Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:45])[C:25]([CH:27]1[CH2:31][C:30]2[CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35][C:29]=2[O:28]1)=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:34]=[CH:35][C:29]4[O:28][CH:27]([C:25]([N:24]([CH3:23])[CH3:45])=[O:26])[CH2:31][C:30]=4[CH:32]=3)[C:16]2=[CH:15][N:14]=1
Reactant: CN(C)C(=O)C1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
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: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CC(C(=O)N(C)C)O5)n[nH]c3n2)c1F
Temperature: 115 °C
Reaction time: 5 h

Procedure:
A mixture of 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (16.7 mg, 0.0400 mmol), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide (19.0 mg, 0.0600 mmol) (Example 1, Step 2), tetrakis(triphenylphosphine)palladium(0) (2.77 mg, 0.00240 mmol) and sodium carbonate (12.7 mg, 0.120 mmol) in 1,4-dioxane (0.42 mL) and water (0.14 mL) in a reaction vial was sealed, and degassed and recharged with nitrogen for three times. The mixture was stirred at 115° C. for 5 h. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=482.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]([NH:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[O:13])=[CH:2]1.[OH-].[K+].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:24]1([S:30]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[CH:11][C:12]([NH:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)=[O:13])=[CH:2]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(C=Cc1c[nH]c2ccccc12)NOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: O=C(C=Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12)NOC1CCCCO1
Reaction time: 0.33 h
Yield: 54.1 %

Procedure:
To a suspension of 18 (0.52 g, 1.82 mmol), tetrabutylammonium bisulfate (0.09 g, 0.27 mmol) and KOH (0.20 g, 3.63 mmol) in CH2Cl2 (15 mL) was stirred for 20 min, benzenesulfonyl chloride (0.35 ml, 2.72 mmol) was added and stirred at room temperature overnight. The reaction mixture was quenched with water extracted with CH2Cl2 (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a yellow residue, which was purified by silica gel chromatography (EtOAc:n-hexane=1:2) to afford 19 (0.42 g)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH3:29])=[C:14]([O:17][CH:18]3[CH2:27][CH2:26][C:21]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][NH:8]1.C(N(CC)CC)C>C(#N)C>[Cl:3][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH3:29])=[C:14]([O:17][CH:18]3[CH2:27][CH2:26][C:21]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC1CCC2(CC1)OCCO2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Cl)c2cc1OC1CCC2(CC1)OCCO2
Temperature: 40 °C
Reaction time: 8 h

Procedure:
6 ml phosphorus oxychloride are added dropwise to 12.1 g of 3,4-dihydro-4-oxo-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazoline in 120 ml acetonitrile and the mixture is heated to an internal temperature of 40° C. Then 9.3 ml triethylamine are added dropwise and the reaction mixture is refluxed for 3 hours. The mixture is cooled to ambient temperature and left to stand overnight. The solution of the product is reacted further without purification (see Example III).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:19]2[CH2:20][CH2:21][O:22][CH2:23][CH:24]=2)[C:5]2C[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=2[N:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>>[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:2]2[N:3]=[C:4]([CH:19]3[CH:20]=[CH:21][O:22][CH2:23][CH2:24]3)[C:5]3[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][C:6]=3[N:7]=2)=[CH:28][N:27]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc(Cl)nc2C2=CCOCC2)C1
Product: CC(C)(C)OC(=O)N1Cc2nc(-c3cnc(N)nc3)nc(C3C=COCC3)c2C1

Procedure:
Compound de was synthesized according to general procedure described in step 2 of Example 1 by reacting tert-butyl 2-chloro-4-(3,6-dihydro-2H-pyran-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate with 2-aminopyrimidin-5-ylboronic acid. LC-MS: m/z=397 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].Cl.Cl[CH2:15][C:16]1[S:20][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:18][CH:17]=1.S([O-])(O)(=O)=O.[K+]>>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]1[S:20][C:16]([CH2:15][S:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])=[CH:17][N:18]=1
Reactant: O=C(O)c1cccc(S)c1
Reactant: ClCc1cnc(Nc2ccccn2)s1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [H-]
Product: O=C(O)c1cccc(SCc2cnc(Nc3ccccn3)s2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-mercaptobenzoic acid (308 mg, 2 mmol) and sodium hydride (60% in oil, 160 mg, 4 mmol) was stirred at RT under argon for 10 min and then cooled to 0° C. and (5-chloromethyl-thiazol-2-yl)pyridin-2-yl-amine hydrochloride salt (262 mg, 1 mmol) was added. The resulting reaction mixture was stirred at 0° C. for 1 h and acidified with 1N potassium hydrogen sulfate solution to pH=4. The mixture was filtered and the collected solid was washed with water and dried in vacuo to provide compound 11A, 3-[2-(pyridin-2-ylamino)thiazol-5-ylmethylsulfanyl]benzoic acid, which was used directly for the next step.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:18]1[CH2:22][O:21]C(C)(C)[N:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[OH:21][CH2:22][C@H:18]([NH:19][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:2]([OH:1])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCC#C[C@@H](O)[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCC#C[C@@H](O)[C@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
The (S)-tert-butyl 4-((R)-1-hydroxy-2-hexadecynyl)-2,2-dimethyloxazolidine-3-carboxylate) (100 mg, 0.23 mmol) obtained in the above-described reaction was dissolved in methanol (4.4 ml); p-toluenesulfonic acid (0.8 mg, 4.6 μmol) was added to the solution, and the mixture was stirred at room temperature for 12 hours. P-toluenesulfonic acid (0.8 mg, 4.6 μmol) was added to this reaction mixture, stirred for 6 hours, heated to 60° C., and further stirred for 2 hours. Saturated sodium hydrogen carbonate was added to this reaction mixture, and the reaction was stopped; the mixture was subsequently extracted with ethyl acetate, and the organic layer was dried and filtered. The resulting filtrate was purified by column chromatography to produce tert-butyl (2S,3R)-1,3-dihydroxyoctadec-4-yn-2-ylcarbamate (85 mg, 93% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:32])[C:29](O)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[C:52]([O:56][C:57](=[O:60])[CH2:58][NH2:59])([CH3:55])([CH3:54])[CH3:53].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:32])[C:29]([NH:59][CH2:58][C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:60])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reactant: CC(C)(C)OC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Temperature: 0 °C
Yield: 79.4 %

Procedure:
To an ice-cooled solution of 2-{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol -3-yl}-2-oxoacetic acid (1.47 g, 3.35 mmol) in methylene chloride (25 mL) was added 1-hydroxybenzotriazole hydrate (0.771 g, 5.03 mmol). The reaction mixture was stirred for few minutes in an ice bath. Triethylamine (0.47 mL, 3.4 mmol), and glycine tert-butyl ester hydrochloride (0.573 g, 3.42 mmol) were added. After stirring for five more minutes in the ice bath, dicyclohexylcarbodiimide (0.88 g, 4.27 mmol) was added. The reaction mixture was then stirred at room temperature for 2 hours under nitrogen. The mixture was filtered. The insoluble matter was washed with ethyl acetate. The combined filtrate was evaporated to dryness. The residue was partitioned in ethyl acetate and 2N hydrochloric acid. The organic phase was washed with brine and evaporated to dryness. The residue was purified by flash chromatography (Biotage apparatus) using 2.5–12.5% ethyl acetate in hexane to yield the title compound as a yellow solid (1.47 g, 80%), mp 167–168° C. Mass spectrum (−ESI, [M-H]−) m/z 551.7; 1HNMR (500 MHz, DMSO-d6): δ9.05 (s, 1H), 9.0 (t, 1H, J=6.0 Hz), 8.5 (d, 1H, J=1.5 Hz), 7.75–7.8 (m, 2H), 7.7 (d, 1H, J=8.4 Hz), 7.6 (dd, 1H, J=8.6 Hz and 1.8 Hz), 7.45 (d, 1H, J=8.1 Hz), 7.3–7.35 (m, 5H), 5.65 ppm (s, 2H), 3.9 (d, 2H, J=6.1 Hz), and 1.45 ppm (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C@H:6]([NH:7][C:8]2[CH2:12][S:11][C:10](=[O:13])[N:9]=2)[CH2:5][CH2:4][NH:3]1.[F:14][C:15]([F:36])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:36][C:15]([F:14])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22](/[CH:25]=[C:12]2/[C:8]([NH:7][C@@H:6]3[CH2:5][CH2:4][NH:3][C:2]3=[O:1])=[N:9][C:10](=[O:13])[S:11]/2)[CH2:21][CH2:20]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(N[C@@H]2CCNC2=O)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2CCNC2=O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 6 h
Yield: 21.9 %

Procedure:
To a solution of 4-{[(3R)-2-oxopyrrolidin-3-yl]amino}-1,3-thiazol-2(5H)-one (140 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (358 mg) in 2-propanol (5 mL) was added piperidinium acetate (102 mg). The reaction mixture was stirred at 80° C. for 6 hr and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol). The obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (80 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][NH:17][CH3:18])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:19]=O>C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: C=O
Reactant: CNCCC1(c2cccc(OC)c2)C=CCCC1
Solvent: O=CO
Product: COc1cccc(C2(CCN(C)C)C=CCCC2)c1
Reaction time: 2 h

Procedure:
5.0 g of 1-(m-methoxyphenyl)-N-methyl-2-cyclohexene-1-ethylamine are treated with a mixture of 1.5 liters of 35% aqueous formaldehyde solution and 2.0 ml of 90% formic acid, and the resulting mixture is held at 100° C. for 2 hours. After distillation of the solvent, the residue is treated with 1 N hydrochloric acid solution. The neutral portion is taken up in ether, the aqueous phase is made alkaline by the addition of 3 N sodium hydroxide and the rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-ethylamine is taken up in methylene chloride. After distillation of the solvent, the oil obtained is purified on a 10-fold amount of aluminium oxide. The fractions eluted with toluene are combined and evaporated, and pure rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-ethylamine remains as the residue. The hydrochloride of this compound melts at 161°-162° C. (after recrystallization from ethyl acetate/ethanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:24])[NH:14][C:15]1[CH:16]([O:21][CH2:22][CH3:23])[O:17][C:18](=[O:20])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N#N.[H][H].ClCCl>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:24])[NH:14][CH:15]1[CH2:19][C:18](=[O:20])[O:17][CH:16]1[O:21][CH2:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC1OC(=O)C=C1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: N#N
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC1OC(=O)CC1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
To a solution of (R )-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (X, R1=Et) (0.09 g, 0.27 mmol) in toluene previously degassed with N2 (20 mL) in a high pressure reactor in a nitrogen filled glove bag, was added (−)-1,2-bis((2R,5R)-2,5-diethyl-phospholano)benzene-(cyclooctadiene)rhodium(I) trifluoromethanesulfonate (5-15 mg). The reactor was sealed and pressurized with hydrogen (950 psi, 65 atm) and was let stand at room temperature for 2 d. Solvent was evaporated and the residue was purified by flash chromatography (SiO2) eluted with 1.5:98.5 methanol:dichloromethane to provide (R)-2-(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.092 g, quant yield) as a colorless oil. Chiral HPLC (chiralpak-AD column, eluted with 1:9 ethanol:hexanes): isomer Ib-35.4%, isomer Id-56.4%, (mixture of isomers Ia and Ic)-8.2%. 1H-NMR (500 MHz, CDCl3) δ 7.60 (br s, 0.25H), 7.40 (br s, 0.25H), 6.5 (br m, 0.25H), 5.38 (d, J=5 Hz, 0.5H), 5.27 (s, 0.5H), 4.65 (br, 0.5H), 4.20 (br m, 1.5H), 3.85 (m, 0.5H), 3.77 (m, 0.5H), 3.57 (m, 1H), 3.30 (m, 2H), 2.95 (m, 0.5H), 2.80 (br m, 0,5H), 2.30 (br m, 2H), 1.85 (br s, 3H), 1.37 (s, 9H), 1.20 (t, J=7 Hz, 1.5H), 1.15 (t, J=7 Hz, 1.5H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[Br:13]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.S(=O)(=O)(O)O>[Br:13][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
A solution of 3-nitrobenzoic acid (16.7 g, 100 mmol) in trifluoroacetic acid (50 mL) and sulfuric acid (20 mL) was stirred at 50° C., and N-bromosuccinimide (26.7 g, 150 mmol) was added in three portions over 3 hours. The mixture was stirred for 16 hours and then cooled to room temperature. The mixture was then poured into ice water (200 mL) and extracted three times with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The residue was recrystallized from dichloromethane to provide a white solid (17.7 g, 72%). 1H NMR (300 MHz, DMSO-d6) δ13.8 (bs, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.37 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[CH:6](=O)[CH2:7][CH3:8].[BH4-].[Na+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:27]>ClCCl.CO.O1CCOCC1>[ClH:27].[CH2:6]([NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])[CH2:7][CH3:8]
Reactant: C[C@H](N)CO
Reactant: CCC=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCN[C@@H](C)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (S)-(+)-2-amino-1-propanol (19.6 g, 0.26 mol) dissolved in dichloromethane (500 ml) was added propionaldehyde (20.9 ml, 0.28 mol) followed by pre-dried powdered 4A molecular sieves (40 g) and the mixture stirred at room temperature overnight. The mixture was filtered through a pad of celite, the pad washed with dichloromethane, and solvent evaporated to give a clear oil. This oil was dissolved in methanol (200 ml) and NaBH4 was added portionwise over 15 minutes. The mixture was stirred at room temperature overnight, then quenched by cautious addition of 2M HCl(aq) (200 ml), basified by addition of 2M NaOH (200 ml) and methanol removed by evaporation. Di-tert-butyldicarbonate (115 g, 0.52 mol) was added followed by 1,4-dioxan (200 ml) and the mixture stirred at room temperature overnight. 1,4-dioxan was removed by evaporation giving a clear oil. To this oil was added 4M HCl in 1,4-dioxan (200 ml) and the mixture stirred at room temperature overnight. The solvent was removed by evaporation to give a white solid (24 g).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1([F:16])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[O:17]1[CH:21]=[C:20]([C:22]2[S:26][CH:25]=[C:24]([C:27](O)=[O:28])[CH:23]=2)[N:19]=[CH:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.C(Cl)Cl>[F:8][C:9]1([F:16])[CH2:15][CH2:14][CH2:13][N:12]([C:27]([C:24]2[CH:23]=[C:22]([C:20]3[N:19]=[CH:18][O:17][CH:21]=3)[S:26][CH:25]=2)=[O:28])[CH2:11][CH2:10]1
Reactant: FC1(F)CCCNCC1
Reactant: O=C(O)c1csc(-c2cocn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1csc(-c2cocn2)c1)N1CCCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
4,4-Difluoro-azepane trifluoroacetate (Synthesis 47, 0.113 g, 0.45 mmol) was dissolved in THF (1 mL) and added to 5-oxazol-4-yl-thiophene-3-carboxylic acid (0.059 g, 0.30 mmol). DIPEA (0.154 mL, 0.90 mmol) was added followed by HATU (0.125 g, 0.33 mmol) and the reaction mixture was then stirred at room temperature overnight. The mixture was diluted with DCM then washed with aqueous sodium carbonate solution. The organics were dried over sodium sulfate, filtered and evaporated. The crude material was purified by HPLC, eluting with 5%-98% methanol in water (0.1% formic acid). The fractions containing the desired product were freeze-dried to give the title compound (0.029 g). LCMS m/z 313.15 [m+H]+ R.T.=8.31 min (Analytical Method 10).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([C@H:17]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][N:18]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=O.[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:37]=1[CH2:38][NH2:39]>CO.C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:37]=1[CH2:38][NH:39][CH2:15][C@H:17]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][N:18]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C=O
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CNC[C@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
Sodium triacetoxyborohydride (3.1 g, 15 mm) was added to a mixture of (3R)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.3 g, 5.0 mmol theory), 2,4-dimethoxybenzylamine (0.77 ml, 5.5 mmol), and dry 4 A sieves in 1,2-dichloroethane (25 ml) stirring at ambient temperature. After stirring at ambient temperature overnight the reaction solution was transferred to a separatory funnel with EtOAc and saturated NaHCO3. Extraction with EtOAc (2×), washing the combined organic layers with brine and drying over MgSO4 afforded 1.6 g of crude product. Flash chromatography (SiO2, 1 to 10% 2N N3 in MeOH/CH2Cl2) gave pure product (1.3 g, 63% yield over the previous 3 steps). MS (ESI) 413 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([NH:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[I:1])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: NNC(=O)c1ccccc1I
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NNC(=O)c1ccccc1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 76.8 %

Procedure:
2-Iodobenzohydrazide (1.38 g, 5.27 mmol) obtained in Step 1 of Example 114 was dissolved in dichloromethane (50 mL), and the mixture was stirred at 0° C. for 1.5 hours after adding pyridine (0.639 mL, 7.90 mmol) and acetyl chloride (0.412 mL, 5.79 mmol). The precipitated solid was filtered off, and the resulting solid was dried under reduced pressure to give N′-acetyl-2-iodobenzohydrazide (1.23 g, 77%).
Reaction SMILES: [CH2:1]([N:6]([CH3:12])[C:7](=O)[N:8]([CH3:10])[CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:6]([CH3:12])[C:7]([N:8]([CH3:10])[CH3:9])=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN(C)C(=O)N(C)C
Reactant: Nc1ccccc1N1CCOCC1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of 3-pentyl-1,1,3-trimethylurea (7.5 g) in benzene (80 ml) with 4-(2-aminophenyl)morpholine (6.46 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.06 ml) for 45 hours at 70° C. gave 1-pentyl-2-(2-morpholinophenyl)-1,3,3-trimethyl guanidine (b.p. 98° C. at 1.5 mm Hg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[N:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:12][CH:13]=2)[N:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(C2CCCCO2)c2cc(O)ccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Ethyl6-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-indazole-3-carboxylate (148 mg) which can be prepared according to the method described in Reference example 20, etc. was dissolved in dehydrated DMF (5.2 mL; manufactured by Kanto Chemical Co., Inc.), added with potassium carbonate (227 mg; manufactured by Sigma-Aldrich Co.) and benzyl bromide (73.6 μL; manufactured by Wako Pure Chemical Industries, Ltd.), followed by stirring for overnight at 60° C. After cooling to room temperature, the reaction solution was added to water, and then extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with ethyl acetate, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography “COLUMN-A”; n-hexane:ethyl acetate=95:5→74:26) to obtain the title compound (187 mg).