Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:15]([C:17]1[C:18]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:21][CH:22]=1)#[CH:16].C(N(CC)CC)C>C1COCC1>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:18]2[C:17]([C:15]3[O:14][N:13]=[C:2]([C:3]4[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=4)[CH:16]=3)=[CH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=2)=[CH:36][CH:35]=1
Reactant: C#Cc1cnc(-c2ccccn2)nc1OCc1ccc(OC)cc1
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3OCc3ccc(OC)cc3)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a mixture of compound 37-e (517 mg, 2.43 mmol), compound 37-j (700 mg, 2.21 mmol) in THF (5 mL) was added triethylamine (335 mg, 3.31 mmol) dropwise. The mixture was stirred overnight at room temperature. The residue obtained from removal of the solvent was purified by flash chromatography (PE:EA=1:2) to afford compound 37-k (420 mg, 38%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.786 (s, 1H), 8.753-8.731 (d, J=6.6 Hz, 1H), 8.172-8.144 (d, J=8.4 Hz, 2H), 8.004-7.976 (d, J=8.4 Hz, 2H), 7.838-7.806 (m, 1H), 7.645 (s, 1H), 7.615 (s, 1H), 7.495-7.470 (s, 1H), 6.875-6.846 (d, J=8.7 Hz, 2H), 6.697-6.668 (d, J=8.7 Hz, 2H), 5.786 (s, 2H), 3.960 (s, 3H), 3.723 (s, 3H), LC-MS (ESI): 495 [M+H]+.
Reaction SMILES: [C:1]1([S:7][CH:8]2[NH:11][C:10](=[O:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[C:1]1([S:7][CH:8]2[N:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:10](=[O:12])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(Sc2ccccc2)N1
Reactant: COC(=O)CBr
Product: COC(=O)CN1C(=O)CC1Sc1ccccc1
Yield: 53.5 %

Procedure:
Treatment of 4-phenylthioazetidin-2-one (Iwata-Reuyl et. al., J. Nat. Prod., 1993, 56(8), 1373) (8 g) with methyl bromoacetate (7.5 g) under the conditions described for Example 1b gave the title compound as a colourless oil (6 g, 53% yield). 1H NMR δ (CDCl3) 2.87 (1H, dd, H3a), 3.42 (1H, dd, H3b), 3.70 (3H, s, CH3), 3.75, 4.29 (each 1H, d, NCH2), 5.22, (1H, dd, H4), 7.26-7.46 (5H, m, Ph-H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[C:19]3[NH:18][C:17](=[O:20])[NH:16][C:15]=3[CH:14]=[C:13]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:12]=2)[C:5]([CH:8]2[CH2:10][CH2:9]2)=[N:6][CH:7]=1.N([O:30][C:31](C)(C)[CH3:32])=O>C(#N)C.CCOC(C)=O>[CH:8]1([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:31](=[O:30])[CH3:32])=[CH:3][C:4]=2[C:11]2[C:19]3[NH:18][C:17](=[O:20])[NH:16][C:15]=3[CH:14]=[C:13]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:12]=2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)ON=O
Reactant: Cc1noc(C)c1-c1cc(-c2cc(N)cnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)Nc1cnc(C2CC2)c(-c2cc(-c3c(C)noc3C)cc3[nH]c(=O)[nH]c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
4-(5-Amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (75 mg, 0.21 mmol) was dissolved in acetonitrile (2 mL), at room temperature added tert-butyl nitrite (32 mg, 0.31 mmol) and CuBr2 (56 mg, 0.25 mmol), stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with brine, evaporated organic solvent, purified with Prep HPLC. (0-100% CH3CN/H2O) to afford 16 mg of N-(6-cyclopropyl-5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)pyridin-3-yl)acetamide.
Reaction SMILES: [O:1]1[CH2:7][CH:2]1[CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:8][O:9][SiH:10]([O:13][CH3:14])[O:11][CH3:12]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1(C)C=CC=CC=1>[O:1]1[CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][Si:10]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:8]
Reactant: CO[SiH](OC)OC
Reactant: C=CCCC1CO1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CO[Si](CCCCC1CO1)(OC)OC
Temperature: 80 °C
Yield: 61 %

Procedure:
In a 100 mL round-bottom flask were placed 8.5 mL of 5,6-epoxy-1-hexene (0.1 moles), 1.5 equivalents of trimethoxysilane (17 mL), 30 mL of toluene dried by refluxing with sodium benzophenone ketyl, and 3 mg of tris(triphenylphosphine)rhodium (I) chloride. The resulting light purple solution was stirred and heated at 80° C. for 12 hours. The solvent was removed under reduced pressure, and the resulting oil subjected to fractional vacuum distillation. 5,6-Epoxyhexyltrimethoxysilane was obtained (13.5 g, 61% yield) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][Cl:26])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(CO)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(CCl)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 30 g of 4'-octyloxy-4-formylbiphenyl, 2.0 g of sodium borohydride and 300 ml of isopropanol was stirred on a water bath maintained at 70° C. for 3 hours. 20 ml of 6 N hydrochloric acid and 10 ml of water were added, and the resulting mixture was stirred for 2 hours. The reaction mixture was allowed to cool and filtered to collect solids. These solids were recrystallized from 300 ml of ethanol to obtain 30 g of 4'-octyloxy-4-hydroxymethyl-biphenyl. The total of 4'-octyloxy-4-hydroxymethyl-biphenyl, 100 ml of toluene and 40 g of thionyl chloride were uniformly mixed and allowed to stand overnight at room temperature. Then, the mixture was heated for 30 minutes on a water bath maintained at 70° C. After being allowed to cool, the mixture was poured into ice water and then extracted with 300 ml of toluene. The extract was washed with saturated saline water, with a saturated aqueous sodium hydrogen-carbonate and further with saturated saline water to make it neutral. Then, the extract was dried over anhydrous magnesium sulfate, concentrated and then recrystallized from 300 ml of ethanol to obtain 26 g of 4'-octyloxy-4-chloromethyl-biphenyl having a melting point of 97.3 to 98.0° C. Analysis of the compound by HPLC showed that the purity was 99.6%. (ii) Preparation of Objective Compound
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH3:45])[N:43]=[CH:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH3:45])[N:43]=[CH:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ncnn4C)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ncnn4C)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(1-methyl-1H-1,2,4-triazol-5-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (565 mg) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.32 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the reaction solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:19→1:9) and further recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(1-methyl-1H-1,2,4-triazol-5-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 124) (515 mg) as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+].B(F)(F)F.CC[O:22]CC.[OH-].[Na+].OO.Cl>COCCOCCOC.O>[CH3:1][N:2]1[CH2:3][CH2:4][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:6]([OH:22])[CH2:7]1
Reactant: CN1CC=C(c2ccccc2)CC1
Reactant: CCOCC
Agent: Cl
Agent: FB(F)F
Agent: OO
Solvent: COCCOCCOC
Solvent: O
Product: CN1CC[C@@H](c2ccccc2)[C@H](O)C1
Temperature: 50 °C

Procedure:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (21.2 g; 122 mmoles, described in Example 3) and sodium borohydride (7.40 g, 195 mmoles) are dissolved in dried redistilled diglyme (100 ml). The solution is cooled, with stirring, under nitrogen and maintained at 0° C. during dropwise addition of a solution of boron trifluoride etherate (32 ml; 250 mmoles) in diglyme (15 ml). When the addition is complete, the mixture is stirred for 1.5 hours at room temperature. Water (10 ml) is added followed by 6N sodium hydroxide solution (30 ml). The temperature is raised to 50° C. followed by dropwise addition of 30% hydrogen peroxide solution (30 ml, 260 mmoles) over a period of 1 hour. Conc. hydrochloric acid (30 ml) is added, and the solvents are evaporated. The residue is redissolved in water and the evaporation is repeated. The residue is dissolved in water, basified with potassium carbonate solution, and the free base is extracted with ether. The extract is dried (Na2SO4), evaporated, and the residual yellow oil is distilled under reduced pressure. The material distilling at 115°-128° C./0.1 mm is crystallized from hexane to give the title compound, mp 78°-79.5° C. (R. E. Lyle et al, supra, reported mp 82°-84° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C1(C)C(C)=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O>[C:16]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:18])[CH3:17]
Reactant: Nc1ccccn1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(=O)Nc1ccccn1
Temperature: 35 °C

Procedure:
To 70.5 g. of 2-aminopyridine, partially dissolved in 180 g. of xylene, was slowly added, with stirring, 79.6 g. acetic anhydride. The addition was carried out over a 20-minute period. The reaction vessel was water-cooled so as to maintain the reaction mixture at 30-40° C during the addition. The reaction solution was then heated for 1 hour at a temperature of 74°-78° C to give 2-acetamidopyridine, which was used without isolation.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([C:9]#[N:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[NH:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C>[CH2:25]([C:8]1[C:7]2[C:6]([N:5]3[C:4]4[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=4[C:2](=[O:1])[NH:10][C:9]=13)=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:26]
Reactant: CCI
Reactant: N#CC1C(=O)c2ccccc2Nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c2ccccc2n2c1[nH]c(=O)c1ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 11-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-10-carbonitrile (500 mg, 2.13 mmol), potassium carbonate (359 mg, 2.6 mmole) and ethyl iodide (0.202 ml, 2.5 mmole) in 4 ml DMF is stirred at r.t. for 18 h.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:31][CH3:32])[C:12]=1[C:13](=[O:30])[NH:14][C:15]1[CH:20]=[CH:19][N:18]2[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=[C:17]2[CH:16]=1)=[O:7])C>C(O)C>[CH2:31]([N:11]1[C:12]([C:13](=[O:30])[NH:14][C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:23]=[C:17]3[CH:16]=2)=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]1)[CH3:32]
Reactant: CCOC(=O)c1cnn(CC)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCn1ncc(C(=O)O)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
KOH (70 mg) was added to a solution of 1-ethyl-5-(2-phenyl-imidazo[1,2-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 12, 215 mg, 0.53 mmol) in ethanol (6 ml), and the mixture was heated to reflux until HPLC control indicated the consumption of the starting material (2 h). Upon cooling, HCl (conc.) was added dropwise, until the pH reached ˜2 (few drops). The suspension was stirred at r.t. (30 min.) and then filtered. The precipitate was washed with little ethanol and dried under vacuum. The thus obtained title compound (160 mg, 80%) was used in the next step without further purification. MS (m/e)=376.4 [M+H+].
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([NH:9]C(=O)OC(C)(C)C)([CH3:8])[CH2:4][CH2:3]1.C(O)C.[ClH:20]>C(OCC)(=O)C>[ClH:20].[ClH:20].[CH3:8][C:5]1([NH2:9])[CH2:6][CH2:7][CH:2]([NH2:1])[CH2:3][CH2:4]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(N)CCC(N)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of tert-butyl (4-amino-1-methylcyclohexyl)carbamate (Preparation Example 399) (3.73 g) and ethanol (30 mL), 4M hydrogen chloride in ethyl acetate (30 mL) was added under ice cooling and stirred at room temperature for 20 hours. The precipitated solid was collected by filtration and washed with ethyl acetate to give 1-methylcyclohexane-1,4-diamine dihydrochloride (2.10 g) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:5]=1[O:17][CH3:18].CON(C)[C:23](=[O:39])[CH:24]([O:37][CH3:38])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[F:19][CH:2]([F:1])[O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[O:13][C:14]([C:23](=[O:39])[CH:24]([O:37][CH3:38])[C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[CH:29][CH:30]=3)=[CH:15][CH:16]=2)=[CH:6][C:5]=1[O:17][CH3:18]
Reactant: COc1cc(-c2ccco2)cc(OC)c1OC(F)F
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1OC(F)F
Yield: 6 %

Procedure:
2-(4-(Difluoromethoxy)-3,5-dimethoxyphenyl)furan was coupled with N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide following the procedure used for the synthesis of Example 12. Purification by chromatography (EtOAc-hexanes) provided 1-(5-(4-(difluoromethoxy)-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)-ethanone as a brown oil (0.021 g, 6% yield). MS: m/z 504.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:15][CH2:14][CH2:13]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]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:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:65][N:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:15][CH2:14][CH2:13]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][N:66]5[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 7) (15 mg, 0.033 mmol, 1 eq), DIPEA (12 μl, 0.066 mmol, 2 eq) and TBTU (12 mg, 0.036 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 5 min before the addition of 1-amino-4-methylpiperazine (5 mg) and DIPEA (13 μL). The RM was then stirred at rt for 3 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][N:8]([CH3:37])[C:9]1[CH:36]=[CH:35][C:12]([CH:13]([C:23]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.OC1C=CC([N+]([O-])=O)=CC=1N=NC1C2C(=CC(S(O)(=O)=O)=CC=2)C=C(S(O)(=O)=O)C=1O.O=O>>[CH3:22][N:20]([CH3:21])[C:17]1[CH:16]=[CH:15][C:14]([C:13]2([C:12]3[CH:11]=[CH:10][C:9]([N:8]([CH3:7])[CH3:37])=[CH:36][CH:35]=3)[C:23]3[C:24](=[CH:28][C:29]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=3)[C:25](=[O:27])[O:26]2)=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: O=O
Agent: O=[N+]([O-])c1ccc(O)c(N=Nc2c(O)c(S(=O)(=O)O)cc3cc(S(=O)(=O)O)ccc23)c1
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Temperature: 90 °C

Procedure:
In accordance with the process of Example 1, the aqueous solution containing sodium carbonate and 2-[4,4'-bis-(dimethylamino)-benzhydryl]-5-dimethylaminobenzoic acid and cobalt complex of 1-[(2-hydroxy-5-nitrophenyl)azo]-2-hydroxynaphthalene-3,6-disulfonic acid, was heated at 90° C. and 1.6 wt. parts of oxygen was fed into it under the atmospheric pressure during 5 hours, and the precipitate was separated by a filtration and washed with a dilute aqueous solution of sodium hydroxide and with water to obtain 40.9 wt. parts of 3,3-bis-(4-dimethylaminophenyl)-6-dimethylaminophthalide having a melting point of 181° to 183° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[N:18][N:17]=2)/[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].O>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[N:18][N:17]=2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCc1nnnn1C)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nnnc1CO/N=C(\C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.7 %

Procedure:
24.9 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[(1-methyl-1H-tetrazol-5-yl)methoxy]imino]-acetate are dissolved in 100 ml of methanol and the solution is treated with 250 ml of 1N aqueous sodium hydroxide solution. The mixture is stirred at room temperature for 12 hours and treated with 150 ml of water. The methanol is subsequently removed under reduced pressure. The aqueous solution is washed with ethyl acetate and treated with 250 ml of 1N aqueous hydrochloric acid. The acid crystallizes upon concentration. The acid is filtered off and, for the removal of water (about 16%), stirred for 6 hours in 350 ml of acetonitrile, filtered and dried. There are obtained 14.2 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-[(1-methyl-1H-tetrazol-5-yl)methoxy]imino]-acetic acid of melting point 185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[CH:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.O=P(Cl)(Cl)[Cl:24]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:24])[CH:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2cc(F)ccc2n1
Product: Fc1ccc2nc(Cl)cc(Nc3ccc(Cl)c(Cl)c3)c2c1
Yield: 29 %

Procedure:
Prepared using general procedure 3; 6-Fluoro-2-hydroxy-4-(3,4-dichlorophenyl)aminoquinoline (2.136 g, 6.6 mmol) and 30 mL of POCl3 were heated to 120° C. for 4 h. Isolation afforded 0.654 g of material (1.914 mmol, 29%). 1H NMR (300 MHz, DMSO): 9.55(s, 1H), 8.27(dd, 1H, J=10.50, 2.02 Hz), 7.92(dd, 1H, J=8.88, 5.65 Hz), 7.70(m, 3H), 7.45(dd, 1H, J=8.48, 2.02 Hz), 6.90(s, 1H).
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.Cl.[CH3:18][N:19](C)C=O>>[C:18]([C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1)#[N:19]
Reactant: O=C1c2cc(I)ccc2CCn2cccc21
Reactant: CN(C)C=O
Agent: Cl
Product: N#Cc1ccc2c(c1)C(=O)c1cccn1CC2
Reaction time: 0.5 h

Procedure:
A stirred mixture of 1 gm. of 9-iodo-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one, 1 gm. of cuprous cyanide and 5 ml. of dimethylformamide is heated to reflux for 5 hr. The mixture is then poured into a solution of 4 gm. of ferric chloride hydrate in 25 ml. of 2N hydrochloric acid. After stirring the resulting mixture at 60° for 30 min., it is extracted with 3 × 50 ml. of ethyl acetate, the organic extracts washed with 3 × 100 ml. of water and dried over Na2SO4. Evaporation of the dried solution yields 9-cyano-6,11-dihydro-5H-pyrrolo-[2,1-b][3]benzazepin-11-one, m.p. 127°-128° C.
Reaction SMILES: [CH3:1][CH:2]1[C:7]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:6][CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][CH:2]1[C:7]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC1CN(Cc2ccccc2)CCC12CNc1ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1CNCCC12CNc1ccccc12
Yield: 37.1 %

Procedure:
3′-Methyl-1′-(phenylmethyl)-1,2-dihydrospiro[indole-3,4′-piperidine] (10 mmol, 2.9 g), acetic acid (30 mL) and Pd/C (5%, 600 mg) were added to a Parr bottle. The mixture was subjected to hydrogen gas at 30 psi for 20 h, after which time the solution was filtered over celite, concentrated and purified by reverse phase chromatography, 10-50% acetonitrile/water (0.1% TFA) over 14 min to give 3′-methyl-1,2-dihydrospiro[indole-3,4′-piperidine] (750 mg) as the TFA salt as an off white solid. MS (ES) m/e 203 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 0.62 (d, J=7.03 Hz, 3 H) 1.83 (d, J=14.31 Hz, 1 H) 2.00 (td, J=13.87, 4.14 Hz, 1 H) 2.13 (dd, J=7.15, 4.39 Hz, 1 H) 2.77 (d, J=11.80 Hz, 1 H) 2.94 (d, J=11.54 Hz, 1 H) 3.17 (d, J=1.51 Hz, 1 H) 3.31 (d, J=13.30 Hz, 1 H) 3.40 (d, J=10.79 Hz, 1 H) 3.61 (d, J=11.04 Hz, 1 H) 6.79 (d, J=7.78 Hz, 1 H) 6.88 (t, J=7.28 Hz, 1 H) 7.03 (d, J=7.28 Hz, 1 H) 7.12 (t, J=7.15 Hz, 1H) 8.74 (br. s., 1 H) 8.87 (br. s., 1H).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[C:35]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.C(OCC)(=O)C>CO.O1CCOCC1.[C].[Pd]>[OH:8][C:9]1[CH:36]=[C:35]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2cccnc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2cccnc2)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-4-(pyridin-3-yl)benzamido)-4-phenylbenzoate (0.13 g) in methanol (2 mL), dioxane (4 mL), and ethyl acetate (4 mL), 10% palladium-carbon (63 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-40% hexane/ethyl acetate] to obtain 0.077 g of tert-butyl 2-(2-hydroxy-4-(pyridin-3-yl)benzamido)-4-phenylbenzoate as a white solid.