Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[N:13]3[N:21]=[CH:22][C:23]([CH:24]=O)=[C:12]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:19][CH2:20]3)[N:13]3[N:21]=[CH:22][C:23](/[CH:24]=[C:32]4/[C:30](=[O:31])[NH:29][C:27](=[O:28])[NH:26]/4)=[C:12]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1cnn2c(NCC3CC3)cc(Nc3ccc(F)c(Cl)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)/C(=C/c2cnn3c(NCC4CC4)cc(Nc4ccc(F)c(Cl)c4)nc23)N1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
To 5-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (40 mg, 0.09 mmol) in 1.0 mL of ethanol was added hydantoin (9 mg, 0.09 mmol) and piperidine (8 ul). The reaction was heated at 80° C. overnight, cooled to room temperature, filtered, and washed with ethanol to yield 20 mg (31% yield) (Z)-5-((5-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione as a yellow powder. LCMS (M+1=442)
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH3:29]>C(#N)C>[CH2:28]([O:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH3:29]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(OC)ccc(-c2cccc3c2CCC3=O)c1OC
Temperature: 80 °C
Yield: 28.5 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (116 mg, 0.843 mmol) and ethyl iodide (131 mg, 0.843 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (25 mg, 28.7%).
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH:16]=[N:17][C:5]=2[C:4](=[O:18])[O:3]1.[H-].[Na+].[Cl:21][C:22]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:23]=1[CH2:24]Cl>CN(C=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:23]=1[CH2:24][N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:7]2[C:6]3[CH:2]([CH3:1])[O:3][C:4](=[O:18])[C:5]=3[N:17]=[CH:16][C:8]1=2
Reactant: CC1OC(=O)c2ncc3[nH]c4ccccc4c3c21
Reactant: ClCc1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1OC(=O)c2ncc3c(c21)c1ccccc1n3Cc1cc(Cl)ccc1Cl
Yield: 33.1 %

Procedure:
6-(2,5-Dichlorobenzyl)-1-methyl-1,6-dihydro-3H-furo[3′,4′:5,6]pyrido[3,4-b]indol-3-one was prepared using Method A from 1-methyl-1,6-dihydro-3H-furo[3′,4′:5,6]pyrido[3,4-b]indol-3-one (9 mg, 0.038 mmol), NaH (0.046 mmol, 2 mg of 60 wt. % suspension in mineral oil) and 2,5-dichlorobenzyl chloride (9 mg, 0.046 mmol) in DMF (1 mL). Purification of the crude product by preparative thin layer chromatography with hexane/ether (2:1) as eluent furnished the desired product (5 mg, 33% yield) as a yellow solid. 1H NMR (CDCl3) δ8.93 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.37-7.46 (m, 3H), 7.16 (d,J=2.2 Hz, 1H), 6.42 (d,J=2.2 Hz, 1H), 6.05 (q,J=6.6 Hz, 1H), 5.70 (s, 2H), 1.92 (d,J=6.6 Hz, 3H); MS (APCI; (M+H)+) m/z 397.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([O:29][CH3:30])[CH:18]=2)[CH2:11][C@H:10]([NH2:35])[CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:51]=[C:50](Cl)[N:49]=[CH:48][N:47]=1>CN(C=O)C>[CH:31]1([N:15]([CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([O:29][CH3:30])[CH:18]=2)[C:14]([C@@H:12]2[CH2:11][C@H:10]([NH:35][C:50]3[CH:51]=[C:46]([Cl:45])[N:47]=[CH:48][N:49]=3)[CH2:9][NH:8][CH2:13]2)=[O:34])[CH2:32][CH2:33]1
Reactant: Clc1cc(Cl)ncn1
Reactant: COCCCOc1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OC(C)(C)C)C2)C2CC2)cc(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCOc1cc(CN(C(=O)[C@H]2CNC[C@@H](Nc3cc(Cl)ncn3)C2)C2CC2)cc(OC)c1
Reaction time: 16 h

Procedure:
To a solution of (3S*,5R*)-3-Amino-5-{cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.10 mmol) in DMF (0.5 mL) are added i-Pr2NEt (26 uL, 0.15 mmol) and 4,6-dichloropyrimidine (23 mg, 0.15 mmol). After stirring for 16 h, the reaction mixture is quenched by H2O (30 mL) and extracted with EtOAc/Et2O (c.a. 1:1, 60 mL). The organic phase is successively washed with 5% KHSO4aq, 5% NaHCO3aq, H2O, and brine, then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo. The residue is purified by silica gel column chromatography to give Boc protected title compound. MS: 604 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.88 min. The Boc protected compound is treated with 4N HCl-1,4-dioxane to give the title compound as a white amorphous solid. MS: 504 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.66 min.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CO[C:13](=O)[CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][O:15][CH2:14][C:13]2[NH:6][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[N:1]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)COCCc1cccc(OC)c1
Reactant: NC(=O)c1cccnc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CCOCc2nc3ncccc3c(=O)[nH]2)c1

Procedure:
In analogy to example 91.3, 2-amino-nicotinamide and [2-(3-methoxy-phenyl)-ethoxy]-acetic acid methyl ester (prepared from 2-(3-methoxyphenyl)ethanol [5020-41-7] in analogy to example 91.1-91.2) reacted in the presence of LiHMDS in THF to yield after purification of the crude product with column chromatography (silica gel, EtOAc) 2-[2-(3-methoxy-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one as white solid. MS (m/e): 312.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.C(N(CC)CC)C.[CH2:35]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)[CH3:36]>C1COCC1>[CH2:35]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([N:25]2[CH2:24][CH2:23][CH:22]([O:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]4[N:12]([C:3]5[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=5[F:1])[N:13]=[CH:14][C:15]=34)[CH2:27][CH2:26]2)=[O:43])=[CH:40][CH:39]=1)[CH3:36]
Reactant: CCOc1ccc(C(=O)Cl)cc1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(=O)N2CCC(Oc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 mL round-bottomed flask fitted with N2 inlet was placed 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.117 mmol) and triethylamine (65 μl) and THF (0.8 mL). The reaction flask was immersed in an ice-bath. 4-Ethoxy-benzoyl chloride (24 mg, 0.129 mmol) was added to the solution and the mixture was stirred 2 h under N2 at 0° C. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was then concentrated under vacuum and purified by column chromatography using EtOAc as eluent to give Compound A184. 1H NMR (CDCl3, 400 MHz) δ 1.43 (t, 3H), 1.96 (m, 2H), 2.17 (m, 2H), 3.13 (s, 3H), 3.55 (m, 2H), 4.06 (m, 2H), 4.12 (m, 2H), 5.71 (m, 1H), 6.92 (d, 2H), 7.43 (d, 2H), 7.92 (m, 3H), 8.33 (s, 1H), 8.62 (s, 1H). Exact mass calculated for C26H26FN5O5S 539.16, found 540.2 (MH+).
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[C:5]1([NH:4][C:2]#[N:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: N#CBr
Reactant: Nc1cccc2ccccc12
Solvent: Cc1ccccc1
Product: N#CNc1cccc2ccccc12
Reaction time: 0.5 h

Procedure:
Cyanogen bromide (4.4 gm, 41.9 mmol) was added in portions to the stirred and ice-bath cooled solution of 1-aminonaphthalene (10.0 gm, 69.8 mmol) in toluene (100 mL). After 0.5 hour, the cooling bath was removed the reaction mixture was stirred at room temperature for 12 hours. The precipitate was filtered and the solid was triturated with water (150 mL) for 0.5 hour. The resulted solid was filtered and washed with water (4×20 mL) and the solid was dried in vacuum oven at 40° C. This material (4.6 gm) was used as such without any further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C@@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](Cl)=[O:14].Cl>N1C=CC=CC=1>[Cl:11][C@@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:14]
Reactant: CC(C)[C@H](Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)[C@H](Cl)C(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 4 h

Procedure:
4-Hydroxybenzoic acid (8.9 g, 0.065 moles) is dissolved in 20 mL of absolute pyridine and 10 g (0.065 moles) of (S)-(+)-2-chloro-3-methylbutyryl chloride are added dropwise with stirring at 0° to 5° C. The mixture is allowed to stand for 4 hours at room temperature and then poured onto ice/conc. HCl (200 g/30 mL). The precipitate is filtered off with suction and washed several times with dilute HCl and water. The residue is recrystallized from methanol/water.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:20](=[O:22])[CH3:21]
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-trifluoromethoxyphenol (10.00 g) was dissolved in chloroform (30 mL), and triethylamine (6.11 mL) and acetic anhydride (6.37 mL) was added to the solution, and then the mixture was stirred at room temperature for 2 hours. To the reaction solution, 10% potassium carbonate was added, and then the mixture was extracted with chloroform. The organic layer was washed with an aqueous 5% citric acid solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (11.39 g) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH:26]([CH3:28])[CH3:27].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:15]([N+:22]([O-:24])=[O:23])=[C:16]([O:21][CH:26]([CH3:28])[CH3:27])[N:17]=[C:18]([CH3:20])[N:19]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(OC(C)C)c([N+](=O)[O-])c(N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
In analogy to the procedure described in example 8, the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1) was treated with 2-bromo-propane, potassium iodide and potassium carbonate in N,N-dimethylformamide at 80° C. to yield the 4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-isopropoxy-2-methyl-5-nitro-pyrimidine as a light yellow solid; m.p. 98-100° C.; MS: [M+H]+=376.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(CC3CC3)c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(CC2CC2)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 76.1 %

Procedure:
4-chloro-N-[(4-chloro-3-{[3-cyano-5-(cyclopropylmethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.027 g, 0.046 mmol) dissolved in DCM (3 mL) was treated with TFA (3 mL) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness and the residue purified by mass-directed HPLC on a SunFire prep C-18 column eluted with 30 to 85% CH3CN/H2O (0.1% formic acid buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(cyclopropylmethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (0.016 g, 0.035 mmol, 76% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.31 (br. s., 1H), 7.61 (s, 1H), 7.20-7.36 (m, 4H), 7.14 (s, 1H), 6.87 (s, 1H), 4.72 (d, J=5.91 Hz, 2H), 2.56 (d, J=6.96 Hz, 2H), 0.84-1.03 (m, 1H), 0.53-0.63 (m, 2H), 0.14-0.27 (m, 2H). LC-MS (ES−) m/z 457.14, 459.12 [M−1]. LC-MS (ES+) m/z 459.09, 461.07 [M+H].
Reaction SMILES: C([C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])=[O:8])=[CH:5][C:4]=1[O:21][CH2:22][O:23][CH3:24])=O.[CH:25]([O:30][CH3:31])([O:28][CH3:29])OC.C(=O)([O-])O.[Na+].O>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:24][O:23][CH2:22][O:21][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:3]=1[CH:25]([O:28][CH3:29])[O:30][CH3:31])[C:7]([NH:9][C:10]([CH3:18])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:11])=[O:8]
Reactant: COC(OC)OC
Reactant: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C(OC)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
4-Formyl-3-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (3.12 g, 9.53 mmol) was dissolved in methanol (30 mL), and the solution was added with trimethyl orthoformate (2.09 mL, 19.1 mmol) and p-toluenesulfonic acid monohydrate (16.4 mg, 0.0952 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3-methoxymethoxy-4-dimethoxymethyl-N-(1-methyl-1-phenylethyl)benzamide (3.61 g, yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([CH:70]([NH2:77])[CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][NH:72]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:72]1[CH2:73][CH2:74][CH2:75][CH2:76][CH:71]1[CH2:70][NH2:77])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(C)(C)OC(=O)C(N)C1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CN)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(tert.-butyloxycarbonyl-aminomethyl)-piperidine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: O=[C:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][NH:4][C:5](=O)[CH2:6][C@H:7]1[N:14]([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)(=[O:17])=[O:16])[CH2:13][C:12]2[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=2[CH2:10][O:9][CH2:8]1.C([O-])(C)=O.[NH4+].C[N:45](C=O)C>O>[C:33]1([C:2]2[N:45]=[C:5]([CH2:6][C@H:7]3[N:14]([S:15]([C:18]4[CH:19]=[CH:20][CH:21]=[C:22]5[C:27]=4[N:26]=[CH:25][CH:24]=[CH:23]5)(=[O:16])=[O:17])[CH2:13][C:12]4[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=4[CH2:10][O:9][CH2:8]3)[NH:4][CH:3]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(C)C=O
Reactant: O=C(C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12)NCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=S(=O)(c1cccc2cccnc12)N1Cc2ccccc2COC[C@H]1Cc1nc(-c2ccccc2)c[nH]1
Temperature: 150 °C
Yield: 30 %

Procedure:
A microwave tube was charged with compound 28a (100 mg, 0.19 mmol), AcONH4 (44 mg, 0.57 mmol) and DMF (3 mL), and then was sealed and heated to 150° C. for 1 h under microwave irradiation. The mixture was taken up in H2O (10 mL) and extracted with DCM (30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by Prep-TLC to give compound 28 (30 mg, 30% yield). LCMS (m/z): 511.1 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[C:14]2=[CH:15][C:16]([CH:18]=[CH:19][C@:13]2([CH3:20])[C@@H:12]2[C@H:4]([C@H:5]3[C@:9]([CH3:22])([CH2:10][C@@H:11]2O)[C@@:8]([OH:30])([C:23]([CH2:25][O:26][C:27]([CH3:29])=[O:28])=[O:24])[CH2:7][CH2:6]3)[CH2:3]1)=[O:17]>CN(C)C=O.O1CCCC1>[C:27]([O:26][CH2:25][C:23]([C:8]1([OH:30])[C@:9]2([CH3:22])[CH:5]([CH:4]3[C:12](=[CH:11][CH2:10]2)[C@:13]2([CH3:20])[C:14](=[CH:15][C:16](=[O:17])[CH:18]=[CH:19]2)[C@@H:2]([CH3:1])[CH2:3]3)[CH2:6][CH2:7]1)=[O:24])(=[O:28])[CH3:29]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)C1(O)CCC2C3C[C@H](C)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C

Procedure:
(see Tetrahedron Letters, 2001, 42 (14): 2639-2642). Alternatively, methyl prednisolone 21-acetate is dissolved in a mixture of dimethylformamide and tetrahydrofuran and cooled in an ice bath. SO2 is bubbled into methanesulfonyl chloride and the mixture is added dropwise to the solution containing the solution of methyl prednisolone 21-acetate. The title product can then be isolated by standard aqueous workup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][C:14]([CH2:22][CH2:23][CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][C:26]=2[F:37])([C:18]([O:20]C)=[O:19])[CH2:13]1.CO.[OH-].[Na+].Cl>O1CCOCC1.ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][C:14]([CH2:22][CH2:23][CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][C:26]=2[F:37])([C:18]([OH:20])=[O:19])[CH2:13]1
Reactant: COC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CN(CCSc2cc(F)ccc2F)CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CN(CCSc4cc(F)ccc4F)CCO3)c2c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of 0.22 g of the enantiomer B of methyl 4-[2-[(2,5-difluorophenyl)thio]ethyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylate in a mixture of 10 cm3 of 1,4-dioxane, 10 cm3 of methanol and 1.23 cm3 of 5 N sodium hydroxide is heated at a temperature in the region of 80° C. with stirring and under an inert atmosphere for 12 hours. After cooling to about 20° C., the reaction medium is evaporated under reduced pressure (2 kPa; 45° C.) to give a whitish crust. The residue is taken up in 25 cm3 of dichloromethane and 10 cm3 of distilled water and then neutralized with 1.2 cm3 of 5 N hydrochloric acid and extracted with 25 cm3 of diethyl ether. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue obtained is purified by chromatography on a silica gel column (particle size 70–200 μm; diameter 2 cm), eluting with a chloroform-methanol-aqueous ammonia (28%) (12/3/0.5 by volume) mixture and collecting 10 cm3 fractions. The fractions containing the expected product are combined and then evaporated according to the conditions described above. 0.2 g of the enantiomer B of 4-[2-[(2,5-difluorophenyl)thio]ethyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylic acid is obtained in the form of a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C@H:14]3[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16][CH2:15]3)[N:7]=2)[CH2:2]1.CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[Br:12][C:11]1[C:6]([O:5][CH:3]2[CH2:2][N:1]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:4]2)=[N:7][C:8]([NH:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16][CH2:15]2)=[N:9][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CC[C@@H](Nc2ncc(Br)c(OC3CNC3)n2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC(Oc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(azetidin-3-yloxy)-5-bromo-N-(cis-4-methylcyclohexyl)-pyrimidin-2-amine (1.24 g, 3.64 mmol) and Et3N (0.6 mL, 3.64 mmol) in DCM (20 mL) at 0° C. was added methanesulfonyl chloride (417 mg, 3.64 mmol). The mixture was stirred at 0° C. for 5 h, diluted by DCM, washed with saturated aqueous sodium carbonate solution and water, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, eluted by 1% methanol in DCM) to give the title compound as a white solid (1.3 g, 85% yield). MS (ESI) m/z: Calc. 418.1 (M+). Found: 420.1 (M++2).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][NH2:16])=[O:14])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][NH2:16])=[O:14])[CH:8]=3)[CH2:2][CH2:3]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NNC(=O)c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NNC(=O)c1cc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)ccn1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of the product of (i) above (7.76 g), 4-fluoronitrobenzene (5.50 g) and sodium carbonate (4.50 g) in N,N-dimethylformamide (40 ml) was heated at 100° C. with stirring for 4 hours. The mixture was evaporated to about half volume and filtered. The residue was washed with ethanol followed by warm water and then dried to give the title compound (9.41 g), m.p. 230°-232° C.