Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH:7]2[C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([CH3:20])[N:13]=1.CN1C=CN=C1.[F:27][CH:28]([F:33])[S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[F:27][CH:28]([F:33])[S:29]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[CH:7]([C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([CH3:20])[N:13]=2)[C:8]1=[O:11])(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)C(F)F
Reactant: COc1nc(C)nc(C2C(=O)Nc3c(F)cccc32)n1
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Product: COc1nc(C)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3c(F)cccc32)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
7-Fluoro-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-1,3-dihydro-2H-indol-2-one (1.20 g) and 1-methyl-1H-imidazole (0.97 g) are introduced as initial charge in 10 ml of dichloromethane and cooled to 0° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (1.21 g) is added in 2 portions and the mixture is warmed to room temperature. After 5 hours, 1-methyl-1H-imidazole (0.32 g) and difluoromethanesulfonyl chloride (0.61 g) are added and the mixture is stirred for 16 hours. After adding water and some hydrochloric acid, the solid is filtered off, washed with dichloromethane and water and dried. This gives the title compound as a solid in an HPLC purity of 91% (1.54 g, 92% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: [CH2:1]([N:4]([C:13]1[NH:14][CH2:15][CH2:16][N:17]=1)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12])[CH:2]=[CH2:3].[H-].[Na+].[CH3:20]I>O1CCCC1>[CH3:20][N:17]1[CH2:16][CH2:15][N:14]=[C:13]1[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12]
Reactant: CI
Reactant: C=CCN(C1=NCCN1)c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C1=NCCN1C)c1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
A mixture consisting of 2.7 gm (0.01 mol) of 2-[N-allyl-N-(2,6-dichloro-phenyl)-amino]-2-imidazoline, 0.44 gm of a 55% sodium hydride dispersion and 25 ml of absolute tetrahydrofuran was refluxed for 5.5 hours while stirring, and the reaction mixture was allowed to stand overnight at room temperature. Thereafter, 1 ml of methyl iodide (about 160% of the stoichiometrically required amount) was added, and the mixture was refluxed for two hours. The reaction mixture was then evaporated to dryness in vacuo, the residue was dissolved in dilute (about 1 N) hydrochloric acid, and the resulting solution was extracted several times with ether (the ethereal extracts were discarded). The aqueous acidic phase was fractionally extracted with ether at stepwisely increasing pH-values (addition of 2 N sodium hydroxide). The thin-layer chromatographically uniform fractions were combined, dried over magnesium sulfate, and the ether was evaporated in vacuo, leaving 0.65 gm (23.0% of theory) of an initially oily residue which crystallized after a short period of time. The crystalline product had a melting point of 59°-61° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-])=O)=[C:8]([NH:11][C:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]1=[O:25].[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:27]1([NH:33][C:34]([N:4]2[C:5]3[CH:6]=[C:7]4[N:22]=[C:12]([C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)[NH:11][C:8]4=[CH:9][C:10]=3[C:2]([CH3:26])([CH3:1])[C:3]2=[O:25])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)C3(C)C)cc1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4C(=O)Nc2ccccc2)cc1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 21.7 %

Procedure:
A solution of N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methoxy-benzamide (100 mg) and phenyl isocyanate (35 mg; 0.3 mmol) in dry toluene (2 ml) is stirred in a microwave apparatus at 150° C. for 900 s. The mixture is filtered and concentrated in vacuo. The residue is dissolved in acetic acid (2 ml), iron (115 mg; powder) is added and the mixture is again stirred in a microwave apparatus at 150° C. for 900 s to achieve reduction of the nitro function and ring closure. The mixture is filtered and concentrated in vacuo. The desired compound (26 mg) is obtained by preparative RP-HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([CH:12]([N:16]2[CH:19]([S:20][N:21]3[C:25](=[O:26])[C:24]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]4[C:22]3=[O:31])[CH:18]([NH:32][C:33](=[O:42])[CH2:34][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]2=[O:43])[C:13]([CH3:15])=[CH2:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:46]N1C(=O)CCC1=O>ClCCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([CH:12]([N:16]2[CH:19]([S:20][N:21]3[C:22](=[O:31])[C:23]4=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]4[C:25]3=[O:26])[CH:18]([NH:32][C:33](=[O:42])[CH2:34][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]2=[O:43])[C:13]([CH2:15][Br:46])=[CH2:14])=[O:11])=[CH:44][CH:45]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Solvent: ClCCCl
Product: C=C(CBr)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Yield: 25 %

Procedure:
A mixture of 1.26 g (2 mmoles) of 1-(1p-nitro-benzyloxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one, 0.71 g (4 mmoles) of N-bromosuccinimide, 50 mg (0.3 mmole) of azoisobutyronitrile and 80 ml of 1,2-dichloroethane was heated in the dark under nitrogen at 70° C for 3 hours. After washing twice with a sodium metabisulfite solution and with water, the reaction mixture was dried and concentrated to a small volume. After treating the residue with hexane, 1.2 g of crude material was isolated which was purified with column chromatography [silica gel, 10:1 (v/v) methylene chloride ethyl acetate] to obtain 0.33 g (0.5 mmole; 23% yield) of 1-(1-p-nitrobenzyloxycarbonyl-2-bromomethylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothioazetidin-2-one.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.[C:23]([C:25]1[CH:26]=[C:27](Br)[CH:28]=[CH:29][C:30]=1[F:31])#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[F:31][C:30]1[CH:29]=[CH:28][C:27]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)=[CH:26][C:25]=1[C:23]#[N:24]
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: N#Cc1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(F)c(C#N)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 80 °C

Procedure:
Prepared according to the method described in Example 12 from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.4 g, Example 33), 3-cyano-4-flurobromobenzene (0.399 g), ethanol (10 ml), 2M aqueous sodium carbonate (1.66 ml) and tetrakis(triphenylphosphine)palladium (0) (0.3 g) with heating at 80° C. for 3 hours. After work-up, the residue was purified by normal-phase HPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid. (0.24 g).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH:10]([NH2:13])([CH3:12])[CH3:11].[OH-].[Na+]>>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:13][CH:10]([CH3:12])[CH3:11])[N:7]=1
Reactant: CC(C)N
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Nc1nc(Cl)nc(Cl)n1

Procedure:
In stage (a) cyanuric chloride, isopropylamine and sodium hydroxide are reacted to produce 2,4-dichloro-6-isopropylamino-s-triazine according to the following scheme ##STR3##
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.O[CH:24]1[CH2:28][CH2:27][O:26][CH2:25]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH:24]3[CH2:28][CH2:27][O:26][CH2:25]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OC1CCOC1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2C1CCOC1
Yield: 34.8 %

Procedure:
Compound 97 was synthesised from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (50 mg, 0.16 mmol) following a similar procedure outlined in Example 86, using 3-hydroxytetrahydrofuran (28 mg, 0.32 mmol) instead of oxetan-3-ol. Compound 97 was purified using preparative HPLC followed by chromatography (silica gel, gradient CH2Cl2), yielding Compound 97 as an off-white solid (21 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](=O)[NH:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C)C=O.C(Cl)([Cl:17])=O.N>C1(C)C=CC=CC=1.O>[Cl:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1
Reactant: O=C(Cl)Cl
Reactant: O=c1[nH]cc(Cl)cc1Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Clc1cnc(Cl)c(Cl)c1

Procedure:
According to a preferred embodiment of the process of the invention, 3,5-dichloro-2-pyridone is suspended in toluene, the water present is separated by azeotropic distillation, 0.05-0.15 mol of N,N-dimethylformamide per mol of 3,5-dichloro-2-pyridone is added, and 1.0-1.3 mols of phosgene per mol of 3,5-dichloro-2-pyridone are introduced at 75°-80° C. After the addition of phosgene has been completed, the reaction mixture is allowed to react for a further one hour at 75°-80° C., and the excess phosgene is subsequently reacted with aqueous ammonia. The phases are afterwards separated, the solvent is distilled off from the organic phase, and 2,3,5-trichloropyridine is obtained as a melt.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][CH:8]=[CH:7]2.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>ClCCl>[Br:1][C:2]1[C:10]2[CH2:9][CH:8]3[O:20][CH:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:11]
Reactant: Fc1ccc2c(c1Br)CC=C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Fc1ccc2c(c1Br)CC1OC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A solution of Example 25C (500 mg, 2.347 mmol) in dichloromethane (30 mL) was cooled to 0° C. and a solution of mCPBA (631 mg, 2.82 mmol) in dichloromethane (5 mL) was added. The mixture was warmed to ambient temperature and stirred for 2 hours. The mixture was diluted with dichloromethane (50 mL), quenched with a saturated solution of Na2S2O3 and partitioned. The organic portion was dried (MgSO4), filtered, concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution with 10% EtOAc/hexanes) to provide the title product (316 mg, 1.38 mmol, 59%). MS (DCI) m/z 230 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.C(N)=O.CN(C=NC=[N+](C)C)C.[Cl-].OC1C2C(=CC=CC=2)N=CN=1.P(Cl)(Cl)(Cl)(Cl)[Cl:36]>O1CCOCC1.P(Cl)(Cl)(Cl)=O>[Cl:36][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][N:3]=1
Reactant: c1ccc2ncncc2c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: CN(C)C=NC=[N+](C)C
Agent: Oc1ncnc2ccccc12
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: NC=O
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ccccc12

Procedure:
Quinazoline starting materials are commercially available or readily prepared using conventional procedures. For example, 4-hydroxy quinazolines can be prepared from commercially available anthranilic acids via condensation with excess formamide at reflux (M. Endicott et al. J. Am. Chem. Soc., 1946, 68, 1299). Alternatively hydroxy quinazolines can be prepared in dioxane at reflux using Gold's reagent (J. Gupton; Correia, K.; Hertel, G. Synthetic Communications, 1984, 14, 1013). Once in hand, the 4-hydroxy quinazoline is chlorinated under standard conditions, using for example phosphorus pentachloride in phosphorus oxychloride, to provide 4-chloroquinazoline starting materials. The 4-hydroxy quinazoline derivatives can advantageously be chlorinated using the chlorinating reagents and procedure disclosed in U.S. Pat. No. 4,230,644.
Reaction SMILES: COCCOCCOCCOC.C[Si](Br)(C)C.Br[C:19]([F:26])([F:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].Br[C:28]1[N:29]=[CH:30][C:31]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[N:32][CH:33]=1.[Cl-].[Na+].Cl>CC(N(C)C)=O.[Zn].[Cu](Br)Br.C1(C)C=CC=CC=1>[CH2:23]([O:22][C:20](=[O:21])[C:19]([C:28]1[N:29]=[CH:30][C:31]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[N:32][CH:33]=1)([F:26])[F:25])[CH3:24]
Reactant: CC(C)OC(=O)c1cnc(Br)cn1
Reactant: CCOC(=O)C(F)(F)Br
Agent: Br[Cu]Br
Agent: C[Si](C)(C)Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: COCCOCCOCCOC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(F)(F)c1cnc(C(=O)OC(C)C)cn1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a mixture of zinc powder (2.29 g, 0.035 mol) and triglyme (17.5 mL) was added TMSBr (0.45 mL, 0.004 mol) under nitrogen, and the mixture was stirred at 70° C. for 1.5 h. After the reaction mixture was cooled to room temperature, ethyl bromodifluoroacetate (5.41 mL, 0.042 mol) was added while maintaining the internal temperature at 22 to 27° C., and the mixture was stirred at 20° C. for 30 min and then cooled to 0° C. After addition of a solution of isopropyl 5-bromopyrazine-2-carboxylate (II, 4.48 g, 0.017 mol) in DMA (51 mL) to the reaction mixture, the resulting mixture was warmed to 20° C. Copper bromide (CuBr, 5.02 g, 0.035 mol) was added in fifth portions over 1 h followed by stirring the mixture for 30 min. The resulting mixture was transferred into a pre-cooled (ice bath) mixture of an aqueous sodium chloride solution (6.3%, 55.5 g), concentrated hydrochloric acid (14.7 mL) and toluene (70 mL), and the resulting mixture was vigorously stirred. After phase separation, the organic layer was washed twice with an aqueous sodium chloride solution (5.7%, 35 g and 2.9%, 35 g) to afford 74.2 g of a toluene solution of isopropyl 5-(2-ethoxy-1,1-difluoro-2-oxoethyl)pyrazine-2-carboxylate (III).
Reaction SMILES: [OH-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.CO>C1COCC1>[O:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCOCC1
Yield: 84.7 %

Procedure:
Sodium hydroxide (7.05 mL, 12.5 M, 88 mmol) was added dropwise to a solution of methyl tetrahydro-2H-pyran-4-carboxylate (2.54 g, 17.6 mmol) in a mix of methanol (30 mL) and THF (30 mL) at 25° C. The reaction was stirred over the weekend. The THF/MeOH was then evaporated and the crude was washed with Et2O (2×). The aqueous layer was acidified and extracted with EtOAc (2×); the organics were dried over Na2SO4, filtered and the solvent was evaporated to give the title compound (D8) (1.94 g, 76%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][Cl:9])#[N:2].Cl>>[ClH:9].[C:1]([C:3]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH:15][CH:11]([CH3:12])[CH3:4])#[N:2]
Reactant: CCCCCC(=O)Nc1cccc(C#N)c1OCC(O)CCl
Agent: Cl
Product: CCCCCC(=O)Nc1cccc(C#N)c1OCC(O)CNC(C)C

Procedure:
From 12.9 gm (0.04 mol) of 1-(2-cyano-6-hexanoylamino-phenoxy)-3-chloro-2-propanol and 13.6 ml (0.16 mol) of isopropylamine, 5.3 gm of amino-alcohol were obtained, which were converted into the hydrochloride by the addition of HCl. Yield: 4.7 gm; M.p.: 107° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=O)[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].O.NN.[OH-].[K+].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc(C(=O)C(=O)O)cc1F
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CSc1ccc(CC(=O)O)cc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 71.3 %

Procedure:
2-(3-Fluoro-4-(methylthio)phenyl)-2-oxoacetic acid (4.5 g, crude) was added to hydrazine hydrate (5.1 mL, 5 eq) at −50° C. The contents were heated to 80° C., KOH (2.7 g, 2.3 eq) was added and the overall reaction mixture was stirred for 12 h at 100° C. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.8). On completion of the reaction, to the contents was added water and ethyl acetate and the layers were separated. The aqueous layer was acidified with diluted HCl at 0-5° C., the precipitate was filtered and dried to yield 2-(3-fluoro-4-(methylthio)phenyl)acetic acid as a white colored solid (3 g, 71%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].[CH2:36]([O:38][CH2:39]CCN)[CH3:37]>>[CH2:36]([O:38][CH2:39][CH2:2][CH2:1][NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:37]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Reactant: CCOCCCN
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCCCOCC)C(O)C3O)c2n1

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 1, step c) and 3-ethoxypropylamine.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].O>C(=O)([O-])[O-].[K+].[K+].ClCCl>[Cl:1][CH2:2][C:3]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:8]1)=[O:4]
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 121.1 %

Procedure:
Chloroacetyl chloride (4.0 cm3, 50.18 mmol) was added dropwise to a vigorously stirred mixture of 4-amino-1-(2-[indol-3-yl]ethyl)piperidine (12.10 g, 49.8 mmol), potassium carbonate (7.0 g 50.72 mmol) water (100 cm3) and dichloromethane (300 cm3). After 3/4 hour more chloroacetyl chloride (0.5 cm3, 6.27 mmol) and potassium carbonate (0.5 g, 3.62 mmol) were added and stirring continued for a further 3/4 hour. The organic phase was separated, washed with water, dried over magnesium sulphate and evaporated to give 2-chloro-N-[1-[2-(1H-indol-3-yl)ethyl]-4-piperidinyl]acetamide (19.29 g crude)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][C:33]([NH2:35])=[NH:34])=[CH:31][C:26]=2[O:25][CH2:24]1>>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][C:33]3[N:35]=[CH:13][C:10]4[CH2:9][C:8](=[O:17])[NH:7][C:6]5[CH:18]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:11]=4[N:34]=3)=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1ccc2c(c1)OCO2
Solvent: O=[N+]([O-])O
Product: O=C1Cc2cnc(Nc3ccc4c(c3)OCO4)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-benzo[1,3]dioxol-5-yl-guanidine nitrate were converted to I-34 (32%): HRMS Calcd. for C19H13ClN4O3: 381.0754, Found 381.0759.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>ClCCl>[C:38]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of 504.9 mg (1.20 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 15 ml of dichloromethane were added 0.50 ml (3.6 mmol) of triethylamine and 0.17 ml (1.44 mmol) of benzoyl chloride, followed by overnight stirring at room temperature in an atmosphere of argon. After addition of water, the reaction mixture was extracted with dichloromethane, and the organic layer was washed with water and dried over sodium sulfate. After the solvent was evaporated, the residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[NH2:37][CH2:38][CH2:39][C:40]#[N:41]>>[C:40]([CH2:39][CH2:38][NH:37][C:23](=[O:24])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:41]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: N#CCCN
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCC#N)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-aminopropionitrile.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][N:27](C3CCCCO3)[CH:28]=2)=[CH:12][C:11]=1[F:35])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:35][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[CH:14]=[C:15]([F:16])[C:10]=1[S:7]([NH:6][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CCCC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1c(F)cc(O[C@H]2CCCC[C@@H]2c2cn[nH]c2)cc1F
Yield: 53.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide (100 mg, 0.171 mmol) prepared in Example 94a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL), dichloromethane (1.0 mL) and methanol (1.0 mL), to yield the title compound (40 mg, 54%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19](/[CH:20]=[C:9]2/[C:10](=[O:11])/[C:12](=[CH:1]/[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)/[O:13][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:8]/2)=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(/C=C2\Oc3ccc(C)cc3O/C(=C\c3ccc(OC)cc3)C2=O)cc1

Procedure:
Calone is reacted with 4-methoxybenzaldehyde analogously to the reaction conditions of Example 1, giving 2,4-bis[1-(4-methoxyphenyl)meth-(Z)-ylidene]-7-methylbenzo[b]-1,4-dioxepin-3-one