Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10](Cl)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][C:10]2=[O:11]
Reactant: O=C(Cl)CCc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2c(F)cccc21
Temperature: 0 °C

Procedure:
To a mixture of 3-(2-fluorophenyl)propionic acid (18.64 g, 0.111 mol) and dimethylformamide (5 drops) at room temperature was added dropwise oxalyl chloride (60 mL). The mixture was stirred at room temperature until gas evolution had ceased. The excess oxalyl chloride was removed by distillation to give 3-(2-fluorophenyl)propionyl chloride. A solution of the 3-(2-fluorophenyl)propionyl chloride in dichloromethane (230 mL) was added dropwise to a mixture of aluminum chloride (16.25 g, 0.12 mol) in dichloromethane (230 mL), and the mixture was refluxed for 3.5 h. The reaction mixture was poured into ice water (1200 mL), and the two phases were separated. The dichloromethane phase was washed successively with 0.1N aqueous sodium hydroxide (2×100 mL), water (200 mL), and brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residual oil was chromatographed on silica gel eluting with hexane:dichloromethane (9:1) to give 11.0 g of crude 4-fluoro-1-indanone as a yellow solid. Recrystallization from acetone:water mixtures gave 8.02 g (48%) of 4-fluoro-1-indanone as a pale yellow solid: m.p., 71-72° C.; NMR (DMSO-d6): d 7.51 (m, 3H, Ar), 3.13 (t, 2H, CH2), 2.74 (t, 2H, CH2).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.[CH3:12][NH:13][C:14]([CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)=O.[OH-].[Na+]>O.C1COCC1>[CH3:12][NH:13][CH2:14][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: CNC(=O)C1CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CNCC1CCc2ccccc21

Procedure:
A mixture of 4.0 g (0.1M) of LAH and 400 ml of ether was stirred while a solution of 9.0 g (51 mmol) of 1-methylaminocarbonyl-indane, a compound of Formula 13 prepared, for example, as described in Preparation 13, dissolved 200 ml of THF was added over a period of 30 minutes. The reaction mixture was stirred and heated to reflux for 6 hours, and then stirred at ambient temperature for an additional 16 hours. The reaction mixture was then digested by treating dropwise with water, 15% NaOH, and then water, yielding 1-methylaminomethyl-indane, an intermediate amine of Formula 14; (HCl salt, ethanol-ether, mp 169°-171° C.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH2:13][CH3:14])([O-:12])=[O:11].C(OC)(OC)OC.Cl.CN.C([O-])(=O)C.[K+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:13](/[N+:10]([O-:12])=[O:11])\[CH3:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Solvent: CO
Solvent: COC(OC)OC
Product: C/C(=C\c1ccc(F)cc1)[N+](=O)[O-]
Yield: 24.9 %

Procedure:
A solution of 4-fluorobenzaldehyde (5.0 g, 40.32 mmol), nitro ethane (3.2 mL, 44.35 mmol), trimethyl orthoformate (9.7 mL, 88.70 mmol), methylamine HCl (2.1 g, 31.44 mmol) and potassium acetate (2.76 g, 28.22 mmol) in methanol (50 mL) was refluxed at 80° C. for 18 h. Methanol was evaporated; the residue diluted with water (100 mL), extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried (Na2SO4) and concentrated. The residue triturated with methanol (10 mL), filtered off and washed with cold methanol (5 mL) to afford the desired product (1.82 g, 25%) as a yellow solid.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1)#[N:41]>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:51]1[CH2:50][CH2:49][CH:48]([C:45]2[CH:46]=[CH:47][C:42]([C:40]#[N:41])=[CH:43][CH:44]=2)[CH2:53][CH2:52]1
Reactant: N#Cc1ccc(C2CCC(=O)CC2)cc1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C2CCC(=CCC3OCCCO3)CC2)cc1
Yield: 56 %

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer, was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (12.2 g, 27 mmols), followed by adding tetrahydrofuran (200 ml), suspending, stirring the suspension under ice cooling till the liquid temperature reached 10° C., adding to the reaction mixture, potassium t-butoxide (30 g, 27 mmols), elevating the temperaure up to room temperature under ice cooling for one hour, stirring the mixture for one hour, dropwise adding a tetrahydrofuran (50 ml) solution of 4-(4-cyanophenyl)cyclohexanone (5.0 g, 25 mmols) from the dropping funnel over 30 minutes. The reaction mixture was stirred for 5 hours after completion of the dropwise addition, followed by adding ether (100 ml), allowing the mixture to stand, filtering off deposited insoluble substance, concentrating the flitrate under reduced pressure, and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)ethylidene)-4-(4-cyanophenyl)-cyclohexane (4.1 g, 14 mmols).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:21]([CH2:22][C@@H:23]5[CH2:27][CH2:26][NH:25][CH2:24]5)=[N:20][NH:19][C:18]4=[O:28])=[CH:13][CH:12]=3)=[CH:10][C:5]=2[CH:4]=[CH:3]1.C(N(CC)C(C)C)(C)C.[C:38](Cl)(=[O:41])[CH2:39][CH3:40]>ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:21]([CH2:22][C@@H:23]5[CH2:27][CH2:26][N:25]([C:38](=[O:41])[CH2:39][CH3:40])[CH2:24]5)=[N:20][NH:19][C:18]4=[O:28])=[CH:13][CH:12]=3)=[CH:10][C:5]=2[CH:4]=[CH:3]1
Reactant: CCC(=O)Cl
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(-c2ccc3occc3c2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 60.9 %

Procedure:
Under nitrogen, a mixture of 4-[4-(1-benzofuran-5-yl)phenyl]-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (116 mg, 0.292 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) in dichloromethane (1.3 mL) was stirred at room temperature for 2 min. The mixture was cooled to 0° C. and treated with propionyl chloride (0.026 mL, 0.292 mmol) dropwise by syringe. The mixture became a dark brown solution and the reaction was stirred at 0° C. for 90 min. The reaction was quenched with water (2 mL) and diluted with ethyl acetate (20 mL). The mixture was transferred to a separatory funnel, water (10 mL) was added and the layers were separated. The pH of the aqueous layer was tested by pH paper and found to be pH˜5-6. The aqueous layer was extracted with ethyl acetate (10 mL). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give a tan foamy solid. Purification of the residue by silica gel chromatography (Analogix IF280, SF10-4 g, 0-10% MeOH/EtOAc, 30 min) provided the title product as an ivory solid (74 mg, 61%). MS(ES)+ m/e 417.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15]([C:17]3[NH:18][C:19](=[N:22][CH:23]=[O:24])[S:20][CH:21]=3)=O)[C@H:4]2[S:3]1.C(=O)(O)[O-].[Na+].O.O.O.C([O-])(=O)C.[Na+].[CH3:40][O:41][NH3+:42].[Cl-]>O.C(OCC)(=O)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15](=[N:42][O:41][CH3:40])[C:17]3[N:18]=[C:19]([NH:22][CH:23]=[O:24])[S:20][CH:21]=3)[C@H:4]2[S:3]1
Reactant: CO[NH3+]
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(=NC=O)[nH]3)[C@H]2S1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(NC=O)n1

Procedure:
To a suspension of 2-methyl-7-[2-(2-formylaminothiazol-4-yl)glyoxylamino]-3-cephem-4-carboxylic acid, which can be represented as 2-methyl-7-[2-(2-formylimino-2,3-dihydrothiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (792 mg.) in water (20 ml.) was added sodium bicarbonate (168 mg.) with stirring. To thus obtained solution were added sodium acetate trihydrate (272.2 mg.) and 0-methylhydroxylamine hydrochloride (334 Smg.), and the mixture was stirred for 2 hours at 48° to 50° C. After cooling the reaction mixture, a saturated aqueous sodium bicarbonate solution (10 ml.) and ethyl acetate (15 ml.) were added thereto in order to dissolve the precipitated insoluble material. The aqueous layer was separated, washed with ethyl acetate, adjusted to pH 1 with 2 N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate extract was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 2-methyl-7-[2-methoxyimino-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (505 mg.). This compound was recrystallized from methanol to give white crystals of the pure object compound.
Reaction SMILES: C([Mg]Cl)#C.[CH2:5]1[CH2:9][O:8][CH2:7][CH2:6]1.[O:10]1CC[C:13](=O)[CH2:12][CH2:11]1.[Cl-].[NH4+]>C(OCC)C>[C:12]([C:11]1([OH:10])[CH2:6][CH2:7][O:8][CH2:9][CH2:5]1)#[CH:13]
Reactant: C1CCOC1
Reactant: O=C1CCOCC1
Agent: C#C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CC1(O)CCOCC1

Procedure:
A solution of ethynylmagnesium chloride in THF (0.5 M, 120 mL, 60 mmol) was added with cooling in an ice—water bath to a solution of tetrahydro-4H-pyran-4-one (4.96 g, 50 mmol) (Aldrich) in diethyl ether (300 mL) dropwise over 15 min. The mixture was stirred with cooling for 3 h. Aqueous ammonium chloride solution (100 mL, 15% W/V) was then added and mixture extracted with ether (2×200 mL). The ether layers were washed with saturated aqueous sodium chloride solution (200 mL), then combined, dried (MgSO4), filtered and concentrated to give 4-Ethynyl-tetrahydro-pyran-4-ol as a colorless oil that solidified on standing. (Yield 6.01 g, 96.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: C1COCCN1
Product: O=C(O)c1cnn(-c2nc(N3CCOCC3)c3cc(N4CCCCC4)c(Cl)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C21H23ClN6O3, 442.9
Reaction SMILES: [CH:1]1([CH2:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8](Cl)(Cl)=[O:9]>>[CH:1]1([CH2:6][NH:7][C:8]([NH:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCC1
Reactant: O=C(Cl)Cl
Product: O=C(NCC1CCCC1)NCC1CCCC1
Yield: 81 %

Procedure:
In the manner of step (a) of Example 1, cyclopentanemethylamine (K. Jewers and J. McKenna, J. Chem. Soc. 1958, 2209-2217; 23.0 g, 0.158 mole) was reacted with phosgene to give 1,3-bis(cyclopentylmethyl)urea as white powder (14.41 g, 81%), m.p. 162°-164° C.;
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:20]([O-:22])=[O:21].Cl>ClCCl>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:20](=[O:21])[OH:22])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2sc(N)nc12
Reactant: O=C([O-])Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc2sc(NC(=O)O)nc12
Reaction time: 0.17 h

Procedure:
2-Amino-4-methoxybenzothiazol (23.6 g, 131 mmol) and pyridine (12.6 ml, 157 mmol) in dichloromethane (230 ml) are slowly treated with methyll chloroformate (10.6 ml, 137 mmol) at 0° C. After 10 minutes, further methyll chloroformate (1.0 ml, 13 mmol) and pyridine (1.0 ml, 12 mmol) are added. After 10 minutes, the mixture is poured into 200 ml 1M aqueous hydrochloric acid, the organic layer is separated, diluted with dichloromethane (250 ml) and washed with brine (50 ml). The organic phase is dried and the solvent evaporated in vacuo. 31.0 g (99.4%) white solid. MS: m/e=238 (M+H+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)O1.I[C:24]1[C:25]([O:32][CH3:33])=[N:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:31][O:30][C:27]1[N:26]=[C:25]([O:32][CH3:33])[C:24]([C:9]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)=[CH:29][N:28]=1
Reactant: COc1ncc(I)c(OC)n1
Reactant: CC1(C)OB(c2cc(C(F)(F)F)cc3[nH]ncc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(C(F)(F)F)cc3[nH]ncc23)c(OC)n1
Temperature: 130 °C
Yield: 48.1 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-indazole (100 mg, 0.320 mmol), 5-iodo-2,4-dimethoxypyrimidine (57 mg, 0.215 mmol), and PdCl2(dppf) (23 mg, 0.032 mmol) were dispersed in dioxane (3 mL). To the resulting slurry was added 2N aqueous sodium carbonate (0.320 mL, 0.641 mmol). The mixture was heated in a microwave reactor at 130° C. for 1 hour, and then filtered through a microfiltration frit, which was rinsed with methanol. The solvents were removed in vacuo and the resulting residue was taken up in DMSO and methanol (1:1) and was purified via preparative HPLC, eluting with a gradient of 40-45% ACN (containing 0.1% formic acid) in H2O (containing 0.1% formic acid). The purified fractions were collected to give a formic acid salt of the title compound (33.5 mg, 32.2%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.95 (s, 3H), 4.00 (s, 3 H), 7.43 (s, 1H), 7.95 (s, 1H), 8.12 (s, 1H), 8.52 (s, 1H), 13.64 (br s, 1H); ESI-MS m/z [M+H]+ calc'd for C14H11F3N4O2, 325.1. found 325.2.
Reaction SMILES: [CH2:1]([N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14](F)[CH:13]=1)[CH:2]=[CH2:3].[CH3:29][O-:30].[Na+]>C1COCC1.CO>[CH2:1]([N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14]([O:30][CH3:29])[CH:13]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(OC)c1
Reaction time: 8 h

Procedure:
8.97 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-fluoro-phenyl]-(4-bromo-phenyl)-methanone in 450 ml of THF are stirred with 37 ml of 5.4M sodium methanolate in methanol at room temperature for 14 hrs. and under reflux for 1 hr. The solution is evaporated and the residue is taken up in methylene chloride/10% sodium chloride solution. The organic phase is dried, dissolved in ether and stirred overnight with 2.08 g of fumaric acid. There are obtained 8.17 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-methoxy-phenyl]-(4-bromo-phenyl)-methanone.fumarate (m.p. 108°-113° C.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[NH:21][N:20]=[C:19]([CH2:22][C:23]([O:25]C)=[O:24])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:27][CH3:28].O.[OH-].[Li+].Cl>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[NH:21][N:20]=[C:19]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:27][CH3:28]
Reactant: COC(=O)Cc1cc(Nc2ncnc3cc(OCCCCl)c(OC)cc23)[nH]n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(Nc3cc(CC(=O)O)n[nH]3)ncnc2cc1OCCCCl
Yield: 74.4 %

Procedure:
Methyl (5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)acetate (100 mg, 0.247 mmol) in tetrahydrofuran (1.2 ml)/water (0.6 ml), was stirred with lithium hydroxide (21 mg, 0.493 mmol) at ambient temperature for 18 hours. The mixture was acidified with 6.0 N hydrochloric acid to pH 4 and the solid was recovered by filtration, washed with water and dried to yield (5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)acetic acid (72 mg, 75% yield) as a beige solid:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>O1CCOCC1.ClCCl>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:12][CH2:11][CH2:10][C:7]2[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[NH:9][CH:8]=2)[N:15]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCCc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1cncc(OCCc2c[nH]c3ccccc23)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
K-t-BuO (2.32 g, 20.6 mmol) was added to a stirred solution of tryptophol (1.7 g, 10.6 mmol) in dioxane (30 mL) at 0° C. (ice-bath). After being stirred for 10 min at 0° C. and 10 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (1.37 g, 9.17 mmol) was added. The yellowish reaction mixture was stirred at 0° C. for 30 min and for a further 20 min at room temperature. The mixture was diluted with dichloromethane, filtered, and concentrated in vacuo to furnish a brownish oil. This material was purified by chromatography on silica gel (14×5 cm) using n-hexane/ethyl acetate (75:25). This furnished 1.38 g (55%) of the title compound as a beige solid. Purity >90% by 1H NMR in CDCl3.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][N:11]([C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)[CH2:12][C:5]=2[CH:4]=1)[NH2:2]>CC(CC)=O>[CH:3](=[N:2][NH:1][C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][N:11]([C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[CH2:12][C:5]=2[CH:4]=1)[CH2:4][CH2:5][CH3:6]
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccc(-c3ccccc3)cc1)C2
Solvent: CCC(C)=O
Product: CCCC=NNc1cc2c(nn1)CCN(C(=O)c1ccc(-c3ccccc3)cc1)C2

Procedure:
0.5 g of 3-hydrazino-6-(p-phenylbenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine are heated in 5 cc of methylethyl ketone on a water bath for 1 hour. The title compound has a M.P. of 260°-262° (decomp., from methylethyl ketone).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:13][C:11]1[C:2]2[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=2[O:7][C:9](=[O:14])[CH:10]=1
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)CC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1cc(=O)oc2c1C(=O)CCC2
Reaction time: 3 h

Procedure:
231.2 g (2.0 mol) of cyclohexan-1,3-dione (97%) are refluxed under nitrogen for 2.5 hours in 670 ml of absolute pyridine with 325.3 q (1.25×2.0 mol) of ethyl acetoacetate and 4.88 (0.02×2 mol) of 4-dimethylaminopyridine. Then 65.1 g (0.25×2.0 mol) of ethyl acetoacetate are again added and the mixture is boiled for a further 3 hours. The pyridine is then distilled off in vacuo and the oily residue is stirred while still warm with 100 ml of a mixture of cyclohexane/ethyl acetate (1:1). The reaction product which crystallises out is suction filtered and dried. Yield: 136.9 g (39.2% of theory) The mother liquor is freed from solvent in vacuo using a rotary evaporator and the oily residue is distilled in vacuo. The distillate solidifies into a white crystalline substance.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([CH3:34])[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:32]#[N:33])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[Cl:31])[CH:16]=2)=[O:11])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][C:7]([CH3:35])([CH3:34])[C:6]([OH:36])=[O:5])=[O:11])[N:13]=[C:14]2[C:32]#[N:33])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
A mixture of 3-{[7-(2-chloro-4-fluoro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid tert-butyl ester (40 mg, 0.08) in (½) TFA/CH2Cl2 (3 mL) was stirred at room temperature for 4 h. Reaction mixture was concentrated. The residue was dissolved in water (30 mL) and the pH was adjusted to 10 by 1 N NaOH. It was then acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 24 mg (0.053 mmol) in 66% yield. LC-MS ESI−: 456.05 (M−1)−.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:18]2[CH:17]=[CH:16][C:15]([S:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[C:14]([NH:13][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:19]=2)=[CH:23][CH:24]=1
Reactant: Nc1cc(COc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(COc4ccc(Br)cc4)ccc3Sc3ccc(O)cc3)ccnc2n1
Temperature: 80 °C

Procedure:
The product from Example 1d (0.03 g, 0.167 mmol) was reacted with the product from Example 223c (0.060 g, 0.15 mmol) for 17.5 h following the procedure from Example 1g. Consumption of starting material required a second addition of the product from Example 1d (0.016 g, 0.09 mmol) and continued heating at 80° C. (18 h). The crude title compound was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.056 g, 55%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3 H) 5.12 (s, 2 H) 6.30 (d, J=6.99 Hz, 1 H) 6.79 (d, J=8.82 Hz, 2 H) 6.92-7.08 (m, 3 H) 7.25 (d, J=8.82 Hz, 2 H) 7.42-7.54 (m, 4 H) 7.81 (d, J=8.82 Hz, 1 H) 8.47 (d, J=6.99 Hz, 1 H) 9.01 (d, J=8.46 Hz, 1 H) 9.98 (s, 1 H); MS (ESI+) m/z 546.0 (M+H)+.