Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)=[N:4][C:5]([OH:9])=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].[CH2:23](I)[CH3:24].CCCCCC.C(OCC)(=O)C>CS(C)=O>[CH2:23]([N:4]1[C:3]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:18])[F:19])[N:12]([CH3:20])[N:11]=2)=[C:2]([F:1])[CH:7]=[C:6]([Cl:8])[C:5]1=[O:9])[CH3:24]
Reactant: CCI
Reactant: Cn1nc(-c2nc(O)c(Cl)cc2F)c(Cl)c1OC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCn1c(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc(Cl)c1=O

Procedure:
1.5 g of 3-(3-fluoro-5-chloro-6-hydroxy-2-pyridyl)-4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example P27) are introduced into 6 ml of dimethyl sulfoxide (DMSO). 2.5 ml of a 2N aqueous sodium hydroxide solution are added thereto. 0.78 g of ethyl iodide in 2 ml of DMSO is then added dropwise, with stirring, and the mixture is further stirred overnight at 70° C. The next day, the reaction mixture is partitioned between dilute hydrochloric acid and diethyl ether. After extraction by shaking, and separation of the phases, the ethereal phase is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Finally, the residue is purified over a flash chromatography column (silica gel; elution gradient: n-hexane/ethyl acetate 4/1 to 1/1 (v/v)). 0.54 g of the desired target compound is obtained in the form of a yellow oil having an Rf value of 0.17 on silica gel 60 F254 (eluant: n-hexane/-ethyl acetate 2/1 (v/v)).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[N:21]1.C(N(CC)CC)C.O>CN(C)C=O>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=4)[N:3]=3)[CH2:34][CH2:33]2)=[O:31])=[N:21]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: Clc1nc(-c2cccnc2)ns1
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3cccnc3)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(5-chloro-1,2,4-thiadiazol-3-yl)pyridine (104 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the desired product as a solid was separated by filtration, which was purified by silica gel column chromatography (ethyl acetate) to give the desired product as a solid. The resulting solid was recrystallized from a mixed solvent of ethyl acetate, tetrahydrofuran and hexane to yield 55.7 mg (24.6%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23]CCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCC1CC[N:68]([C:71]([O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:72])[CH2:67][CH2:66]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:68]([C:71]([O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:72])[CH2:67][CH2:66]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 4-(3-bromopropyl)-1-piperidinecarboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][C:13]=1[O:25][CH3:26].C(O)(=O)C.C(OCC)(=O)C>O>[CH3:26][O:25][C:13]1[CH:14]=[C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:17][C:12]=1[NH:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CCOC(=O)CCc1ccc(N)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(Nc2ccc([N+](=O)[O-])cn2)c(OC)c1
Temperature: 100 °C
Reaction time: 13 h

Procedure:
To 2-chloro-5-nitropyridine (3.11 g, 20 mmol) were added ethyl 3-(4-amino-3-methoxyphenyl)propionate (4.38 g, 20 mmol) and acetic acid (10 mL), and the resulting solution was stirred for 13 hours at 100° C. To the reaction solution were added ethyl acetate and water. The ethyl acetate layer was separated, washed with brine, a saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 3.78 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][C:15]([OH:24])([CH3:23])[CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C>[CH3:23][C:15]([OH:24])([CH3:14])[CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=3)=[O:13])[CH2:21][CH2:22]1
Reactant: CC(C)(O)CC1CCNCC1
Reactant: Cc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c(C(=O)N3CCC(CC(C)(C)O)CC3)cc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.4 %

Procedure:
To a solution of 1800 mg of 5-methylindole-2-carboxylic acid and 1500 mg of 2-methyl-1-(piperidin-4-yl)-2-propanol in 25 mL of DMF were added 2100 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 1500 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.5M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then crystallized from a mixture of ethyl acetate/diisopropyl ether to obtain 2140 mg of 2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol as a white crystal.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.[N:67]1([C:72]2[CH:77]=[CH:76][N:75]=[C:74]([Sn](CCCC)(CCCC)CCCC)[CH:73]=2)[CH:71]=[CH:70][CH:69]=[N:68]1.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:76]4[CH:77]=[C:72]([N:67]5[CH:71]=[CH:70][CH:69]=[N:68]5)[CH:73]=[CH:74][N:75]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(-n2cccn2)ccn1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3cc(-n4cccn4)ccn3)nc12)C(=O)N1CC(C#N)C1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 4-pyrazol-1-yl-2-tributylstannanyl-pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=442.
Reaction SMILES: C(OC(=O)[N:7]([CH2:27][C:28]1[S:29][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[N:31][N:32]=1)[C:8]1[CH:13]=[C:12]([O:14][CH2:15][C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[N:11]=[C:10]([CH3:26])[N:9]=1)(C)(C)C.Cl>>[C:33]([C:30]1[S:29][C:28]([CH2:27][NH:7][C:8]2[CH:13]=[C:12]([O:14][CH2:15][C@@H:16]3[CH2:18][C@H:17]3[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[N:11]=[C:10]([CH3:26])[N:9]=2)=[N:32][N:31]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1ccc([C@H]2C[C@@H]2COc2cc(N(Cc3nnc(C(C)(C)C)s3)C(=O)OC(C)(C)C)nc(C)n2)nc1
Agent: Cl
Product: Cc1ccc([C@@H]2C[C@H]2COc2cc(NCc3nnc(C(C)(C)C)s3)nc(C)n2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 117.8 %

Procedure:
15-4 (40 mg, 0.06 mmol) was treated with HCl (4 M in 1,4-dioxane) (2 mL) and the mixture was stirred at room temperature for 6 h. Then it was concentrated, diluted with water (1 mL), and adjusted to pH 11 with aq NaOH (4 N). The resulting mixture was extracted with DCM (10 mL×4) and the organic layer was dried over Na2SO4, concetrated to afford the title compound (30 mg, 93%). 1H NMR (400 MHz, MeOD) δ 8.08 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 5.60 (s, 1H), 4.16 (dd, J=10.9, 6.5 Hz, 1H), 4.03 (dd, J=10.8, 7.5 Hz, 1H), 3.02 (s, 2H), 2.26 (s, 3H), 2.18 (s, 3H), 2.05-1.96 (m, 1H), 1.69 (d, J=6.2 Hz, 1H), 1.34 (s, 9H), 1.15-1.04 (m, 1H), 1.04-0.91 (m, 1H). LRMS (ES) calculated M+H for C22H28N6OS: 425.6. Found: 425.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCc1ccc(S(=O)(=O)Nc2cncc(-c3ccc(C#N)c(Cl)c3)c2)cc1
Yield: 41.3 %

Procedure:
According to General Sulfonylation Procedure 2 in example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added 4-ethyl-benzenesulfonyl chloride (15.5 μl, 96 μmol, 1.1 eq). The product was purified by precipitation in methanol and lyophilized to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-4-ethyl-benzenesulfonamide (14.3 mg, >95% purity, yield: 41.4%).
Reaction SMILES: [CH:1]1(C(C2C=C(OC)C=C(OC)C=2)=O)CCCCC1.[CH:19]1([C:24]([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=2)([CH3:26])[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>CCCCCC.C(OCC)(=O)C>[CH:19]1([C:24]([C:27]2[CH:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=2)([CH3:26])[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:1]1
Reactant: COc1cc(OC)cc(C(=O)C2CCCCC2)c1
Reactant: COc1cc(OC)cc(C(C)(C)C2CCCC2)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(OC)cc(C(C)(C)C2CCCCC2)c1

Procedure:
Compound 14 was prepared from Compound 7 using the same procedure as described above for Compound 13. Yield 3.69 g (70.3%) as an oil. Rf=0.55 (hexane:ethyl acetate 95:5); IR (neat) 2932, 1457, 1422, 1208, 1066 702 cm−1; 1H NMR δ 6.48 (d, J=2.4 Hz, 2H), 6.35 (t, J=2.1 Hz, 1H), 3.80 (s, 6H), 1.72–1.55 (m, 6H), 1.45–1.39 (m, 1H), 1.21 (s, 6H), 1.18–1.05 (m, 2H), 0.97–0.85 (m, 2H); 13C NMR δ 160.52, 153.48, 105.35, 96.64, 55.44, 49.28, 41.06, 28.18, 27.44, 26.96, 25.50; MS: (ESI, Pos.) m/z 263 ([M+H]+).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1)C=C.C(OCC)(=O)C.C(N(CC)[C:22]1[CH:27]=CC=C[CH:23]=1)C>>[CH2:27]([C:10]1[C:9]([CH3:11])=[CH:8][C:7]([CH3:12])=[CH:6][C:5]=1[OH:4])[CH:22]=[CH2:23]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1cc(C)cc(C)c1
Solvent: CCOC(C)=O
Product: C=CCc1c(C)cc(C)cc1O
Temperature: 210 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
A solution of 1-(allyloxy)-3,5-dimethylbenzene obtained in Reference Example 214 (1.0 g, 6.2 mmol) in N,N-diethylaniline (4 mL) was stirred under argon atmosphere at 210° C. for 5 hours. To the reaction solution was added ethyl acetate, and the mixture was washed with hydrochloric acid and a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 7:3) to obtain 938 mg (yield 94%) of the title compound. Oily matter.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([O:5][C:6]([C:8]1([CH2:12][NH2:13])[CH2:9][CH2:10][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1(C#N)CCC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)C1(CN)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A mixture of 1-cyano-cyclobutanecarboxylic acid tert-butyl ester (6.58 g) and Raney Ni (10 mL in water) in MeOH (250 mL) was stirred at rt under H2 atmosphere (balloon) overnight. Then the reaction mixture was filtered over Celite pad, filtrate was concentrated to give the desired product (5.59 g). 1H NMR in CDCl3, δ in ppm: 2.94 (s, 2H), 2.4-2.2 (m, 2H), 2.0-1.8 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](Cl)=[N:10][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:30][OH:31])[CH:20]=[N:21][C:22]=1[N:23]1[CH2:28][CH2:27][NH:26][C@H:25]([CH3:29])[CH2:24]1>O1CCOCC1>[Br:1][C:2]1[C:7]2[NH:8][C:9]([N:26]3[CH2:27][CH2:28][N:23]([C:22]4[N:21]=[CH:20][C:19]([CH2:30][OH:31])=[CH:18][C:17]=4[Cl:16])[CH2:24][C@H:25]3[CH3:29])=[N:10][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)c2[nH]c(Cl)nc2c1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1

Procedure:
A mixture of 7-bromo-2-chloro-5-trifluoromethyl-1H-benzoimidazole (96 mg, 0.32 mmol, Example 6b) and {5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-yl}-methanol (96 mg, 0.4 mmol, Example 150a) in dioxane (2 mL) reacted under the conditions of Example 3c to give the title compound. MS (ESI, pos. ion) m/z: 506 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18].O>CC(C)=O>[CH2:18]([O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Oc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1cc(F)ccc1F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
10 g of 2,5-difluorophenol was dissolved in 120 ml dimethylformaldehyde, 21 g of potassium carbonate and 8.57 ml allyl bromide were added in this order thereto at room temperature and then the resulting mixture was stirred at 80° C. for 1 hour. After water was added to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was subjected to silica gel chromatography (developing solvent: 5% ethyl acetate/n-hexane) to give 13 g of 2,5-difluorophenol allyl ether as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][CH:10]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:24][O+](C)C>C(Cl)Cl>[CH3:24][O:18][C:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:9][CH:8]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:17]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCCC(CC=Cc2ccccc2)N1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(CC=Cc2ccccc2)CCCCC1

Procedure:
The product of Example 68 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24]>C(Cl)Cl>[F:21][C:22]([F:26])([F:25])[CH2:23][NH:24][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: NCC(F)(F)F
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
5.0 g (24 mmol) of 4-trifluoromethylbenzoyl chloride and 5.0 ml (36 mmol) of triethylamine were dissolved in 50 ml of CH2Cl2 and 2.4 g (24 mmol) of 2,2,2-trifluoroethylamine were slowly added dropwise at RT. The mixture was stirred at RT for 4 h, then the volatile constituents were removed under reduced pressure. The residue was taken up using 100 ml of MTB and washed initially with 30 ml of a saturated aqueous Na2CO3 solution and then with 30 ml of a saturated aqueous NaHSO4 solution. Drying was effected over MgSO4 and 6.1 g (94%) of a colorless resin were obtained which crystallized when left to stand; mp: 117° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1.Br[CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:37])[CH3:38])=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)[nH]c3cc2Br)CC1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)n(CCCO[Si](C)(C)C(C)(C)C)c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 1, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (Example 6, step 4) and (3-bromopropoxy)-tert-butyldimethylsilane. The desired product was obtained in a yield of 65% as colorless oil. MS (m/e): 670.5 (M+H, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[NH:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[CH2:16]([O:15][C:13]([CH:12]1[CH2:18][CH2:19][N:9]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=2)[CH2:10][CH2:11]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Fc1ccc(Br)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C1CCN(c2ccc(F)cn2)CC1
Yield: 29.7 %

Procedure:
A mixture of 3.4 g (20 mmol) 2-bromo-5-fluoropyridine, 4.61 g (29 mmol) ethyl isonipecotate and 3.79 g (29 mmol) DIPEA in 5 mL NMP was heated for 15 min to 170° C. and 60 min to 200° C. After cooling to room temperature water was added and the mixture was extracted with ethyl acetate and heptane. The combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 1.5 g (30%) of the title compound as light yellow oil. MS m/e: 253.3 [M]+.
Reaction SMILES: C(#N)C.C(N(CC)C(C)C)(C)C.[CH3:13][C:14]1[C:19]([C:20]([OH:22])=[O:21])=[C:18]([CH3:23])[CH:17]=[CH:16][N:15]=1.Cl[CH2:25][N:26]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][C:32]([O:41][CH3:42])=[CH:33][C:34]=2[CH:38]([CH3:40])[CH3:39])[S:27]1(=[O:29])=[O:28]>C(OCC)(=O)C>[CH3:13][C:14]1[C:19]([C:20]([O:22][CH2:25][N:26]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][C:32]([O:41][CH3:42])=[CH:33][C:34]=3[CH:38]([CH3:40])[CH3:39])[S:27]2(=[O:28])=[O:29])=[O:21])=[C:18]([CH3:23])[CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: Cc1ccnc(C)c1C(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)c1c(C)ccnc1C)C2=O
Reaction time: 0.08 h
Yield: 58 %

Procedure:
Acetonitrile (20 ml), followed by N,N-diisopropylethylamine (5.8 ml, 33 mmol) were added to 2,4-dimethyl-3-pyridinecarboxylic acid (5.1 g, 33 mmol). The mixture was stirred for 5 minutes, then 2-chloromethyl-4-isopropyl-6-methoxysaccharin (4.3 g, 14 mmol) was added. The reaction mixture was stirred at room temperature for 47 hours, then at 80° C. for 1 hour. The mixture was diluted with ethyl acetate (100 ml), washed with saturated NaHCO3, and the organic layer was dried over Na2SO4. The solvent was removed in vacuo and the residue was recrystallized from ether to afford 3,4 g (57%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl 2,4-dimethylpyridine-3 carboxylate, m.p. 132.1°-133.5° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[CH:34][C:33]=1[Cl:46]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:31][C:32]1[C:33]([Cl:46])=[CH:34][C:35]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)=[CH:36][C:37]=1[Cl:38])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cc(Cl)c(CBr)c(Cl)c2)cc1
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 65.7 %

Procedure:
Dissolve (R)-4-Benzyl-3-pent-4-enoyl-oxazolidin-2-one (3.86 mmoles; 1.00 g) in THF (2 mL) and cool the mixture in a dry ice acetone bath. Add Lithium Bis(trimethylsilyl)amide (4.24 mmoles; 4.24 mL) dropwise at −78° C. under nitrogen. Stir the mixture at −78° C. for 10 minutes, and then warm to −25° C. for 1 hour. Cool the mixture back down to −78° C. and add 4-Bromomethyl-3,5-dichloro-4′-fluoro-biphenyl (4.43 mmoles; 1.48 g) in THF (2 mL) dropwise at −78° C. Warm the reaction to ambient temp. After stirring overnight, the LCMS analysis indicated 2 peaks. Purify the mixture over silica gel using hexane to 1:1 EtOAc/hexanes to obtain 1.3 g oil/foam. WY=65.8%, LCMS=89.6% (M+1=512.0).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[Br:13]Br>CO>[Br:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: BrBr
Solvent: CO
Product: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Reaction time: 48 h
Yield: 83.6 %

Procedure:
5-Nitroindazole (20.0 g, 123 mmol, 1 equiv) was suspended in 500 mL MeOH. The mixture was refluxed and bromine (6.3 mL, 123 mmol, 1 equiv) was added dropwise. The reaction was stirred at reflux for 3 hours, then at room temperature for 2 days. The reaction mixture was filtered and the solid was washed with diisopropyl either to afford 24.9 g (84%) of the title compound as a yellow solid.