Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5]N(C=O)C.[Br:10][C:11]1[CH:20]=[C:19]([Br:21])[CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[C:16]2[C:22](Cl)=[O:23].Cl.COCN>C(N(CC)CC)C>[C:22]([C:16]1[C:17]2[C:12](=[C:11]([Br:10])[CH:20]=[C:19]([Br:21])[CH:18]=2)[CH:13]=[CH:14][CH:15]=1)(=[O:23])[CH3:5]
Reactant: O=C(Cl)c1cccc2c(Br)cc(Br)cc12
Reactant: CN(C)C=O
Agent: COCN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc2c(Br)cc(Br)cc12

Procedure:
The 1-acetyl-5,7-dibromonaphthalene used in the foregoing procedure was prepared by dibromination of benz[cd]-indol-2(1H)-one with bromine in glacial acetic acid to give 41 g of 6,8-dibromobenz[cd]indol-2(1H)-one, m.p. 259°-260° C. The latter (12.8 g) was heated under reflux for one hour in two liters of 5% potassium hydroxide, the reaction mixture was cooled, filtered and then treated with 2.8 g of a solution of sodium nitrite in 50 ml of water. The resulting solution, cooled to 0° C., was added dropwise to 800 ml of a 40% solution of sulfuric acid while maintaining the temperature at -5° C. The reaction mixture was stirred for one hour, then poured slowly into a solution of 140 g of sodium hypophosphite in 800 ml of water at 0° C. with stirring. The solid which separated was collected by filtration and dissolved in 3 liters of 2% sodium carbonate solution, and the resulting solution was filtered, acidified with concentrated hydrochloric acid and the mixture extracted with ethyl acetate The combined organic extracts were dried and taken to dryness to give 8 g of 5,7-dibromo-1-naphthalenecarboxylic acid which was heated with thionyl chloride in the presence of a small amount of DMF. The resulting crude 5,7-dibromo-1-naphthalenecarboxylic acid chloride, together with 6.0 g of methoxymethylamine hydrochloride in 750 ml of MDC, was treated dropwise at 0° C. with 60 ml of triethylamine in 250 ml of MDC. The reaction mixture was filtered, the filtrate was taken to dryness, and the resulting residue (12.0 g) was dissolved in THF and treated at 0° C. with stirring with a solution of 29.5 ml of 3M methyl magnesium bromide The reaction mixture was stirred for ten minutes, quenched with water, taken to dryness and the residue partitioned between ethyl acetate and water. The mixture was filtered, the organic extracts were separated, dried and taken to dryness to give 9.9 g of 1-acetyl-5,7-dibromonaphthalene.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)c1N

Procedure:
2-amino-3-bromobenzoic acid (1.00 g) was mixed with methanol (10 ml) and concentrated sulfuric acid (1 ml). The mixture was stirred at reflux for 31 hours. The solvent were evaporated, and saturated aqueous sodium bicarbonate was carefully added. The solid was extracted with CH2Cl2 (3×). The combined extracts were dried over Na2SO4 and the solvents removed in vacuo to afford methyl 2-amino-3-bromobenzoate as a semi-crystalline solid (976 mg, 91% yield). LCMS (ES): >85% pure, m/z 230 [M+1]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[O:19][CH:16]1[CH2:17][CH2:18][C:11]2([CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1CCC2(CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 120.2 %

Procedure:
To a ice cooled solution of 9-(3,4-dichloro-phenoxy)-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (60 mg, 0.19 mmol) in dichloroethane (10 mL), formaldehyde (37% in water, 54 μL, 0.72 mmol) was added and stirred for 1 h at 0° C. Sodium triacetoxyborohydride (102 mg, 0.48 mmol) was added and stirred over night at room temperature. The reaction was quenched with aqueous sodium hydrogen-carbonate and evaporated. The remaining aqueous phase was extracted four times with dichloromethane and the combined organic phase was dried (sodium sulfate), filtered and evaporated to give 75 mg (95%) 9-(3,4-dichloro-phenoxy)-3-methyl-3-aza-spiro[5.5]undecane as a yellow oil. LC-ESI-HRMS of [M+H]+ shows 328.1249 Da. Calc. 328.123495 Da, dev. 4.3 ppm.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:39]=[CH:40][CH:41]=1)[CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:38])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])[CH:22]=1>O1CCCC1.CO>[F:3][C:4]1[CH:5]=[C:6]([CH:39]=[CH:40][CH:41]=1)[CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:38])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])[CH:22]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCc2cccc(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCc2cccc(F)c2)c1
Yield: 68 %

Procedure:
In a manner similar to that of Example 19g, by reaction of 400 mg (10 mmol, 10 eq) of sodium hydroxide and methyl 3-[2-(3-fluorobenzyloxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 305 mg of 3-[2-(3-fluorobenzyloxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=73° C.). Yield=68% over the two steps.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:8]=1[C:9]([OH:12])([CH3:11])[CH3:10].[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH4+].[Cl-]>C1COCC1>[CH2:18]([N:25]1[CH2:30][CH2:29][C:28]([C:7]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:8]=2[C:9]([OH:12])([CH3:11])[CH3:10])([OH:31])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(O)c1cc(F)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)ccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To an anhydrous THF (50 mL) cooled at −70° C. stirred under nitrogen a 2.5 M solution of n-BuLi (4.22 mL, 10.54 mmol) was added. Then 2-bromo-5-fluoro-α,α-dimethyl-benzylalcohol (1.17 g, 5.02 mmol) [C.A.S.853271-16-6] was added dropwise. The resulting mixture was stirred at −70° C. for 2 h. Then a solution of 1-benzylpiperidin-4-one (1.33 g, 7.028 mmol) in anhydrous THF (10 ml) was added dropwise. Then, the resulting solution was stirred at r.t. overnight. The reaction mixture was poured into NH4Cl (aqueous sat. solution) at 5-10° C. The resulting aqueous solution was extracted with DCM. The organic layer was separated and concentrated in vacuo. The residue was purified by column chromatography (silica gel; heptane/EtOAc from 100/0 to 60/40 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D83 (0.4 g, 23%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:8][C:9](=[S:28])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1c(Br)cccc1NC(=O)c1ccccc1F
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1NC(=S)c1ccccc1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 150 %

Procedure:
Step 2 A mixture of N-(3-bromo-2-methylphenyl)-2-fluorobenzamide (2.00 g, 6.49 mmol) and 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson reagent, 1.575 g, 3.89 mmol) in toluene (25 mL) was heated at reflux. After 3.5 h, the solution was cooled to rt and concentrated to provide a dark yellow solid. This was purified by column chromatography (eluting with a gradient from 95:5 to 90:10 hexane-EtOAc) to provide N-(3-bromo-2-methylphenyl)-2-fluorobenzothioamide as a yellow solid (1.892 g, 90%). 1H NMR (400 MHz, chloroform-d) δ 9.18 (1H, d, J=7.7 Hz), 8.23 (1H, td, J=8.0, 1.8 Hz), 7.60 (1H, d, J=7.9 Hz), 7.45-7.52 (1H, m), 7.43 (1H, d, J=7.7 Hz), 7.23-7.30 (1H, m), 7.11-7.21 (2H, m), 2.41 (3H, s). Mass spectrum m/z 324, 326 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:23])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:12]=2[C:13]=1[CH3:14])(=O)=O.Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(O)(C)C>[CH3:22][O:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:11]2[O:10][C:9](=[O:23])[C:8]([CH2:7][CH2:6][N:36]3[CH2:35][CH2:34][N:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])[CH2:38][CH2:37]3)=[C:13]([CH3:14])[C:12]=2[CH:15]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cc2oc(=O)c(CCOS(C)(=O)=O)c(C)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4OC)CC3)c(C)c2cc1OC
Yield: 14 %

Procedure:
Process A; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-6,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 28) and 1-(2-methoxyphenyl)piperazine hydrochloride; yield 14%; m.p. 174°-175° C. (from isopropanol).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH:5]=[CH2:6].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH2:3]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: BrCc1ccccc1
Reactant: C=CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCOCc1ccccc1
Reaction time: 0.5 h

Procedure:
NaH (0.24 g) was slowly added to a solution of 3-buten-1-ol (0.72 g) in DMF (15 ml) at 0° C., and the reaction stirred for 30 minutes. Benzyl bromide (1.9 g) was added and the reaction was stirred at 25° C. for 18 hours. The mixture was filtered and concentrated. The residue was dissolved in hexane, washed with water (3×), dried over MgSO4, and concentrated. Purification by chromatography over silica gel (5% ethyl ether in hexane) afforded the titled compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]1[CH3:18])([CH3:6])[CH3:5].[Mn]([O-])(=O)(=O)=[O:20].[K+]>CC(C)=O.O>[CH3:1][O:2][CH2:3][C:4]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:20])=[O:17])=[C:8]1[CH3:18])([CH3:6])[CH3:5]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COCC(C)(C)n1c(C)c(C=O)c2ccccc21
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCC(C)(C)n1c(C)c(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole-3-carbaldehyde (50 mg, 0.2 mmol) in acetone (2 mL) and water (2 mL) was added potassium permanganate (95 mg, 0.6 mmol). The resulting reaction mixture was allowed to stir for 3 hours at room temperature. The reaction mixture was lyophilized directly to give 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole-3-carboxylic acid (50 mg, 94%) as a brown solid. LCMS (M+H+) m/z: calcd. 261.14. found 261.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH3:11])[CH:5]=1.Br[CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[C:6]([CH3:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: CC(C)=CCCC(C)=CCBr
Product: COC(=O)c1ccc(OCC=C(C)CCC=C(C)C)c(C)c1

Procedure:
By utilizing the procedure of Example 19, by reacting 3-methyl-4-hydroxybenzoic acid methyl ester with 1-bromo-3,7-dimethyl-2,6-octadiene, there is obtained 3-methyl-4-[(3,7-dimethyl-2,6-octadienyl)oxy]benzoic acid methyl ester; nD28 = 1.5248.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:24]([O:25][CH3:26])=[CH:23][C:7]([CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][CH2:11]N2)=[CH:6][CH:5]=1.[CH2:27](N(CC)CC)C.[CH2:34]([O:36][C:37](=[O:46])[CH2:38][C:39]1[N:44]=[C:43](Br)[CH:42]=[CH:41][N:40]=1)[CH3:35]>CN(C=O)C.CCOC(C)=O>[CH2:34]([O:36][C:37](=[O:46])[CH2:38][CH:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]1[CH:27]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:9]1[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[C:24]([O:25][CH3:26])[CH:23]=1)[CH3:35]
Reactant: CCOC(=O)Cc1nccc(Br)n1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1N=CC=CN1C1CCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1
Yield: 63.1 %

Procedure:
To a white suspension of 1-(4,5-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-hydrochloride (1.65 g, 4.36 mmol) in dry DMF (5 ml), were added triethylamine (1.82 ml, 0.013 mol) and bromo-pyrimidin-acetic acid ethyl ester (1.07 g, 4.36 mmol). The reaction mixture was stirred at reflux under argon for 20 h. After cooling, the mixture was diluted in AcOEt and washed with water. The aqueous phase was extracted twice with CH2Cl2, the combined organic phases were dried over anhydrous AcOEt, filtered and concentrated to give a crude brown-orange oil. Flash chromatography (AcOEt) gave 1.4 g (63%) of the title product as a brown-orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=[C:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccc(C2CCC(=CC(=O)OC(C)(C)C)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(C2CCC(CC(=O)OC(C)(C)C)CC2)cc1
Yield: 85 %

Procedure:
5.04 g of ethyl 4-(4-tert-butoxycarbonylmethylenecyclohexyl)benzoate (14.63 mmol, 1 eq.) and 15 mL of ethanol are placed in a Parr bottle. 0.31 g of 10% palladium-on-charcoal (0.29 mmol, 0.02 eq.) is added and the reaction medium is placed under 50 psi of hydrogen for 3 hours at a temperature of 25° C. The reaction medium is filtered and concentrated to give 4.31 g of ethyl 4-(4-tert-butoxycarbonylmethylcyclohexyl)benzoate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:31])([CH2:27][CH2:28][C:29]#[N:30])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:31])([CH2:27][CH2:28][C:29]4[NH:36][N:35]=[N:34][N:30]=4)[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(CCC#N)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CCc1nnn[nH]1)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 110 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(4-cyano-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (83 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (1 mL) containing ammonium chloride (128 mg, 2.41 mmol), sodium azide (156 mg, 2.40 mmol), and a magnetic stir bar. The reaction mixture was heated at 110° C. for 40 minutes in a microwave reactor. The crude product was filtered and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(2-methyl-4-(1H-tetrazol-5-yl)butan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 458.2, found 459.2 (M+1)+. Retention time of 1.53 minutes. 1H NMR (400 MHz, CD3CN) 9.23 (s, 1H), 7.51-7.48 (m, 2H), 7.19 (d, J=8.6 Hz, 1H), 7.06-7.03 (m, 2H), 6.95-6.89 (m, 2H), 6.17 (dd, J=0.7, 2.2 Hz, 1H), 6.02 (s, 2H), 2.61-2.57 (m, 2H), 2.07-2.03 (m, 2H), 1.55-1.51 (m, 2H), 1.39 (s, 6H), 1.12-1.09 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:29][CH3:30])=[CH:9][C:10]3[C:11]4[N:19]([C@@H:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH3:21])[C:18](=O)[NH:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:31])[O:4][N:3]=1.O=P(Cl)(Cl)[Cl:34].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:34][C:18]1[N:19]([C@@H:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21])[C:11]2[C:10]3[CH:9]=[C:8]([O:29][CH3:30])[C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:31])=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1[nH]c(=O)n([C@H](C)c3ccccc3)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n([C@H](C)c3ccccc3)c12
Reaction time: 8 h
Yield: 8.99 %

Procedure:
7-(3,5-Dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (for a preparation see Intermediate 11) (0.33 g, 0.796 mmol) was heated in a mixture of POCl3 (1 ml, 10.73 mmol) and PCl5 (0.166 g, 0.796 mmol) at 120° C. for 5 h, then cooled and allowed to stand at room temperature overnight. The mixture was evaporated in vacuo and then the residue suspended in toluene and evaporated to a brown gum. This was dissolved in DCM (20 ml) and washed with saturated sodium hydrogen carbonate solution, then the organic layer was loaded onto a 25 g silica cartridge. The column was eluted with EtOAc/cyclohexane (0-100%) and the product-containing fractions evaporated in vacuo to give 2-chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline (31 mg, 0.072 mmol, 8.99% yield) as a beige glass. LCMS (formate) Rt 1.05 min, MH+ 433.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([O:20][CH3:21])=[O:19])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1sccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A mixture of 4-cyanobenzoyl chloride (1.0500 g, 6.4 mmol), methyl 3-aminothiophenecarboxylate (1.0000 g, 6.4 mmol), and triethylamine (1mL, 7.0 mmol) in dichloromethane was stirred at room temperature for 18 hours. The mixture was poured into a separatory funnel and washed by 1 N HCl. The organic layers were combined. dried over MgSO4, concentrated in vacuo, and chromatographed through a silica gel column to give the title compound 1.6588 g (91%). ES-MS 287 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:27]1(C)C=CC=C[CH:28]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:27]([C:2]1[N:7]=[C:6]([C:8]2[C:16]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1)=[CH2:28]
Reactant: Clc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Reactant: Cc1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Yield: 20 %

Procedure:
Add tributylvinylstanane (0.056 mL, 0.182 mmol) to a solution of 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (59 mg, 0.165 mmol) in toluene (0.83 mL) at room temperature and bubble nitrogen through the solution for 5 minutes. Add tetrakis(triphenylphosphine) palladium (0) (9 mg, 0.008 mmol) and bubble nitrogen through the solution for 1 minute. Heat the reaction to 110° C. for 15 hours. Purify by flash column chromatography (Silica Gel, 20-40% acetone/hexanes) to provide the title compound 11.5 mg (20%) as a white solid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]([CH3:8])[CH3:7])C.Cl.[S:13](S([O-])=O)([O-:16])(=[O:15])=[O:14].[Na+].[Na+].C(O)C>O>[CH3:7][N:6]([CH2:5][CH:4]=[O:3])[CH3:8].[S:13]([O-:16])([OH:15])=[O:14]
Reactant: CCOC(CN(C)C)OCC
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)CC=O
Product: O=S([O-])O
Reaction time: 1 h

Procedure:
40 g of dimethylaminoacetaldehyde diethylacetal are heated to 40° C. in a mixture of 48 g conc, hydrochloric acid and 20 ml of water for 3 h. Then a solution of 42.4 g sodium pyrosulphite in 72 ml of water (sodium hydrogen sulphite solution) is added dropwise and the mixture is stirred for 1 h. 200 ml of ethanol are added and then the mixture is stirred for 2 h at 0° C. The suspension is suction filtered, washed with 160 ml of ethanol and dried at 45° C. in vacuo.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:14][C:15]#[CH:16])[C:4](=[O:17])[C:3]=1[CH3:18].[CH3:19][NH:20][CH3:21]>O1CCCC1.CCOCC>[CH3:19][N:20]([CH3:21])[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:14][C:15]#[CH:16])[C:4](=[O:17])[C:3]=1[CH3:18]
Reactant: CNC
Reactant: C#CCn1c(-c2ccccc2)nc(Cl)c(C)c1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCn1c(-c2ccccc2)nc(N(C)C)c(C)c1=O
Temperature: 25 °C

Procedure:
To an ice cooled solution of 1.5 g (3.8 mmol) 6-chloro-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone in 4 mL of tetrahydrofuran, was added 22 mL (99 mmol) of 4.5M dimethylamine in ether portionwise (2-4 mL) over a period of 7 days. The reaction mixture was allowed to warm and stir at room temperature after each addition. The progress of the reaction was followed by gas chromatography and proceeded to 80% completion. The solvent was removed in vacuo and the residue was taken up in ether and washed twice with water. The organic layer was dried over MgSO4 and concentrated to yield 1.15 g crude solid product. Flash column chromatography on silica gel (gradient elution 25-30% ethyl acetate-hexane) afforded pure 6-dimethylamino-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (compound 23), as a white solid. 1H-NMR (CDCl3)δ2.2 (3H, s); 2.35 (1H, t); 3.5 (6H, s); 4.6 (2H, d); 7.65 (3H, m); 7.75 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1(C)C=CC=CC=1>[N:1]([C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)=[C:20]=[O:22]
Reactant: COC(=O)c1ccc(N)nn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N=C=O)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of methyl 6-aminopyridazine-3-carboxylate (14 g, 91.5 mmol) in anhydrous toluene (700 mL) was added Et3N (11.1, 109.8 mmol). A solution of triphosgene (27.2 g, 91.5 mmol) in anhydrous toluene was added slowly at 0° C. The reaction mixture was stirred for 2 hrs at room temperature and then heated at 90° C. for 5 hrs. After cooling to room temperature, toluene and water were added to the mixture, the mixture was separated and the organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to give the title compound as a solid.