Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30].Cl>C(Cl)Cl.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[CH:10]=2)[C:29](=[O:31])[CH3:30])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Nc2ccc3cc(O)ccc3c2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(O)cc1)c1ccc2cc(O)ccc2c1
Reaction time: 0.83 h
Yield: 10 %

Procedure:
A solution of 830 mg (3.30 mmol) of 6-[(4-hydroxyphenyl)amino]-2-naphthalenol (prepared as described in Example 3) and 840 ul (6.60 mmol, 2 eq.) of dimethylaniline in 15 ml of dry CH2Cl2 and 5 ml of dry THF was stirred at 0° C., then 415 ul (5.80 mmol, Mallinckrodt) of acetyl chloride was added dropwise. After 50 minutes, 1N aqueous HCl was added and this was extracted with EtOAc. The organic layers were washed with 1N aqueous HCl, dried (MgSO4) and concentrated in vacuo. The aqueous layers were extracted with hot EtOAc and the organic layers were combined, dried (MgSO4) and concentrated in vacuo. Purification of all the organic phases was accomplished via flash chromatography (1:2, 1:1 EtOAc/petroleum ether) and recrystallization (aqueous MeOH) afforded 97 mg (10%) of title compound as pale orange crystals: m.p. 255° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:30]1[CH:31]=[C:32]([C:35]([F:37])([F:38])[F:36])[CH:33]=[CH:34][C:29]=1[F:28])=[CH:13][CH:12]=[C:11]([C:24]([F:25])([F:26])[F:27])[CH:10]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C(F)(F)F)ccc1F

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 2-fluoro-5-trifluoromethylphenylboronic acid (142 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(2-fluoro-5-trifluoromethyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a slight yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.[CH2:24]([O:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)[CH:25]=[CH2:26]>>[CH2:24]([O:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:19]=[CH:18][C:14]([C:15](=[O:16])[NH:23][CH:20]5[CH2:22][CH2:21]5)=[CH:13][CH:12]=3)[CH:6]=[CH:5]4)=[O:39])=[CH:41][CH:42]=2)[CH2:32][CH2:33]1)[CH:25]=[CH2:26]
Reactant: Nc1ccc2c(ccn2-c2ccc(C(=O)O)cc2)c1
Reactant: C=CCOC1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: NC1CC1
Product: C=CCOC1CCN(c2ccc(C(=O)Nc3ccc4c(ccn4-c4ccc(C(=O)NC5CC5)cc4)c3)cc2)CC1

Procedure:
Compound 951 was prepared according to the procedure described in Scheme IV from 4-(5-amino-1H-indol-1-yl)benzoic acid, cyclopropaneamine, and 4-(4-allyloxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C33H34N4O3: 535.26; found 535.10.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2/[C:19](/[C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:20]\[CH:21]2[CH2:29][CH2:28][C:23]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[O:24]1[C:23]2([CH2:28][CH2:29][CH:21](/[CH:20]=[C:19](\[C:11]3[NH:10][C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)/[C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[CH2:22]2)[O:27][CH2:26][CH2:25]1
Reactant: CS(=O)(=O)c1ccc(/C(=C/C2CCC3(C2)OCCO3)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C/C2CCC3(C2)OCCO3)c2cc3cccnc3[nH]2)cc1
Yield: 94.6 %

Procedure:
A mixture of (Z)-1-benzenesulfonyl-2-[2-(1,4-dioxa-spiro[4.4]non-7-yl)-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (800 mg, 1.42 mmol) in ethanol (24 mL), tetrahydrofuran (16 mL) and an aqueous sodium hydroxide solution (10%, 4 mL) was heated at 45° C. for 3 h. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford (Z)-2-[2-(1,4-dioxa-spiro[4.4]non-7-yl)-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (570 mg, 95%): LC/MS m/e calcd for C23H24FN2O4S [M+H]+ 425.52, observed 425.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:11]([S:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ccc1SCc1ccccc1
Yield: 33.1 %

Procedure:
Following General Procedure A, the title compound (560 mg, 33%) was prepared from 2-amino-4-chlorobenzenethiol (1.08 g, 6.77 mmol), (bromomethyl)benzene (0.8 ml, 6.77 mmol) and K2CO3 (3.18 g, 23.04 mmol) in DMF (20 ml).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[CH2:16]([NH:23]CC)[C:17]1C=CC=CC=1>>[ClH:1].[ClH:1].[CH2:16]([NH:23][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1)[CH3:17]
Reactant: CCNCc1ccccc1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: CCNCC1CNCCO1
Product: Cl

Procedure:
By the use of 2-chloromethyl-4-benzylmorpholine and N-benzyl-N-ethylamine, the reaction is similarly carried out as Reference example 2 to give 2-(ethylaminomethyl)morpholine dihydrochloride as white crystals, melting at 222°-223° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](OC)(=[O:13])[C:11]#[CH:12]>CO>[CH2:1]([NH:9][C:10](=[O:13])[C:11]#[CH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CC(=O)OC
Reactant: CCCCCCCCN
Solvent: CO
Product: C#CC(=O)NCCCCCCCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred, cooled (-30° C.) solution of 18.42 g (0.143 mol) of n-octylamine in 25 ml of aqueous methanol was added 10 g (0.119 mol) of methyl propiolate dropwise. After the addition the reaction mixture was allowed to warm to room temperature and stir for 12 h. The reaction mixture was poured into ice-cold 10% aqueous hydrochloric acid and extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate. Filtration and removal of solvents gave a crude mixture which was purified by column chromatography (Merck 60® silica gel, 25% ethyl acetate/hexane eluant) to give N-octylpropiolamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:22][O:23][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14][C:13]3=[O:21].[NH:24]1[C:32]2[C:27](=CC=C[CH:31]=2)[C:26]2(COC3C=C4C(=[CH:43][C:33]2=3)CCO4)C1=O.Br.BrCC1C=CC=CN=1.ClCC1C=NC(OC)=NC=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:22][O:23][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[N:14]([CH2:31][C:32]1[CH:27]=[CH:26][CH:33]=[CH:43][N:24]=1)[C:13]3=[O:21]
Reactant: COCCOc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Br
Agent: BrCc1ccccn1
Agent: COc1ncc(CCl)cn1
Product: COCCOc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using 6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 5-(chloromethyl)-2-methoxypyrimidine, 6-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (72%): mp 94-95° C.; 1H NMR (300 MHz, CDCl3) δ8.56 (d, J=4.7 Hz, 1H), 7.69-7.59 (m, 1H), 7.25-7.09 (m, 4H), 7.05-6.95 (m, 1H), 6.92-6.82 (m, 2H), 6.81-6.73 (m, 1H), 6.37 (s, 1H), 5.08 (ABq, 2H), 4.83 (ABq, 2H), 3.93 (t, J=4.7 Hz, 2H), 3.62 (t, J=4.7 Hz, 2H), 3.36 (s, 3H); 13C NMR (75 MHz, CDCl3 δ 177.2, 155.5, 155.1, 153.7, 149.5, 142.1, 137.1, 132.0, 129.6, 128.9, 123.8, 123.5, 122.8, 121.6, 115.8, 110.5, 110.4, 109.5, 79.8, 71.0, 68.1, 59.1, 58.5, 46.1; MS (ES+) m/z 403.0 (M+1).
Reaction SMILES: C(O)=O.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([NH:27]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[O:16])=[CH:5]1>C(Cl)Cl>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([NH2:27])[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[O:16])=[CH:5]1
Reactant: COc1ccccc1CNC(=O)C(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=CO
Product: COc1ccccc1CNC(=O)C(N)Cc1c[nH]c2ccccc12
Reaction time: 4 h
Yield: 90 %

Procedure:
Formic acid (9.0 ml, 238.540 mmol) was added to a stirring solution of 3-(1H-indol-3-yl)-N-(2-methoxybenzyl)-2-(N-triphenylmethylamino) propanamide (14.11 g, 23.763 mmol) in anhydrous methylene chloride under a nitrogen atmosphere at 0° C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0N hydrochloric acid. The aqueous layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound 3-(1H-indol-3-yl)-2-amino-N-(2-methoxybenzyl)propanamide (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further purification was necessary.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]5[CH:31]=[C:32]([O:36][CH3:37])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[CH:29]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: COc1cc(-c2ccc3c(c2)ncn3-c2ccnc(N[C@@H](C)c3ccccc3)n2)cc(OC)c1OC

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 3,4,5-trimethoxyphenyl boronic acid. Mass spectrum (ESI) 415.4 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:27]([Cl:28])=[CH:26][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18](C(OCC)=O)[CH2:17][CH2:16]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[OH-].[K+].C(O)C.C1C=CC=CC=1>O>[Cl:1][C:2]1[C:27]([Cl:28])=[CH:26][C:5]2[CH:6]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCN(C2Cc3ccccc3Sc3cc(Cl)c(Cl)cc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: Clc1cc2c(cc1Cl)C(N1CCNCC1)Cc1ccccc1S2

Procedure:
The same product was prepared by the following procedure: A mixture of crude 7,8-dichloro-10-(4-ethoxycarbonylpiperazino)-10,11-dihydrodibenzo(b,f)thiepine (3.5 g) (prepared according to the preceding Example), potassium hydroxide (1.75 g) and ethanol (3.5 ml) was refluxed for 3 hours in a bath heated to 120°-125° C. The reaction mixture was cooled and shaken with benzene and water. The isolation procedure is the same as described in the preceding Examples, yielding the crude base in an almost theoretical yield. On crystallization from acetone it melts at 131°-133° C.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].C(=[O:11])C(C)C.[C:12]([O:21]CC)(=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)(C)(C)C>[C:15]([C:14]([CH:13]([CH2:1][CH:2]([CH3:5])[CH3:3])[C:12]([OH:21])=[O:20])=[O:11])([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(C)C=O
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCC(=O)OCC
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(=O)C(CC(C)C)C(=O)O

Procedure:
Potassium t-butoxide, 24.7 g (0.35M), was dissolved in 200 ml of refluxing t-butanol. A mixture of isobutyraldehyde, 18.2 ml (0.20M) and diethyl succinate 41.55 ml (0.25M) was added to the t-butanol solution over 30 min. The reaction mixture was stirred under reflux, for 2 h. The solvent was removed from the reaction mixture by evaporation under reduced pressure and acidified with 2N HCl. The product was extracted with ethyl ether, Et2O (3×200 ml). The ether solution was washed with water (3×200 ml); and the product was extracted with 10% Na2CO3 (4×200 ml). The solution was acidified with conc. HCl solution and the product was isolated by extraction with Et2O (4×150 ml). The ether layer was washed with water, dried over sodium sulfate, and evaporated. The remaining oil was dissolved in ethanol (300 ml) and hydrogenated in the presence of 10% palladium on charcoal (3.0 g). The resultant mixture was filtered through Celite and the solvent was evaporated to yield 38.04 g 2-carboethoxycarbonyl-4-methyl pentanoic acid as a mixture of isomers in the form of an oil. The isolated monoethyl ester was further purified on silica gel by flash chromatography using as eluent mixture ethyl acetate: hexane:acetic acid (1:10:0.05, v/v).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[CH2:9]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC(NCc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Combine trans-4-amino-cyclohexanol (2.0 g, 17.4 mmol) in methanol (75 mL) in a sealed tube then add benzaldehyde (1.85 mL, 18.23 mmol). Heat the reaction mixture at 70° C. while stirring for 2 h. Then let the reaction cool down and add sodium borohydride (2.46 g, 65.1 mmol) in portions. Stir overnight. Evaporate the solvent till ⅓ of the original volume. Partition the reaction mixture between EtOAc (50 mL) and water (40 mL). Reextract the aqueous layer with EtOAc (20 mL). Combine the organic layers and dry over sodium sulfate. Filter and concentrate to provide the title compound (3.5 g) that will be use directly in the next step.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:36][CH3:37])[CH2:23][CH2:24][CH2:25][N:26]([CH3:35])[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1)[CH3:21].O.[ClH:39].Cl>>[OH2:3].[ClH:1].[ClH:39].[CH2:36]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][N:26]([CH3:35])[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH3:37]
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Reactant: CCN(CC)CCCN(C)CCC1CCCCN1
Agent: Cl
Solvent: O
Product: CCN(CC)CCCN(C)CCC1CCCCN1C(=O)N1c2ccccc2NC(=O)c2cccnc21
Yield: 48 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 2-[2-[[3-(diethylamino)propyl]methylamino]ethyl]piperidine in a yield of 48% of theory. The colourless dihydrochloride-hydrate melted at 145°-150° C. (D.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:23]1([NH:26][C:27]([C:29]2[S:42][C:32]3=[N:33][C:34](S(C)=O)=[C:35]([Cl:38])[C:36]([CH3:37])=[C:31]3[C:30]=2[NH2:43])=[O:28])[CH2:25][CH2:24]1>C1COCC1>[CH:23]1([NH:26][C:27]([C:29]2[S:42][C:32]3=[N:33][C:34]([O:1][CH2:2][CH2:3][NH:4][C:5]([C:6]4[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=4)=[O:12])=[C:35]([Cl:38])[C:36]([CH3:37])=[C:31]3[C:30]=2[NH2:43])=[O:28])[CH2:25][CH2:24]1
Reactant: O=C(NCCO)c1ccncc1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCNC(=O)c2ccncc2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 10.3 %

Procedure:
To a solution of N-(2-hydroxyethyl)-isonicotinamide (0.831 g, 5.00 mmol) in THF (2.5 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl) amide (1.0 M in hexanes)(2.50 ml, 2.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 80° C. in a sealed tube for 2 hours, cooled to room temperature, and then quenched by the addition of water (15 ml). The mixture is diluted to 100 ml with water and then cooled to 0° C. and stirred. A yellow precipitate is formed. This solid is collected by filtration, slurried in EtOAc, and filtered again to give a yellow solid which is placed in the vacuum oven to dry (50° C. for 3 hours). This affords the title compound as a yellow solid (0.046 g, 10%). Mass (m/z): 446.3 (M++1), 444.2 (M+−1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([C:17](O)=[O:18])=[CH:12][C:11]=3[N:10]=[C:9]([NH:20][C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:8]=2[N:40]=1)[CH3:2].CN([C:49]([O:53][N:54]1N=NC2C=CC=C[C:55]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>CN(C=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:41][C:42]([OH:45])([CH3:43])[CH3:44])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([C:17]([N:54]([O:53][CH3:49])[CH3:55])=[O:18])=[CH:12][C:11]=3[N:10]=[C:9]([NH:20][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:8]=2[N:40]=1)[CH3:2]
Reactant: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C(=O)O)ccc3c2n1CC(C)(C)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C(=O)N(C)OC)ccc3c2n1CC(C)(C)O
Yield: 111.1 %

Procedure:
To a solution of 2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carboxylic acid (484 mg, 741 μmol) in DMF (5.19 mL) in an inert atmosphere was added TBTU (357 mg, 1.11 mmol), DIEA (388 μL, 2.22 mmol) and N,O-dimethylhydroxylamine hydrochloride (108 mg, 1.11 mmol) with stirring. The reaction mixture was stirred for 1 h at room temperature and afterwards the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (40 mL, 2×20 mL) and water (40 mL). The organic phases were washed with water (2×20 mL), combined, dried over MgSO4, concentrated in vacuo and purified by flash chromatography (silica gel, 50% to 100% ethyl acetate in heptane) to give the title compound (0.53 g, quant.) as white foam; LC-MS (UV peak area, ESI) 92%, 644.4 (MH+).
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[CH:18]([C:26]([OH:28])=[O:27])[C:19](=[O:25])[N:20]2[CH2:23][CH3:24])=[CH:15][C:14]=1[NH:30][N:31]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]1[CH3:37].[C:38]([O:44][CH2:45]Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>C(#N)C>[Cl:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[CH:18]([C:26]([O:28][CH2:45][O:44][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[O:27])[C:19](=[O:25])[N:20]2[CH2:23][CH3:24])=[CH:15][C:14]=1[NH:30][N:31]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]1[CH3:37]
Reactant: CCN1C(=O)C(C(=O)O)C(=O)c2cc(Nn3c(C)ccc3C)c(Cl)cc21
Reactant: CC(C)(C)C(=O)OCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCN1C(=O)C(C(=O)OCOC(=O)C(C)(C)C)C(=O)c2cc(Nn3c(C)ccc3C)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
18 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to a solution of 21 mg of 7-chloro-6-(2,5-dimethylpyrrol-1-ylamino)-1-ethyl-4-oxo-1,4-dihydroquinolonecarboxylic acid (Example 36) in 3 ml of acetonitrile and stirred at room temperature for 30 minutes. Then 36 μl of chloromethyl pivalate were added, and reaction was allowed to take place at room temperature for 5 days. The resulting precipitate was filtered off with suction to afford 3.3 mg of pure product.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: C1COCCN1
Product: COc1ccc(N(C)c2nc(N3CCOCC3)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and morpholine (30 μL) by a procedure similar to Example 10 and was isolated as white powder (10 mg, 66%). 1H NMR (CDCl3): 7.46 (d, J=8.4 Hz, 1H), 7.35 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 7.13-7.07 (m, 2H), 6.91-6.85 (m, 3H), 6.67 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 3.94-3.90 (m, 4H), 3.85-3.81 (m, 7H), 3.52 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH2:7][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:5]=2[S:4][N:3]=1.[N+](=[CH2:17])=[N-]>CCOCC.C(O)C>[CH3:17][O:1][C:2]1[C:6]2[CH2:7][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:5]=2[S:4][N:3]=1
Reactant: C=[N+]=[N-]
Reactant: COC(=O)N1CCc2snc(O)c2C1
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)N1CCc2snc(OC)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.60 g (7.5 mmol) of methyl 3-hydroxy-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine-5-carboxylate (1)1 in ether (50 ml) and ethanol (2 ml) was added an excess of diazomethane. The mixture was stirred at room temperature for 1 hour, and the excess of diazomethane was destroyed by addition of glacial acetic acid. The mixture was evaporated in vacuo and the residue submitted to column chromatography on silica gel (eluent: toluene-ethyl acetate) yielding 890 mg of the title compound as a colourless oil.