Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:44]([Cl:46])[Cl:45]>C(O)(=O)C>[NH3:1].[CH2:44]([Cl:46])[Cl:45].[CH:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)[CH2:24][CH2:23]1)([CH3:21])[CH3:20]
Reactant: CC(C)N1CCNCC1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Product: N
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (200 mg), 1-isopropyl-piperazine (100 mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (290 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (225 mg). 1H NMR (400 MHz, CDCl3): 7.19 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 3.98 (t, J=6.6 Hz, 2H), 3.43 (s, 2H), 2.63 (m, 1H), 2.53 (br, 4H), 2.46 (m, 4H), 2.39 (br, 4H), 1.96 (m, 2H), 1.58 (m, 4H), 1.46-1.40 (m, 2H), 1.03 (d, J=6.5 Hz, 6H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18]C(=O)OC(C)(C)C)[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[ClH:26]>C(Cl)Cl.O1CCOCC1>[Cl-:26].[C:1]([N:4]1[CH2:5][CH2:6][NH+:7]([CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH2:18])[CH:12]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)N1CCN(Cc2cc(C)nc(NC(=O)OC(C)(C)C)c2)CC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N1CC[NH+](Cc2cc(C)nc(N)c2)CC1
Product: [Cl-]
Temperature: 0 °C

Procedure:
tert-Butyl 4-[(4-acetylpiperazin-1-yl)methyl]-6-methylpyridin-2-ylcarbamate (13-3) was dissolved in CH2Cl2 and the solution was cooled to 0° C. 4.0M HCl in dioxane was added and the solution allowed to warm to room temperature. The reaction was concentrated in vacuo to afford 1-acetyl-4-[(2-amino-6-methylpyridin-4-yl)methyl]piperazin-4-ium chloride. 1-Acetyl-4-[(2-amino-6-methylpyridin-4-yl)methyl]piperazin-4-ium chloride (0.095 g, 0.30 mmol) was dissolved in 2 mL THF. 2-Chloro-1,3-thiazole-5-carbonitrile (0.051 g, 0.36 mmol) and sodium hydride (60% dispersion in mineral oil) (0.028 g, 1.19 mmol) were added and the solution was heated to 75° C. After 4 hours more 2-chloro-1,3-thiazole-5-carbonitrile (0.051 g, 0.36 mmol) was added. After 5.5 hours the solution was allowed to cool to room temperature and concentrated in vacuo. Acetic acid (0.070 mL, 1.19 mmol) was added and was concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient, 5-100% CH3CN/H2O+0.1% TFA). The fractions containing the desired compound were concentrated to dryness to afford the TFA salt of 13-4. TFA salt: 1H NMR (CD3OD) δ 8.04 (s, 1H), 6.99 (s, 1H), 6.95 (s, 1H), 4.13 (bs, 2H), 3.74 (bs, 2H), 3.06 (bs, 6H), 2.61 (s, 3H), 2.13 (s, 3H). [M+H]+=357.1494.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:17][C:6]2=[CH:7][C:8]3[C:9]([CH3:16])=[CH:10][C:11]([CH3:15])=[N:12][C:13]=3[CH:14]=[C:5]2[CH:4]=[CH:3]1.CN1C=CN=C1.Cl[O-].[Na+].S([O-])([O-])(=[O:30])=S.[Na+].[Na+]>C(OCC)(=O)C.O>[O:30]1[C@@H:4]2[C:5]3[C:6]([O:17][C:2]([CH3:18])([CH3:1])[C@H:3]12)=[CH:7][C:8]1[C:9]([CH3:16])=[CH:10][C:11]([CH3:15])=[N:12][C:13]=1[CH:14]=3
Reactant: Cc1cc(C)c2cc3c(cc2n1)C=CC(C)(C)O3
Reactant: O=S([O-])([O-])=S
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)c2cc3c(cc2n1)[C@H]1O[C@H]1C(C)(C)O3
Yield: 68 %

Procedure:
To a solution of 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline (4.64 g, 19.4 mmol) in ethyl acetate (70 mL), N-methyl imidazole (0.303 mL, 3.88 mmol) and Ph,Ph salen manganese complex (201 mg, 0.194 mmol) were added at room temperature and sodium hypochlorite aqueous solution (25.6 g, 1.513 mol/kg, 38.8 mmol) was added dropwise in water bath, and the resulting mixture was stirred in water bath for 1 hour. Further, in water bath, sodium hypochlorite aqueous solution (25.6 g, 1.513 mol/kg, 38.8 mmol) was added, and the resulting mixture was stirred in water bath for 1 hour. Upon the completion of the reaction, sodium thiosulfate aqueous solution was added to the reaction solution, the resulting mixture was filtered through celite and extracted. The organic phase was washed with sodium hydrogencarbonate aqueous solution and then with sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=1/3) and the aimed product was obtained (yield: 68%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:20][C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[CH2:23]Br>>[F:20][C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[CH2:23][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(F)ccc2F)c(=O)[nH]c1=O
Yield: 47.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (185 mg, yield: 47.9%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:26][C:27](=O)[CH3:28])(=O)C.[C:30](OCC)(=O)C>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[NH:22][C:27](=[O:26])[CH2:28][CH3:30])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)=O
Product: CCC(=O)Nc1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-Benzyl-4-(2-amino-4-fluoro-phenylamino)-piperidine (6 g) in ethyl acetate (50 ml) at room temperature was added acetic anhydride (3.3 ml). After 2 h, the reaction was concentrated in vacuo, and the crude oil partitioned between 2:1 DCM and water (150 ml) which was made alkaline with NaOH(aq). The organic layer was separated, washed with water and dried followed by in vacuo concentration to yield 7 g of the title compound as a yellow oil. The compound was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][C:5]=1[F:11].CN(C)C=O.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1.C(N(CC)CC)C>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:18][C:19]2[CH:24]=[N:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[N:6][C:5]=1[F:11]
Reactant: COC(=O)c1ccc(F)nc1F
Reactant: COc1ccc(N)cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2ccc(OC)nc2)nc1F
Temperature: -40 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a round bottom flask, 2,6-difluoro-nicotinic acid methyl ester (52, 2.00 g, 11.6 mmol) is combined with 20.0 mL of N,N-dimethylformamide under an atmosphere of nitrogen at −40° C. To this, 5-amino-2-methoxypyridine (53, 1.55 g, 12.5 mmol) and triethylamine (5.0 mL, 36.0 mmol) are added and the reaction stirred at −40° C., then warmed to room temperature and reacted overnight. The reaction is then heated to 50° C. over the weekend, then at 70° C. for 3 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (54, 1.20 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH:9]([CH3:31])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][C:20]=2[CH3:28])=[C:15]([C:29]#[CH:30])[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[N:40]([CH3:44])[C:39](=[O:45])[CH:38]=[CH:37]2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[N:7]([CH3:8])[CH:9]([CH3:31])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][C:20]=2[CH3:28])=[C:15]([C:29]#[C:30][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH3:44])[C:39](=[O:45])[CH:38]=[CH:37]3)[N:14]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)ccc1-c1c(C)nc2ccccn12
Reactant: Cn1c(=O)ccc2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccn2c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2c(ccc(=O)n2C)c1

Procedure:
A mixture of tert-butyl-N-[1-[[6-ethynyl-5-(2-methylimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate F1a (60 mg, 0.14 mmol), 6-bromo-1-methylquinolin-2-one (82 mg, 0.35 mmol), copper(I) iodide (2.6 mg, 0.01 mmol), Dichlorobis(triphenylphosphine)palladium(II) (8.1 mg, 0.01 mmol) and DIPEA (94 μl, 0.55 mmol) is stirred under argon atmosphere in NMP (0.5 ml) for 2 h at 50° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 17 mg (21%). HPLC-MS: M+H=591; tR=1.79 min (*Method—4).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].FC1C(OC)=C(F)C=C2C=1C=CN2C.CCN(CC)CC>C(Cl)Cl>[O:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: COc1c(F)cc2c(ccn2C)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]

Procedure:
Combine phenyl boronic acid (7.32 g, 60 mmol), 4-methyl-3-nitrophenol (4.5 g, 30 mmol), and Cu(oAC)2—H2O (6 g, 30 mmol) in 30 mL CH2Cl2 and treat with 6 g 4 A molecular sieves powder. Add Et3N (15.18 g, 150 mmol) dropwise, and stir the reaction at ambient temperature for 8 days. Dilute with 100 mL CH2Cl2 and filter through celite and concentrate to dryness. Purification by chromatography using 2% EtOAc in hexanes gave the desired product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:25])[C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
18.2 g (0.056 mol) of 5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 150 ml of dry acetone, treated with 18 g of powdered potassium carbonate and 9 ml of methyl iodide and stirred at room temperature for 21/2 hours. Subsequently, the reaction mixture is evaporated and the residue is partitioned between methylene chloride and water. After separating the organic phase, it is extracted several times more with methylene chloride. The combined organic extracts are then dried and evaporated. The residue is recrystallized from benzene/hexane/petroleum ether and gives 5-(o-fluorphenyl)-1,3-dihydro-1,3,3-trimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 128°-129°.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:21](Cl)(=[O:23])=[O:22])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2].[NH3:25].O1CCOCC1>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:21]([NH2:25])(=[O:23])=[O:22])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)OCCc1cc(S(=O)(=O)Cl)c2c([N+](=O)[O-])cccc2c1Br
Solvent: C1COCCO1
Product: CC(=O)OCCc1cc(S(N)(=O)=O)c2c([N+](=O)[O-])cccc2c1Br
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Solid 3-(2-acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-1-sulfonyl chloride (5.00 g, 11.45 mmol) was added at room temperature to 0.5M ammonia in dioxane (92 mL, 46 mmol). After stirring at room temperature for 40 minutes, the mixture was evaporated under vacuum to a residue which was mixed with water (100 mL), sonicated, and filtered. The collected pale-yellow solid was washed with water (2×20 mL) and vacuum dried to afford the title compound (4.75 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH:30]1[CH2:44][CH2:43][CH2:42][C@H:31]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([N:30]1[CH2:44][CH2:43][CH2:42][C@H:31]1[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
A solution of t-butoxycarbonyl-L-alanine (2.48 g., 13.1 mmole) in 23 ml. of dry chloroform at -15° (ice-salt bath) is treated with N-methylmorpholine (1.47 ml., 13.1 mmole) followed by isobutyl chloroformate (1.8 ml., 13.1 mmole) to give a precipitate. After 15 minutes, L-proline, phenylmethyl ester, hydrochloride salt (3.18 g., 13.1 mmole) and N-methylmorpholine (1.47 ml., 13.1 mmole) are added. Gas evolution ensues and the mixture is kept below -10° for one hour, then allowed to warm to room temperature, and stirred overnight under argon. The mixture is diluted with ethyl acetate, filtered, and the filtrate evaporated to dryness. The residue is taken up in ethyl acetate and washed successively with 5% potassium bisulfate, saturated sodium bicarbonate, saturated sodium chloride, dried (Na2SO4) and evaporated. The residue is purified by flash chromatography on silica gel (210 g.) eluting with ethyl acetate/hexane (1:2) to give t-butoxycarbonyl-L-alanyl-L-proline, phenylmethyl ester (4.37 g.) as a colorless oil; Rf (ethyl acetate/hexane, 1:1) is 0.47.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].[O:16]1[CH2:21][CH2:20][CH2:19][O:18][CH:17]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3Cl)[CH:29]=2)=[N:26][CH:27]=1>CS(C)=O.O>[O:16]1[CH2:21][CH2:20][CH2:19][O:18][CH:17]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3[O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=3[F:9])[CH:29]=2)=[N:26][CH:27]=1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCCO4)cn3)sc12
Reactant: Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To a solution of 4-amino-2-fluorophenol (4) (7.42 g, 58.4 mmol) in DMSO (65 mL) was added potassium tert-butoxide (7.75 g, 69.0 mmol)). After 30 min, intermediate 29 (17.67 g, 53.1 mmol) was added and the reaction mixture was heated at 100° C. for 1.5 h, cooled down to room temperature, poured in water (300 mL) at 40-45° C. and stirred for 30 min. The solid was collected by filtration, washed with water (2×30 mL) and dried for 2 h. This material was triturated with ether (60 mL), to afford intermediate 31 (19.80 g, 88% yield) as a brown solid. MS (m/z): 424.1 (M+H).
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[CH:7]([N:10]=[C:11]=[N:12][CH:13]([CH3:15])[CH3:14])([CH3:9])[CH3:8]>>[CH2:1]([N:5]([CH3:6])[C:11]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:10][CH:7]([CH3:9])[CH3:8])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N=C=NC(C)C
Reactant: CCCCNC
Product: CCCCN(C)C(=NC(C)C)NC(C)C
Yield: 100 %

Procedure:
A mixture of 32.68 g of N-butyl-N-methylamine (0.375 mol) and 23.66 g of diisopropylcarbodiimide (0.1875 mol) is refluxed for 3 h. GC analysis then shows a conversion of greater than 99.5% of the diisopropylcarbodiimide. The colorless final mixture is concentrated at 60° C. under 5 mbar for 2 h so as to give 40 g of a colorless and virtually odorless liquid of low viscosity, corresponding to the expected guanidine (yield 100%).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:5]([O:24][CH3:25])[CH:4]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH2:32].CN1C=CN=C1>CC#N>[F:1][CH:2]([F:26])[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:32][C:28]4[S:27][CH:31]=[CH:30][N:29]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: Nc1nccs1
Reactant: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(S(=O)(=O)Cl)ccc12
Agent: Cn1ccnc1
Solvent: CC#N
Product: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
A solution of 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)quinazoline-7-sulfonyl chloride (0.334 g, 0.829 mmol) and thiazol-2-amine (0.249 g, 2.488 mmol) in 4 mL MeCN was placed under argon and was treated with 1-methylimidazole (0.081 ml, 0.829 mmol). After stirring for 3 hours at room temperature, LC/MS showed mostly product, so the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18 30μ, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (0.171 g, 0.367 mmol, 44.2% yield). 1H NMR (MeCN-d3) δ: 9.42 (s, 1H), 8.52 (s, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.38 (d, J=5.4 Hz, 1H), 7.32 (d, J=9.9 Hz, 1H), 6.93-7.24 (m, 2H), 6.64 (d, J=4.7 Hz, 1H), 3.70-3.73 (s, 3H); (M+H)+=467.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([CH3:12])[OH:11])=[CH:4][CH:3]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Si:13]([O:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)CCc1ccc(Br)cc1
Product: CC(CCc1ccc(Br)cc1)O[Si](C)(C)C(C)(C)C
Yield: 73.1 %

Procedure:
3-(4-Bromophenyl)-1-methyl-1-propanol (2.186 g) and t-butyldimethylsilyl chloride (1.575 g) were treated in the same manner as in Example 163-1, to give 4-[3-(t-butyldimethylsilyloxy)-3-methylpropan-1-yl]-1-bromobenzene as a colorless oil (2.396 g). Subsequently, the resulting compound was treated with 7-(1-ethylpiperazin-4-yl)-5-bromofuro[2,3-c]pyridine (404 mg), in the same manner as in Example 167-2, to give the hydrochloride of the title compound as colorless crystals (recrystallized from ethanol/isopropyl ether) (390 mg, yield; 69%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([S:27]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:45]4[CH2:46][CH2:47][CH:42]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH2:43][CH2:44]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=23)=[CH:12][CH:13]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(Cl)nn45)ccnc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCC(N7CCCC7)CC6)nn45)ccnc32)cc1
Temperature: 140 °C
Yield: 78.1 %

Procedure:
A mixture of 0.15 g (0.29 mmol) of 6-chloro-2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine, prepared according to the method described in step 3.2 of Example 3, and 0.179 g (1.16 mmol) of 4-pyrrolidin-1-ylpiperidine is heated under reflux for 40 hours at 140° C. The reaction medium is cooled. The crystalline solid which forms on cooling is triturated in 1 ml of diisopropyl ether and is isolated by centrifugation and removal of the supernatant in order to give 0.144 g of 2-(4-fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine, used without additional purification in the remainder of the synthesis.
Reaction SMILES: [CH2:1]1[C:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH:8]=2)[CH2:3][CH2:2]1.[H][H]>[Pd].[Pt].[Rh]>[CH2:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C2CCCC2CCC1
Reactant: [H][H]
Agent: [Pd]
Agent: [Pt]
Agent: [Rh]
Product: C1CCC2CCCC2C1

Procedure:
Hydrogenating the tetrahydroindane derivative with hydrogen in the presence of a palladium-, platinum-, or rhodium-containing hydrogenation catalyst to produce a perhydroindane derivative;
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5][C:6]1[NH:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[N:7]=1.ClC1C=CC=C(C(OO)=[O:27])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([C:6]1[NH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=2[N:10]=1)=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ccccc1CSc1nc2c([nH]1)CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1ccccc1CS(=O)c1nc2c([nH]1)CCCC2
Temperature: 0 °C
Yield: 45.4 %

Procedure:
To a solution of 1.3 g (5.0 mmol) of 2-(2-aminobenzylthio)-4,5,6,7-tetrahydro-1H-benzimidazole in 13 ml of chloroform was added under stirring and chilling with ice (5°-10° C.) 1.08 g (5.0 mmol) of 80% m-chloroperbenzoic acid for approx. 15 min. The mixture was further stirred for 15 min., and to the mixture was added saturated aqueous sodium hydrogencarbonate solution. Thus precipitated solid was collected by filtration and washed with two portions of water and one portion of acetonitrile. There was obtained 590 mg of a crude product. The chloroform portion of the mother liquor was taken out and subjected to extraction using 10 ml of 0.2N aqueous NaOH. The aqueous alkaline solution was made ammonia alkaline by addition of 20% aqueous NH4Cl to precipitate a crystalline product. The crystalline product was collected and washed successively with two portions of water and one portion of acetonitrile to give 130 mg of a crude product. The crude products were combined and dissolved in 30 ml of 0.5N aqueous NaOH. The aqueous solution was washed with three portions of chloroform and then made ammonia-alkaline by addition of 20% aqueous NH4Cl to precipitate a crystalline product. The obtained product was washed successively with two portions of water, one portion of acetonitrile and one portion of diethyl ether and then dried under reduced pressure at 35° C. for 8 hrs. to 624 mg of the desired compound as a white crystalline product, yield 45.4%.