Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[Cl-].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](O)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([C:6]1[CH:5]=[C:4]([CH3:8])[C:3]([O:9][CH3:10])=[C:2]([CH3:1])[CH:7]=1)=[O:18]
Reactant: COc1c(C)cccc1C
Reactant: O=C(O)c1cccs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1c(C)cc(C(=O)c2cccs2)cc1C
Temperature: 10 °C

Procedure:
Into a solution of 60 g of 2,6-dimethyl anisole and 62.7 g of the chloride of 2-thiophene carboxylic acid in 250 ml of anhydrous methylene chloride there was introduced over 30 minutes 58.5 g of aluminium chloride while maintaining the temperature at about 10° C. The reaction medium was brought to the reflux temperature of the solvent for 21/2 hours, then poured onto one kg of crushed ice mixed with 150 ml of concentrated hydrochloric acid. The organic phase was decanted, the aqueous phase extracted with methylene chloride, and the organic phase washed with an aqueous solution of sodium hydroxide, then with water. After drying and evaporation of the solvent, 110 g of an oil was isolated which was distilled under reduced pressure to give 89 g of ketone. Boiling point (14 mm Hg)=225° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:66]=[CH:65][C:53]2[NH:54][C:55]([CH:57]([NH2:64])[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.CO>[Cl:49][C:50]1[CH:66]=[CH:65][C:53]2[NH:54][C:55]([CH:57]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[NH:64][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: NC(c1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(=O)NC(c2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.—C-(5-chloro-1H-benzimidazol-2-yl)-C-phenylmethylamine in tetrahydrofuran. Yield: quantitative; Rf value: 0.39 (silica gel; dichloromethane/methanol=9:1); C27H25ClN4O2 (472.97); mass spectrum: (M+H)+=473/475 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].[CH:15](S([O-])(=O)=O)(O)[CH:16](S([O-])(=O)=O)O.O.[Na+].[Na+]>Cl>[CH2:9]([N:6]1[C:7]2[C:2](=[N:1][CH:15]=[CH:16][N:8]=2)[C:3](=[O:14])[NH:4][C:5]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Reactant: O=S(=O)([O-])C(O)C(O)S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Cn1c(=O)[nH]c(=O)c2nccnc21
Yield: 19.3 %

Procedure:
After dissolving 19.8 g (100 mmol) 5,6-diamino-1-isobutyluracil in 1 liter of 1N HCl at 70° C., 186.3 g of glyoxal sodium bisulfite addition compound hydrate was added and the mixture refluxed for 1 hour. After extracting the mixture several times with ethyl acetate, the collected ethyl acetate fractions were washed with water, dried over MgSO4 and evaporated. The crude product was purified by preparative column chromatography using chloroform/methanol 9:1 as eluant yielding 4.25 g (18%) of 1-isobutyl-1H-pteridine-2,4-dione (m.p. 200–201° C., Lit. 195–197° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:10])[CH3:9])=[O:4].[CH2:18]([O:22][CH2:23][CH2:24][CH:25]([CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH3:26])[CH2:19][CH2:20][CH3:21].Cl(O)(=O)(=O)=O>C(Cl)Cl>[CH2:18]([O:22][CH2:23][CH2:24][CH:25]([CH3:26])[CH2:27][CH2:28][CH2:29][C:30]([C:15]1[CH:16]=[C:11]([C:8]([CH3:10])([CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH3:9])[CH:12]=[CH:13][C:14]=1[OH:17])([CH3:32])[CH3:31])[CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)cc1
Reactant: CCCCOCCC(C)CCC=C(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CCCCOCCC(C)CCCC(C)(C)c1cc(C(C)(C)CCCC(=O)OC)ccc1O

Procedure:
10.3 Parts of 4-(5-methoxycarbonyl-2-methyl-pent-2-yl)-phenol, 4.2 parts of citronellyl n-butyl ether, and 0.5 parts of 70% perchloric acid in 25 parts of methylene chloride were stored at room temperature for 4 days. The work-up followed Example 61 and gave on distillation 2-(8-n-butyloxy-2,6-dimethyl-oct-2-yl)-4-(5-methoxycarbonyl-2-methyl-pent-2-yl)-phenol with b0.8, 228°-36° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13]S([O-])(=O)=O)[O:10][N:9]=2)=[CH:4][C:3]=1[F:18].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[N:19]([CH2:13][CH:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:18])[CH:4]=2)[CH2:12]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)([O-])CC1CC(c2ccc(Br)c(F)c2)=NO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CC(c2ccc(Br)c(F)c2)=NO1
Temperature: 80 °C
Reaction time: 5 h
Yield: 96.1 %

Procedure:
[3-(4-Bromo-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl]methane sulfonate (9.85 g, 28 mmol) was dissolved in dry DMF (100 ml). Sodium azide (2.73 g, 42 mmol) was added and the reaction mixture stirred at 80° C. for 5 hours. The reaction mixture was concentrated in vacuo then azeotroped with xylene (20 ml). The crude product was dissolved in ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was separated, dried over magnesium sulfate, filtered then concentrated in vacuo to yield 8.046 g of the desired compound.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13](I)[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[C:21]1([CH3:33])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([C:22]4[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[CH3:33])[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)n1ccc2c(C)nc3c(I)cccc3c21
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CCC(CC)n1ccc2c(C)nc3c(-c4c(C)cc(C)cc4C)cccc3c21
Temperature: 80 °C
Reaction time: 8 h
Yield: 6.7 %

Procedure:
1-(1-Ethylpropyl)-6-iodo-4-methyl-1H-pyrrolo[3,2-c]quinoline (170 mg, 0.45 mmol), mesitylboric acid (82 mg, 0.50 mmol), barium hydroxide octahydrate (213 mg, 0.68 mmol) and tetrakistriphenylphosphinepalladium (26 mg, 0.02 mmol) were suspended into a mixture of 1,2-dimethoxyethane (6 mL) and water (1 mL), followed by stirring at 80° C. overnight in nitrogen atmosphere. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then evaporated. The residue was purified by silica gel column chromatography (5% ethyl acetate/hexane), to give the title compound (11 mg, 0.03 mmol) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:18][C:5]2[C:6]([OH:17])=[C:7]([C:13]([O:15]C)=O)[N:8]([CH3:12])[S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[S:18][C:5]2[C:6]([OH:17])=[C:7]([C:13](=[O:15])[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:8]([CH3:12])[S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: COC(=O)C1=C(O)c2sc(Br)cc2S(=O)(=O)N1C
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2sc(Br)cc2S1(=O)=O
Temperature: 25 °C

Procedure:
3.54 g. of 6-bromo-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno[2,3-e]-1,2-thiazine-1,1-dioxide are boiled under reflux for 6 hours with 1.42 g. of 2-aminopyridine in 150 ml. of absolute xylene. The reaction mixture is allowed to cool to room temperature. The precipitated crude product is recrystallized from dioxane and 6-bromo-4-hydroxy-2-methyl-3-(2-pyridylcarbamyol)-2H-thieno[2,3-e]-1,2-thiazine-1,1-dioxide having a melting point of 232°-235° is obtained.
Reaction SMILES: CON(C)[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH3:18].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:16]([O:15][C:6]1[CH:7]=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:9]=[CH:10][C:5]=1[CH:4]=[O:19])[CH2:17][CH3:18]
Reactant: CCCOc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCOc1cc(C(F)(F)F)ccc1C=O
Reaction time: 0.5 h
Yield: 105.1 %

Procedure:
N-Methoxy-N-methyl-2-propoxy-4-trifluoromethyl-benzamide (277 mg) in THF was reacted with 1 M LAH (1 ml) on −50° C. for 1 hr. The reaction mixture was quenched by adding aqueous potassium hydrogen sulfate (5 ml). The mixture was stirred for 30 min. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with brine (30 ml) and dried over MgSO4 and concentrated in vacuo to yield title compound (232 mg, 100%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH:13]([P:21]([OH:23])[OH:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[OH-].[Na+].O.O1CCOCC1>[CH2:5]([O:4][C:2]([NH:12][CH:13]([P:21]([OH:23])[OH:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1ccccc1)P(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC(Cc1ccccc1)P(O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
2.25 ml (14.25 mmol) of benzyl chloroformate are added dropwise, at 0° C. and within the space of 30 min., to a suspension of 1.76 g (9.5 mmol) of 1-amino-2-phenylethylphosponous acid in 15 ml of 1M NaOH, 5 ml of water and 5 ml of dioxane. During a further 2.5 h of stirring at 0° C., the pH of the mixture is maintained at 9-10 using 1M NaOH (approximately 10 ml). After removing the cooling medium, the mixture is stirred at RT overnight. The reaction solution is then washed several times with diethyl ether. The aqueous phase is adjusted to pH 2, at 0°-5° C., using 6M HCl and extracted several times with ethyl acetate. The combined extracts are washed with a saturated solution of NaCl, dried with Na2SO4, filtered and subjected to rotary evaporation i.V. A solid residue remains which is recrystallized from ether/petroleum ether.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C@H:17]([CH2:29][OH:30])[CH2:18][CH2:19][N:20]2[CH2:27][CH2:26][C:23]3([CH2:25][CH2:24]3)[C@H:22]([OH:28])[CH2:21]2)[C:13](=[O:31])[C@@H:12]1[CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C@H:17]([CH2:29][O:30][C:36](=[O:37])[NH:35][CH2:33][CH3:34])[CH2:18][CH2:19][N:20]2[CH2:27][CH2:26][C:23]3([CH2:25][CH2:24]3)[C@H:22]([OH:28])[CH2:21]2)[C:13](=[O:31])[C@@H:12]1[CH3:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1C(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Reactant: CCN=C=O
Solvent: CC#N
Product: CCNC(=O)OC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1=O
Temperature: 40 °C
Reaction time: 72 h
Yield: 45.6 %

Procedure:
To a solution of (S)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (intermediate 39; 63 mg, 0.14 mmol) in acetonitrile (1 mL) was added ethyl isocyanate (11 mg, 0.14 mmol) at 0° C. The ice bath was removed, then after 16 h another portion of ethyl isocyanate (11 mg, 0.14 mmol) was added, and the reaction mixture was stirred at 40° C. for 72 h. Volatile material was removed by concentration under vacuum, and the residue was chromatographed (SiO2; dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) to afford the title compound (33 mg, 45%). Colorless gum, MS (ISP)=517.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](/[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)\[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28][C:29]=2[CH3:30])=[CH:21][CH:20]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[CH3:30][C:29]1[O:28][C:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:26][C:25]=1[CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:3]/[N:4]=[C:5](/[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)\[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:38][CH:37]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)/C(=N\O)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccnc1
Reaction time: 3 h
Yield: 74.5 %

Procedure:
Sodium hydride (60% in oil, 153 mg) was added to a solution of ethyl Z-2-hydroxyimino-2-(3-pyridyl)acetate (619 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) in N,N-dimethylformamide (10 ml) at room temperature under nitrogen atmosphere and stirred for 3 hours. 1N hydrochloric acid (7 ml) was added, an aqueous saturated solution of sodium bicarbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetate (1.12 g, yield 74%) as a pale-yellow oil from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:14](=[O:33])[N:13]1[CH3:34].[OH-].[Li+]>O1CCOCC1.O>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[C:14](=[O:33])[N:13]2[CH3:34])=[C:4]([CH:9]=1)[C:3]([OH:35])=[O:2])#[N:11]
Reactant: COC(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1C(=O)O

Procedure:
5-Cyano-2-[3-methyl-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-benzoic acid methyl ester (INTERMEDIATE 24, 5.3 g, 11 mmol) and lithium hydroxide (0.78 g, 32.9 mmol) are stirred in 1.4-dioxane (90 ml) and water (30.0 mL) at room temperature for 7.5 h. The reaction mixture is diluted with water and the extracted with diethyl ether. The aqueous phase is acidified with hydrochloric acid to a pH of 2 and extracted with ethyl acetate. The ethyl acetate phase is evaporated under reduced pressure and the crude product is purified by reversed phase HPLC. Yield: 1.5 g; ESI mass spectrum [M+H]+=470; Retention time HPLC: 0.61 min (X012_S02).
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[C:5]#[N:6].ClC1C([CH2:22][CH:23]=[O:24])=CC=C(F)C=1C#N>>[CH3:11][O:10][C:7]1[C:4]([C:5]#[N:6])=[C:3]([CH3:12])[C:2]([CH2:22][CH:23]=[O:24])=[CH:9][CH:8]=1
Reactant: COc1ccc(Br)c(C)c1C#N
Reactant: N#Cc1c(F)ccc(CC=O)c1Cl
Product: COc1ccc(CC=O)c(C)c1C#N

Procedure:
6-methoxy-2-methyl-3-(2-oxoethyl)benzonitrile was prepared in two steps starting from 3-bromo-6-methoxy-2-methylbenzonitrile in an analogous fashion to that described for the synthesis of 2-chloro-6-fluoro-3-(2-oxoethyl)benzonitrile (Steps B and C) above.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]([O:32][CH3:33])=[O:31]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:15]([C:30]([O:32][CH3:33])=[O:31])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)OC)C(OC)=N1
Yield: 67.5 %

Procedure:
To a well stirred solution of (−)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-diflurophenyl)pyrimidine (0.6 g, 1.5 mmol) and 4-(N,N-dimethylamino)pyridine (0.32 g, 2.66 mmol) in CH2Cl2 (6 mL) was added methyl chloroformate (0.2 mL, 2.66 mmol) at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with 3:1 Petroleum ether/EtOAC as the eluting system to obtain 0.45 g (78% yield) of (−)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.S(=O)(=O)(O)[OH:15].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:15])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: O=Cc1cc(Cl)cc2c1OCCO2
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cc(Cl)cc2c1OCCO2
Temperature: 5 °C
Yield: 77.2 %

Procedure:
7-Chloro-2,3-dihydro-1,4-benzodioxine-5-carbaldehyde (6.25 g, 31.4 mmol) was dissolved in acetone (150 mL) and the solution was then cooled to 5° C. A solution of CrO3 in sulfuric acid (4 M in 4 M H2SO4, 12.5 mL, 50 mmol) was added dropwise over 2 min and the mixture was refluxed for 30 min. Water (150 mL) was added and then most of the acetone was removed by evaporation. The mixture was extracted with ether (150 mL) and the organic solution was then extracted with a solution of NaOH (0.5 M, 150 mL). The aqueous solution was acidified with 2 M hydrochloric acid and then extracted with ether (150 mL). The organic solution was washed with brine and dried over Na2SO4. The solvent was removed by evaporation and the residue treated with CH2Cl2. After filtration and drying there was obtained 5.2 g (77%) of 7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid. 1H NMR (400 MHz, acetone-d6): 4.3-4.4 (m, 4H), 7.1 (d, 1H), 7.3 (d, 1H), 11-12 (b, 1H).
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:45]/[O:46][CH3:47])/[C:12]([NH:14][C:15]2([CH2:43][OH:44])[CH2:19][O:18][N:17]([C:20]3([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:24][CH2:23][C:22](=[O:25])[O:21]3)[C:16]2=[O:42])=[O:13])[N:10]=1)=O.CNC(=S)[S-].[Na+].O>CN(C)C=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:45]/[O:46][CH3:47])/[C:12]([NH:14][C:15]2([CH2:43][OH:44])[CH2:19][O:18][N:17]([C:20]3([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:24][CH2:23][C:22](=[O:25])[O:21]3)[C:16]2=[O:42])=[O:13])[N:10]=1
Reactant: CO/N=C(\C(=O)NC1(CO)CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)CCC(=O)O2)C1=O)c1csc(NC(=O)CCl)n1
Agent: CNC(=S)[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1(CO)CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)CCC(=O)O2)C1=O)c1csc(N)n1
Yield: 76.1 %

Procedure:
In 3 ml of dimethylformamide was dissolved 170 mg of the Compound (9a) obtained as above. To the solution was added, under ice-cooling, 48 mg of sodium N-methyldithiocarbamate, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The concentrate was subjected to a silica-gel column chromatography, eluting with ethyl acetate - n-hexane (2:1) to give 115 mg of the above-titled Compound (9b).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[Cl-].Cl[C:31](Cl)=[N+:32]([CH3:34])[CH3:33]>C(#N)C.CS(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:31]([N:32]([CH3:34])[CH3:33])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: C[N+](C)=C(Cl)Cl
Reactant: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Agent: [Cl-]
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(N(C)C)n(CC3CCOCC3)c12
Temperature: 120 °C
Yield: 77.1 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for preparation see intermediate 17) (50 mg, 0.131 mmol) and N-(dichloromethylene)-N-methylmethanaminium chloride (available from Aldrich) (42.5 mg, 0.261 mmol) were combined in anhydrous acetonitrile (0.5 ml) and heated at 120° C. for 10 min (microwave). The reaction mixture was reduced to dryness under a stream of nitrogen and the residue dissolved in DMSO (1 ml) and purified by MDAP (HpH). The solvent was evaporated under a stream of nitrogen to give 7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-N,N-dimethyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-c]quinolin-2-amine (44 mg, 0.101 mmol, 77% yield) as a yellow gum.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:9]=3[N:10]([CH2:18][CH2:19]4)[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:9]=3[N:10]([CH:18]=[CH:19]4)[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2=Nc3ccccc3N3CCc4cccc2c43)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1C
Product: c1ccc(C2=Nc3ccccc3-n3ccc4cccc2c43)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution, under N2, of 8.7 g of 1,2-dihydro-6-phenylindolo[1,7-ab][1,5]benzodiazepine in 125 ml of xylene is heated to 100° C. when 7.34 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is added in one portion. The mixture is brought to reflux and kept there for 3.0 hours. After cooling to room temperature, the liquid is filtered and the residue remaining in the flask is rinsed with xylene. The xylene filtrate is concentrated to an oil. This oil is dissolved in ethanol, and the solution is allowed to cool at 0° C. The crystals so obtained are filtered, washed with a little ethanol, then dried to yield 6-phenylindolo[1,7-ab][1,5]benzodiazepine, m.p. 128°-136° C.