Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[F:10][C:11]1[N:16]=[C:15]([CH:17]=O)[CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([F:10])[N:16]=1)[CH3:2]
Reactant: O=Cc1cccc(F)n1
Reactant: CCOC(CN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(CNCc1cccc(F)n1)OCC
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
To a mixed solution of a commercially available product of 2,2-diethoxyethan-1-amine (926 μL, 6.39 mmol), THF (10.0 mL) and acetic acid (1.00 mL) was added a commercially available product of 6-fluoropyridine-2-carbaldehyde (800 mg, 6.39 mmol) at room temperature. The resultant mixture was stirred at room temperature for 25 minutes. Subsequently, sodium triacetoxyborohydride (2.71 g, 12.8 mmol) was added to the reaction mixture at room temperature and then stirred for 1 hour and 10 minutes. To the reaction mixture was added sodium hydrogen carbonate and water to terminate the reaction. The resultant solution was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1), and was then further purified by silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (1.14 g, yield: 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1.C(N(CC)C(C)C)(C)C.ClCCC[NH:28][C:29]([C:31]1[C:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:33][O:34][C:35]=1[CH3:36])=[O:30].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:32]3([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]([C:29]([NH2:28])=[O:30])=[C:35]([CH3:36])[O:34][NH:33]3)[CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NCCCCl
Reactant: Cc1cc(F)ccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1=C(C(N)=O)C(c2ccccc2)(N2CCN(c3ccc(F)cc3C)CC2)NO1
Temperature: 120 °C
Yield: 48.1 %

Procedure:
A stirred mixture of 0.380 g of Compound 31A, 0.50 mL of N,N-diisopropylethylamine, 0.545 g of Compound 2B and 3 mL of N,N-dimethylformamide was heated at 120° C. for 5 h. The solution was diluted with water (60 mL) and extracted with dichloromethane (3×30 mL); the organic layer was washed with water (3×20 mL), dried (anhydrous sodium sulphate) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (chloroform-2N methanolic ammonia 100:1) affording 0.373 g (43.7%) of the title compound as an ivory solid. M.p. 139-141° C.
Reaction SMILES: CI.[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:15]3[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=3[NH:9][C:8]=2[N:17]=1.[C:18]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:15]3[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=3[N:9]([CH3:18])[C:8]=2[N:17]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCc2[nH]c3nc(Br)ccc3c21
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(Br)nc31)C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
Methyl iodide (0.45 mL, 7.1 mmol) was added to a solution of 2-bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one (1.6 g, 5.9 mmol) and Cs2CO3 (2.3 g, mmol) in DMF (21 mL) under N2 and stirred for 3 h at ambient temperature. The mixture was quenched with H2O (30 mL), upon which a solid precipitated out of solution. The solids were collected by filtration and washed with H2O (100 mL) to provide the title compound (1.47 g, 88%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=8.1 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 3.74 (s, 3H), 3.03 (t, J=6.0 Hz, 2H), 2.50-2.44 (m, 2H, overlap with H2O peak), 2.20-2.12 (m, 2H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5]CCC1.[Li+].CC([N-]C(C)C)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:24]1[CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:16]([CH:28]([CH2:24][CH2:25][CH2:26][OH:27])[C:1]([O:6][CH3:5])=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1CCOC1
Reactant: O=C1CCCCO1
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)C(CCCO)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 40 %

Procedure:
δ-Valerolactone (7.14 g, 71.35 mmol) was slowly added to a flask containing freshly made LDA (80 mmol) in 200 ml of dry THF at -78° C. under N2. After stirring the solution for 40 min at -78° C., benzyl bromide (12.20 g, 71 mmol) was added. The bath was removed and the reaction was stirred at room temperature for 40 min. At the end, the crude mixture was poured to a slurry of AcOEt-Hexane and 0.5 N H2SO4. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was then dissolved in 60 ml of MeOH and 10 ml of concentrated H2SO4. After stirring the solution at room temperature overnight, the acid was neutralized with aqueous NaHCO3. The crude product was extracted with AcOEt-Hexane and purified by column chromatography (silica gel, AcOEt-Hexane, 1:3) which gave 6.2 g (40% yield) of methyl 2-benzyl-5-hydroxy-pentanoate; 1H NMR (CDCl3, 300 MHz) δ: 7.30-7.10 (m,5H), 3.58 (s,3H,OCH3, 3.56 (t,J=6Hz,2H), 2.95 (dd,J=7,12Hz,1H), 2.75 (dd,J=6,12Hz,1H), 2.69 (m,1H), 2.15 (s,1H,-OH), and 1.70-1.50 (m,4H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6]1.C[O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1.Cl>ClC(Cl)C.O>[OH:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:19][C:20]=1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]([OH:11])=[O:12]
Reactant: O=C1CCCC(=O)O1
Reactant: COc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: O=C(O)CCCC(=O)c1ccc(-c2ccccc2)cc1O
Reaction time: 0.25 h

Procedure:
24 g aluminium chloride are added at 0° C. to a solution of 10 g glutaric acid anhydride in 300 ml dichloroethane. After stirring for 15 mins. at 0° to 5° C., 15 g 3-methoxy-biphenyl in 50 ml dichloroethane are added rapidly at ca. 0° C. The reaction mixture is stirred for 24 hours at room temperature, poured onto a mixture of ice and conc. HCl and diluted with water. The organic phase is separated off and the aqueous phase extracted 3×with methylene chloride. The combined organic phases are washed thoroughly with water, dried over MgSO4 and clarified with activated charcoal. The solvent is evaporated off and the obtained oil crystallised from ether to yield the title compound: m.p.=168°-170° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[CH2:13][CH2:12][CH:11]([C:14]([F:17])([F:16])[F:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:35])=[O:23])=[CH:25][CH:26]=3)[CH2:13][CH2:12][CH:11]([C:14]([F:15])([F:16])[F:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc(C2(c3ccc(O)cc3)CCC(C(F)(F)F)CC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C2(c3ccc(O)cc3)CCC(C(F)(F)F)CC2)cc1
Temperature: 50 °C

Procedure:
To a solution of the title compound of Example 4, Step A (43 mg, 0.09 mmol), β-alanine ethyl ester hydrochloride (28 mg, 0.18 mmol), HOBt (28 mg, 0.18 mmol) and EDC (35 mg, 0.18 mmol) in 1 mL of DMF was added DIEA (0.047 mL, 0.27 mmol). The reaction was heated at 50° C. for 1.5 h, then partitioned between EtOAc/brine. The organic layer was collected and the aqueous layer was washed twice with EtOAc. The combined organic phase was concentrated under reduced pressure to provide the title compound. LC-MS (ESI): m/z=464.3 [M+1]+.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([N:4]([CH2:12][CH2:13][C:14]([C:27]4[NH:31][N:30]=NN=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:5]3)[CH2:2]1)[CH2:9]2.[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>O>[CH:8]12[CH2:7][CH:6]3[CH2:11][CH:1]([CH2:2][CH:3]([N:4]([CH2:12][CH2:13][C:14]([C:27]4[O:34][C:32]([CH3:33])=[N:30][N:31]=4)([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(C(CCN2CC3CC4CC(C3)CC2C4)(c2ccccc2)c2nnn[nH]2)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1nnc(C(CCN2CC3CC4CC(C3)CC2C4)(c2ccccc2)c2ccccc2)o1

Procedure:
A solution of 48 parts of 5-{3-[4-azatricyclo(4.3.1.13,8)undecan-4-yl]-1,1-diphenylpropyl}-1H-tetrazole and 140 parts of acetic anhydride in 400 parts of pyridine is heated at the boiling point under reflux for 3 hours, then cooled and thereupon diluted with 100 parts of water. The resultant mixture is stirred for 10 minutes, whereupon solvent is removed by vacuum distillation and the residue partitioned between a saturated aqueous solution of sodium bicarbonate and diethyl ether. The ethereal phase is separated and consecutively washed with a saturated aqueous solution of sodium bicarbonate and water, then extracted with 2% hydrochloric acid. The acid extract is made alkaline, and the resultant mixture is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate, stripped of solvent by vacuum distillation, affords 2-{3-[4-azatricyclo(4.3.1.13,8)undecan-4-yl]-1,1-diphenylpropyl}-5-methyl-1,3,4-oxadiazole melting at approximately 120°-121° as the residue. It has the formula ##STR11##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24]2)[CH:3]=1.[NH3:32]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:32])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:24]2)[CH:3]=1
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCN(S(C)(=O)=O)C3)c12
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCN(S(C)(=O)=O)C3)c12

Procedure:
Prepared analogously to example 1.4 from 4-[4-fluoro-2-((R)-1-methanesulfonyl-pyrrolidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and Ammonia in Methanol.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]([CH3:29])[N:19]=[N:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)=[CH:11][N:10]=1)=[O:8])C>O.C1COCC1.CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[N:20]=[N:19][N:18]([CH3:29])[C:17]=2[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:7]([OH:8])=[O:6])=[N:10][CH:11]=2)=[N:23][CH:24]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)nnn2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of lithium hydroxide monohydrate (59 mg, 1.41 mmol) in water (1.8 mL) was added dropwise to a suspension of 5-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (252 mg, 0.71 mmol) in THF (1.8 mL) and MeOH (0.4 mL). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (180 mg, 78%) as a white solid after trituration with ethyl acetate. MS: m/e=330.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]2[CH:11]=[C:12]([C:14]([OH:16])=O)[NH:13][C:8]2=[CH:7][CH:6]=1)=[O:4].Cl.Cl.[N:19]1([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]2[CH:11]=[C:12]([C:14](=[O:16])[NH:25][CH:22]3[CH2:21][CH2:20][N:19]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)[CH2:24][CH2:23]3)[NH:13][C:8]2=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(C(=O)O)cc2n1
Reactant: NC1CCN(c2ccncc2)CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(c4ccncc4)CC3)cc2n1
Reaction time: 2 h

Procedure:
To a solution of 450 mg 1H-pyrrolo[3,2-b]pyridine-2,5-dicarboxylic acid 5-methyl ester in 9 mL dichloromethane and 1.13 mL triethylamine, 614 mg 3,4,5,6-tetrahydro-2H-[1,4′]bipyridyl-4-ylamine dihydrochloride and 520 mg bis(2-oxo-3-oxazolidinyl)phophinic chloride were added at room temperature and the mixture was stirred for 2 hours. After treatment of the reaction mixture with 5 mL saturated aqueous solution of potassium carbonate the precipitate was collected by filtration and coevaporated twice with toluene. The residue was directly subjected to the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH:9]=2)[CH:4]=[C:3]1[C:18]([O:20]CC)=[O:19].[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH:9]=2)[CH:4]=[C:3]1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1cc2ccc(-c3ccc(C)cc3)cc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2ccc3cc(C(=O)O)n(C)c3c2)cc1
Reaction time: 24 h
Yield: 94.8 %

Procedure:
Into a mixed solution of ethyl 1-methyl-6-(4-methylphenyl)-1H-indole-2-carboxylate (0.7 g) in ethanol/THF (20/10 ml) was added at room temperature a 2 N aqueous solution of sodium hydroxide (1.5 ml), and the resulting mixture was stirred for 24 hours. After addition of 1 N hydrochloric acid (5 ml), the reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with hexane to obtain 1-methyl-6-(4-methylphenyl)-1H-indole-2-carboxylic acid (600 mg) as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([N+:17]([O-])=O)[CH:8]=1)(=[O:4])=[O:3].Cl.[H][H]>CO.[Pd]>[NH2:17][C:9]1[CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(CNS(C)(=O)=O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1N
Yield: 87.5 %

Procedure:
13.25 g (46 mmol) of methyl 4-methanesulfonylaminomethyl-2-nitrobenzoate are dissolved in 200 ml of methanol. After addition of 1.4 ml (46 mmol) of concentrated hydrochloric acid and 1 g of Pd catalyst (10% on active charcoal), the mixture is hydrogenated with hydrogen under atmospheric pressure until the hydrogen uptake is complete. The mixture is removed from the catalyst by filtration and the filtrate is concentrated completely. Crystallization of the residue from water yields 10.4 g (88%) of methyl 2-amino-4-methanesulfonylaminomethylbenzoate of melting point 121–122° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:61])[NH2:60]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:60][N:59]([CH3:61])[CH3:58])=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)N
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N,N-dimethyl-hydrazine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.43 (m, 2 H) 1.53-1.92 (m, 8 H) 2.92 (s, 6 H) 3.32 (s, 3 H) 3.96 (s, 3 H) 4.14 (t, J=13.0 Hz, 2 H) 4.42-4.52 (m, 1 H) 7.44-7.52 (m, 2 H) 8.20-8.27 (m, 2 H) 8.49 (br. s., 1 H). [M+H] calc'd for C24H31F2N7O3 504; found 504.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3](OC)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:19](=[O:21])=[O:20].[NH4+].[Cl-].Cl.[CH2:25]([O:27]CC)C>>[CH3:25][O:27][C:15]1[CH:14]=[C:13]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:18]=[CH:17][C:16]=1[C:19]([OH:21])=[O:20]
Reactant: CCCCCCCC(OC)C(Br)c1ccccc1
Reactant: O=C=O
Reactant: CCOCC
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CCCCCCCCCc1ccc(C(=O)O)c(OC)c1
Reaction time: 1 h
Yield: 20 %

Procedure:
To dry diethyl ether (10 mL) containing Mg turnings (0.24 g; 10 mmol) under N2 was added 1-bromo-2-methoxy-nonyl benzene (3.1 g; 10 mmol). 1,2-Dioiodoethane was added to initiate the reaction. Solid dry Ice (excess) was added after stirring for 1 hour and after additional stirring for 1 hour was added sat. NH4Cl (aq.; 20 mL) and then 4 M HCl (aq.; 2 mL). The organic phase was isolated, dried (MgSO4), filtered and purified by column chromatography (SiO2; EtOAc/PE80-100° C.=1:5) to yield 600 mg (20%) pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:32])[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=1.NC1N=NC=CC=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:31][C:6]1[CH:5]=[N+:4]([O-:32])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[O:10][C:11](=[O:20])[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][OH:19])=[CH:16][CH:17]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)cc2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Nc1cccnn1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CO)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-((4-formylbenzoyl)oxy)ethyl)pyridine 1-oxide (412 mg, 0.87 mmol) in DCM (10 mL) was added 3-aminopyridazine (165 mg, 1.73 mmol) followed by glacial acetic acid (150 μL, 2.61 mmol). The reaction was stirred at room temperature for 30 minutes then NaB(OAc)3H (551 mg, 2.61 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted with DCM (10 mL) and quenched with water. The organic phase was washed with saturated aqueous NaHCO3 solution, filtered through hydrophobic fit and evaporated to dryness. The residue was triturated with DCM (2 mL) and CH3CN (5 mL). The solid was collected by filtration, washed with DCM and dried to provide the title compound (300 mg, 72%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[C:29]([F:53])=[CH:30][C:31]([Cl:52])=[C:32]([CH:51]=1)[O:33][C:34]1[CH:48]=[CH:47][C:37]2[N:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[S:40][C:36]=2[C:35]=1[C:49]#[N:50]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[CH:51]=[C:32]([O:33][C:34]2[CH:48]=[CH:47][C:37]3[N:38]=[C:39]([NH:41][C:42]([CH:44]4[CH2:46][CH2:45]4)=[O:43])[S:40][C:36]=3[C:35]=2[C:49]#[N:50])[C:31]([Cl:52])=[CH:30][C:29]=1[F:53])=[O:6]
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c(Oc2cc(NC(=O)c3cccc(C4(C#N)CC4)c3Cl)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (75 mg, 0.339 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (36 μL, 0.427 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.248 mmol) was added to the solution, and the mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (25 mL) and saturated brine (25 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound (85 mg, 57%) as a white powder.
Reaction SMILES: C(O[C@H:5]1[CH2:9][C@@H:8]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:6]1)(=O)C.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C.O1CCCC1.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>[CH3:16][C:14]([CH3:17])([O:13][C:11]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:8]1[CH2:9][CH2:5][CH:6]=[CH:7]1)=[O:12])[CH3:15]
Reactant: CC(=O)O[C@@H]1C=C[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C=CCC1
Yield: 79.2 %

Procedure:
To a solution of (1S-cis)-4-(di-tert-butoxycarbonylamino)cyclopent-2-enyl acetate (prepared as described by D. Zhang et.al. Tett. Lett. 1996, 3799–3802) (8.98 g), tetrakis(triphenylphosphine)palladium(0) (0.463 g) in isopropanol (135 ml) and tetrahydrofuran (135 ml) was added sodium borohydride (4.97 g) portionwise at 0° C. The mixture was stirred at 0° C. for 3 hours before the careful dropwise addition of glacial acetic acid (20 ml). The solution was concentrated in vacuo and the residue purified by chromatography (SiO2, diethylether 1:9 isohexane as eluent) to afford the sub-title compound (5.90 g).