stirred at 180° C. for 40 min using microwave. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallization (ethyl acetate/hexane) to give the title compound (52 mg, yield 31%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[O:20][CH2:21][CH3:22])/[C:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.CO[C:25](C)(C)[CH3:26]>[Pd]>[CH2:25]([O:19][C:17](=[O:18])[CH:16]([O:20][CH2:21][CH3:22])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[CH3:26]
Reactant: CCO/C(=C\c1ccc(OCc2ccccc2)cc1)C(=O)[O-]
Reactant: COC(C)(C)C
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Temperature: 25 °C
Reaction time: 60 h
Yield: 99 %

Procedure:
Ethyl E/Z-3-(4-benzyloxyphenyl)-2-ethoxyacrylate (20.0 g, 61.3 mmol) dissolved in tert-butyl methyl ether (40 mL) charged with palladium on carbon (5%) (1.0 g, Engelhard Tech code no. 4531) was hydrogenated with vigorous stirring at atmospheric pressure at room temperature for 2-3 days. The catalyst was filtered off and washed with a few milliliters of tent-butyl methyl ether. The combined filtrates were concentrated in vacuo to yield 14.5 g (99% yield) of the title compound as a viscous oil, which crystallizes upon standin.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=C2C(=C[CH:21]=1)C1(CC1)CC2.[Li]CCCC.CN(C=O)C>>[C:1]12([CH2:2][CH2:3]1)[C:4]1[C:11](=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH2:21][CH2:13]2
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: Brc1ccc2c(c1)CCC21CC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)CCC21CC1
Yield: 56 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 5′-bromo-2′,3′dihydro-spiro[cyclopropane1,1′-[1H]indene] (345 mg, 1.55 mmol), n-BuLi (1.16 ml, 1.6M solution in hexane, 1.86 mmol) and DMF (481 μl, 6.19 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 2′,3′-dihydro-spiro[cyclopropane-1,1′-[1H]indene]-5′-carboxaldehyde (148 mg, 56%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 9.93 (s, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 3.10 (apt t, J=8.0 Hz, 2H), 2.18 (apt t, J=8.0 Hz, 2H), 1.08-0.98 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([S:32][CH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](CSCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of (3R)-1-(tert-butoxycarbonyl)-3-[(methane-sulfonyloxy)methyl]pyrrolidine (0.5071 g, 1.82 mmol) and anhydrous potassium carbonate (0.3764 g, 2.72 mmol) in DMF (13 ml), under argon, was added benzyl mercaptan (0.428 ml, 3.65 mmol) and the mixture was stirred overnight at room temperature, then at 60° C. for 4 h. The mixture was then partitioned between water (50 ml) and diethyl ether (30 ml). The aqueous layer was separated and reextracted with more diethyl ether (2×30 ml). The combined organic layers were dried (MgSO4) and evaporated in uacuo. The residue was purified by flash chromatography (silica gel, 20% EtOAc/pet. ether) to give 0.5186 (93%) of the title compound as a colourless oil. δH (360 MHz, CDCl3) 1.45 (9H, s), 1.56 (1H, m), 1.99 (1H, m), 2.32 (1H, m), 2.45 (2H, t, J=6.4 Hz), 2.97 (1H, m), 3.26 (1H, m), 3.61 (2H, m), 3.72 (2H, s), 7.22-7.40 (5H, m). m/e (ES+) 330 (M+Na)+, 308 (M+H)+, 252 (M-CMe3 +2H)+, 234, 213, 208 (M-Boc+2H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([O:19]CCCC)=O)[O:14][C:13]3=[O:24])=[CH:11][C:6]=2[S:5][C:4]1=[O:25])[CH3:2].[CH3:26][NH2:27]>CO.CCOCC>[CH3:26][NH:27][C:17]([C@@H:15]1[O:14][C:13](=[O:24])[N:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:3]([CH2:1][CH3:2])[C:4](=[O:25])[S:5][C:6]=3[CH:11]=2)[CH2:16]1)=[O:19]
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3CC)C(=O)O1
Reactant: CN
Solvent: CCOCC
Solvent: CO
Product: CCn1c(=O)sc2cc(N3C[C@H](C(=O)NC)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The butyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 30, Step 3, 300 mg, 0.823 mmol) is treated with 2N methylamine in MeOH (8.2 mL), and the mixture is stirred at ambient temperature for 1 h. The resulting slurry is diluted with Et2O (10 mL) and filtered to give the title compound, mp 227-229° C.; MS (ESI+) for C14H15N3O4S m/z 322 (M+H)+; [α]25D−43 (c 0.93, DMSO).
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][C:17](=[O:20])[CH:18]=[CH2:19]>C(O)C.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[CH:1]1([C:7](=[O:8])[CH2:19][CH2:18][C:17](=[O:20])[CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: C=CC(C)=O
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)CCC(=O)C1CCCCC1
Temperature: 85 °C
Yield: 27.1 %

Procedure:
To a solution of cyclohexanecarbaldehyde (3.22 mL, 26.7 mmol) in ethanol (9.5 mL) was added triethylamine (7.46 mL, 53.5 mmol), but-3-en-2-one (2.22 mL, 26.7 mmol), and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium bromide (1.35 g, 5.35 mmol). The reaction mixture was heated at 85° C. for 18.5 hours. The reaction was then concentrated under vacuum and the resulting residue was extracted with ethyl acetate (3×50 mL). The organic layer was dried (sodium sulfate), filtered and concentrated to an orange residue which was purified on silica gel using an automated system (ISCO 120 g, 20 mL/min) and 0 to 45% ethyl acetate in hexanes over 60 minutes as the eluent. The product was isolated as a yellow oil (1.32 g, 7.24 mmol, 27% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 2.68-2.73 (m, 4H), 2.35-2.42 (m, 1H), 2.19 (s, 3H), 1.85-1.89 (m, 2H), 1.76-1.79 (m, 2H), 1.65-1.69 (m, 1H), 1.17-1.39 (m, 5H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C1([O:24][C:25](=O)[NH:26][CH:27]([CH3:38])[CH2:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)C=CC=CC=1>O1CCOCC1>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:25]([NH:26][CH:27]([CH3:38])[CH2:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)=[O:24])[CH2:8][CH2:7]1
Reactant: CC(Cc1c[nH]c2ccccc12)NC(=O)Oc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Solvent: C1COCCO1
Product: CC(Cc1c[nH]c2ccccc12)NC(=O)NCC1CCC(c2ccccc2)(N(C)C)CC1

Procedure:
The more polar diastereoisomer of (4-aminomethyl-1-phenyl-cyclohexyl)-dimethylamine (162.7 mg, 0.7 mmole) was added to a solution of [2-(1H-indol-3-yl)-1-methyl-ethyl]-carbamic acid phenyl ester (206 mg, 0.7 mmole) in dioxane (7 ml). The batch was then refluxed for 14 h. A precipitate formed at RT. The precipitate was filtered out, and washed once with cold dioxane (2 ml) and with diethyl ether (3×3 ml). The more polar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-[2-(1H-indol-3-yl)-1-methyl-ethyl]-urea was obtained in this manner as a colorless solid with a melting point of 140-146° C. in a yield of 231 mg (76%).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[O:9]2)=[C:4]2[CH2:22][CH2:23][CH2:24][O:25][C:3]=12>C1COCC1.[Pd]>[F:12][C:11]1[C:2]([F:1])=[C:3]2[C:4]([CH2:22][CH2:23][CH2:24][O:25]2)=[C:5]2[CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[O:9][C:10]=12
Reactant: CCCC1CCC(C2C=Cc3c4c(c(F)c(F)c3O2)OCCC4)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCc3c4c(c(F)c(F)c3O2)OCCC4)CC1

Procedure:
4.0 g (11.5 mmol) of 5,6-difluoro-8-(4-propylcyclohexyl)-1,2,3,8-tetrahydropyrano[3,2-f]chromene are hydrogenated at atmospheric pressure in THF and in the presence of Pd/C (5% of Pd). The reaction solution is filtered, and the filtrate is evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=1:1). The further purification is carried out by repeated recrystallisation from n-heptane at 5° C., giving 5,6-difluoro-3-(4-propylcyclohexyl)-1,2,3,8,9,10-hexahydropyrano[3,2-f]chromene as a colourless solid (m.p. 152° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:19][NH:20][CH3:21].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:20]([CH3:21])[CH3:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 91 %

Procedure:
1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-one (300 mg, 1.20 mmol) in dichloroethane (6 mL) was treated with 2 M Dimethylamine in THF (3 mL, 6 mmol) followed by sodium triacetoxyborohydride (420 mg, 2 mmol) at rt. After 16 h the mixture was treated with saturated aqueous NaHCO3, stirred 45 minutes. The layers were then separated, and the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 305 mg (91%) of desired [1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-yl]dimethyl-amine, which was used without further manipulation. LC/MS (E/I+) 280.12 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([O:26]CC)=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10]1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3cccc(C)c3)C2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(CN2CC[C@@H](Nc3ncc(/C=C/C(=O)O)cc3Cl)C2)c1
Yield: 53.8 %

Procedure:
A solution of ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (820 mg) and 1N NaOH solution (4.1 ml) in MeOH (20 ml) was stirred at 80-85° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of AcOEt and brine. The aqueous solution was adjusted to PH 5.4 with 5% HCl solution and extracted with THF and AcOEt. The solvent was evaporated in vacuo and The precipitate was washed with n-hexane to give (2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (410 mg).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1.O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[CH:23][N:24]=1
Reactant: COc1ccc(C#N)cn1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (1.8 g, 8.7 mmol) in toluene (50 ml) at 0° C., trimethylaluminum (2M solution in toluene, 5.2 ml, 10.4 mmol) was added over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of 6-methoxy-3-cyanopyridine (1.75 g, 13 mmol) in toluene (100 ml) was added over 10 minutes and the mixture was heated to 85-90° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride and methanol and later with methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate (1000 ml) and filtered. The white solid (2 g, 75%) was used in the next reaction without further purification. Anal. Calc'd. for C14H16N3SClO3.0.5 H2O: C, 47.93, H, 4.88, N, 11.98. Found: C, 48.01, H, 4.82, N, 11.32.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[C:15]([O:22][CH:23]([CH3:25])[CH3:24])(=[O:21])[CH2:16][CH2:17][C:18]([O-])=[O:19]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([C:18](=[O:19])[CH2:17][CH2:16][C:15]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:12][CH:13]=1
Reactant: CC(C)OC(=O)CCC(=O)[O-]
Reactant: Fc1ccccc1-c1ccccc1
Agent: [Cl-]
Product: CC(C)OC(=O)CCC(=O)c1ccc(-c2ccccc2F)cc1

Procedure:
Prepared analogous to Example 2 from 2-fluoro-biphenyl and isopropyl succinate chloride. Melting point 65°-66° C (from cyclohexane/petroleum ether).
Reaction SMILES: Br[CH2:2]C1C=CC(C(O)=O)=CC=1.[H-].[Na+].[CH2:14]([O:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[CH2:15]C=C>C(O)(C)C>[CH:14]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=1)([CH3:15])[CH3:2]
Reactant: C=CCCOCc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OCc1ccc(C(=O)O)cc1

Procedure:
The reaction of isopropanol and 4-Bromomethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 4-Isopropoxymethyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.89 (d, J=8.2, 2 arom.H); 7.41 (d, J=8.2, 2 arom.H); 4.51 (s, OCH2C6H4—); 3.63 (m, CH(CH3)2); 1.14 (d, CH(CH3)2). 13C-NMR (100 MHz, d6-DMSO): 167.24 (—C═O); 144.47; 129.52; 129.23 (2 arom.C); 126.93 (2 arom. C); 70.67; 68.47; 22.00 (2 C).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([OH:16])[C@H:12]([NH2:15])[CH2:13][F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:17][CH:18]([Cl:23])[C:19](OC)=[O:20].C(N(CC)CC)C>CO>[Cl:17][CH:18]([Cl:23])[C:19]([NH:15][C@H:12]([CH2:13][F:14])[C@@H:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[OH:16])=[O:20]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Reactant: COC(=O)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
To a solution of (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (5 g, 0.02 moles) in methanol (50 ml) was added methyl dichloroacetate (14.5 g; 0.10 g) and triethylamine (2.05 g, 0.02 mole) and stirred at room temperature for 18 hours. After completion of reaction, methanol was distilled off from the reaction mass, toluene (25 ml) and water (5 ml) were added. The product thus precipitated was filtered, washed with methylene chloride (20 ml) and crystallized from 2-propanol/water (5:1) to give 5 g of title compound having purity 99.20% by HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([N:40]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46](B4OC(C)(C)C(C)(C)O4)[CH:47]=3)[CH:42]=[N:41]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:46]1[CH:47]=[C:48]2[C:43]([CH:42]=[N:41][N:40]2[S:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)(=[O:39])=[O:38])=[CH:44][CH:45]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S(=O)(=O)n2ncc3ccc(B4OC(C)(C)C(C)(C)O4)cc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)n2ncc3ccc(-c4c(N)ncnc4N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)cc32)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added 1-((4-methoxyphenyl)sulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (201 mg, 0.34 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (18 mg, 0.02 mmol) and 227 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (50% to 75%, hexane-ethyl acetate) to obtain 97 mg (66% yield) of the title compound as a white solid. Purity 100%. LRMS (m/z): 648 (M−1)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][N:9]=[C:8]([NH:13][CH2:14][CH2:15][O:16][CH3:17])[N:7]=1)=[O:5])[CH3:2].[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)=[CH:10][N:9]=[C:8]([NH:13][CH2:14][CH2:15][O:16][CH3:17])[N:7]=1)=[O:5])[CH3:2]
Reactant: Nc1cncnc1
Reactant: CCOC(=O)c1nc(NCCOC)ncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(NCCOC)ncc1Nc1cncnc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A microwave reaction tube was charged with a suspension of 5-bromo-2-(2-methoxy-ethylamino)-pyrimidine-4-carboxylic acid ethyl ester (30 mg, 0.1 mmol), 5-aminopyrimidine (14 mg, 0.15 mmol) and cesium carbonate (45 mg, 0.14 mmol) in dioxane (0.6 ml) and flushed with argon. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 19 mg, 32 μmol) and tris(dibenzylideneacetone)-dipalladium(0) chloroform adduct (10 mg, 10 μmol) were consecutively added and the reaction tube was sealed and stirred overnight at 130° C. After cooling-down to ambient temperature, the reaction mixture was filtrated. The filtrate was concentrated in vacuo and the product was obtained after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (11 mg, 35%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([O:20][CH2:21][CH3:22])[CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[CH2:23]([O:25][P:26]([O:30]CC)[O:27][CH2:28][CH3:29])[CH3:24]>>[CH2:21]([O:20][C:18]1[CH:19]=[C:3]([CH:4]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[CH:17]=1)[CH2:2][P:26](=[O:30])([O:27][CH2:28][CH3:29])[O:25][CH2:23][CH3:24])[CH3:22]
Reactant: CCOc1cc(CCl)cc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: CCOP(OCC)OCC
Product: CCOc1cc(CP(=O)(OCC)OCC)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
2-(3-(Chloromethyl)-5-ethoxyphenoxy)-5-(trifluoromethyl)pyridine from Step 3 was treated neat with triethylphosphite (0.30 mL, 1.75 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled and purified by silica gel chromatography (0-50%, EtOAc:CH2Cl2) to afford the title compound (400 mg, 82% yield) as a thick oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:38](=[CH:39][CH:40]=2)[O:37][CH2:36][C:32]2([CH2:35][O:34][CH2:33]2)[C:12]23[CH2:16][O:15][C:14]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:13]2)O1.Br[C:43]1[CH:44]=[N:45][CH:46]=[C:47]([C:49]#[C:50][CH2:51][O:52][CH3:53])[CH:48]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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.O>[CH3:53][O:52][CH2:51][C:50]#[C:49][C:47]1[CH:48]=[C:43]([C:9]2[CH:10]=[C:11]3[C:38](=[CH:39][CH:40]=2)[O:37][CH2:36][C:32]2([CH2:35][O:34][CH2:33]2)[C:12]23[CH2:16][O:15][C:14]([N:17]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])=[N:13]2)[CH:44]=[N:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1OCC21COC1
Reactant: COCC#Cc1cncc(Br)c1
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: C1COCCO1
Solvent: O
Product: COCC#Cc1cncc(-c2ccc3c(c2)C2(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N2)C2(COC2)CO3)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere, a mixture of di-tert-butyl [6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (213 mg, 0.372 mmol), 3-bromo-5-(3-methoxyprop-1-yn-1-yl)pyridine (252 mg, 1.12 mmol), Na2CO3 (158 mg, 1.49 mmol), tetrakis(triphenylphosphine)palladium(0) (21.5 mg, 0.019 mmol), dioxane (3.4 mL) and water (0.85 mL) was stirred for 3 hours at 110° C. The reaction mixture was cooled down to ambient temperature, and water was added to the mixture. The mixture was extracted with MeOH—CHCl3 (1:9), and the organic layer was dried over Na2SO4 prior to filtration. The filtrate was concentrated at reduced pressure to give crude di-tert-butyl {6′-[5-(3-methoxyprop-1-yn-1-yl)pyridin-3-yl]dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl}imidodicarbonate, which was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Br:11]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[Br:11][C:8]1[CH:9]=[C:2]([F:1])[C:3]([OH:10])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(F)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1cc(Br)cc(F)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
596 mg of 3-fluoro-2-hydroxybenzaldehyde was dissolved in 5 ml of acetonitrile, and 770 mg of N-bromosuccinimide was added. The solution was stirred for 15 minutes at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was evaporated, to give 928 mg of 5-bromo-3-fluoro-2-hydroxybenzaldehyde.