Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH3:7][O:8][C:9]([O:19][CH3:20])([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.O>O1CCCC1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH3:7][O:8][C:9]([C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:1][CH3:2])([O:19][CH3:20])[CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: COC(C)(OC)C(=O)c1ccccc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC=C(c1ccccc1)C(C)(OC)OC
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
At 5° C., a solution of 2.5 g of potassium tert-butoxide in 25 ml of tetrahydrofuran (THF) was added dropwise to 8.2 g of ethyltriphenylphosphonium bromide dissolved in 50 ml of THF. The mixture was then stirred at 5° C. for about 10 min, and a solution of 3.9 g of 2,2-dimethoxy-1-phenylpropan-1-one from Example 1 in 10 ml of THF was added dropwise. The reaction mixture was stirred at 20 to 25° C. for 72 h and then admixed with about 300 ml of water and extracted with methyl tert-butyl ether (MTBE). The organic phases were washed with water, dried and freed of the solvent. Silica gel chromatography (MTBE/cyclohexane 1:10) of the residue gave 2.2 g of product as an isomer mixture which can be further reacted without purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[NH2:9].[C:10](Cl)(Cl)=[O:11]>ClC1C=CC=CC=1Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[N:9]=[C:10]=[O:11]
Reactant: CC1CCCC(C)C1N
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CC1CCCC(C)C1N=C=O

Procedure:
The thus formed oxime is thereafter reduced in the presence of a Na--alcohol couple to 2,6-dimethylcyclohexylamine at a temperature in the range 0° to 80° C. at 1-5 atmospheres pressure: ##STR10## Amine is then dissolved in o-dichlorobenzene and in the presence of excess phosgene with the reaction being performed in two temperature stages with the first temperature stage in the range -20° to 20° C. and the second from 20° to 200° C. with pressures ranging from 1 to 15 atmospheres to form 2,6-dimethylcyclohexylisocyanate, thusly: ##STR11##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13](O)([CH3:16])([CH3:15])[CH3:14].S(=O)(=O)(O)O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: Cc1ccc(-c2nn[nH]n2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nnn(C(C)(C)C)n2)cc1

Procedure:
A solution of 5-(4-methylphenyl)-2H-tetrazole (W. G. Finnegan, R. A. Henry, R. Lofquist J. Am. Chem. Soc. 1958, 80, 3908.) (19.9 g, 0.12 mol), t-butanol (19.5 g, 0.26 mol) and concentrated sulfuric acid (5.84 g, 0.06 mol) in trifluoroacetic acid (122 mL) was stirred at room temperature (3 h) and then diluted with ethyl acetate (250 mL). The mixture was washed sequentially with water (2×50 mL), 10% aqueous sodium hydroxide until washings were basic, water (2×30 mL), and then dried over sodium sulfate (Na2SO4) and filtered. Following removal of the solvents in vacuo, the resultant oil was purified by HPLC on silica gel eluting with 20:1 mixture of hexanes-ethyl acetate to provide 17.5 g of 5-(4-methylphenyl)-2-(1,1-dimethylethyl)-2H-tetrazole as a clear oil, bp. 120°-122° C. (0.3 mm Hg).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[C:20]1([S:26]([N:29]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][NH:38][CH2:37][CH2:36][NH:35]3)=[CH:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:38]4[CH2:37][CH2:36][NH:35][CH:34]([C:31]5[CH:32]=[CH:33][N:29]([S:26]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)(=[O:28])=[O:27])[CH:30]=5)[CH2:39]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: O=S(=O)(c1ccccc1)n1ccc(C2CNCCN2)c1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4ccn(S(=O)(=O)c5ccccc5)c4)C3)c(F)cc2c1=O
Temperature: 135 °C
Yield: 42.1 %

Procedure:
A mixture of 337 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.2 g of 1-(phenylsulfonyl)-3-(2-piperazinyl)-1H-pyrrole and 5 ml of pyridine was heated in a pressure bottle at 135° C. for 16 hours, then allowed to cool and the pyridine removed under reduced pressure. The crude substance was purified by column chromatography using chloroform:methanol:water:triethylamine (9:0.5:0.01:0.01), giving 270 mg of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]-1-piperazinyl]-3-quinolinecarboxylic acid.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5](C(F)(F)F)=[CH:4][CH:3]=1.I[C:34]1SC2C(C#N)=CC=CC=2[N:38]=1>>[NH2:28][C:12]1[C:11]([C:8]2[S:9][C:10]3[C:2]([C:34]#[N:38])=[CH:3][CH:4]=[CH:5][C:6]=3[N:7]=2)=[CH:16][C:15]([C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:21]=2)=[CH:14][N:13]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Reactant: N#Cc1cccc2nc(I)sc12
Product: N#Cc1cccc2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)sc12

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-iodo-1,3-benzothiazole-7-carbonitrile and conducting the Suzuki coupling at 55° C. for 3 h, the title compound was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.31 (m, 4H), 3.05-3.18 (m, 2H), 3.37-3.44 (m, 2H), 3.77 (brs, 2H), 4.45-4.54 (m, 1H), 7.51 (brs, 1H), 7.75-7.78 (m, 1H), 8.07 (d, J=7.2 Hz, 1H), 8.10 (s, 1H), 8.44-8.48 (m, 3H), 8.58 (brs, 1H), 8.88 (brs, 1H), 9.10 (brs, 1H). MS(ES+): m/z=402.13 (100) [MH+]. HPLC: tR=2.06 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH3:18])=[CH:13][N:12]=2)=[O:10])=[CH:4][C:3]=1[C@:19]12[CH2:27][O:26][C@H:25]([CH2:28][F:29])[C@H:24]1[CH2:23][S:22][C:21]([NH:30]C(=O)OC(C)(C)C)=[N:20]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C:21]1[S:22][CH2:23][C@@H:24]2[C@@H:25]([CH2:28][F:29])[O:26][CH2:27][C@:19]2([C:3]2[CH:4]=[C:5]([NH:8][C:9]([C:11]3[CH:16]=[N:15][C:14]([O:17][CH3:18])=[CH:13][N:12]=3)=[O:10])[CH:6]=[CH:7][C:2]=2[F:1])[N:20]=1
Reactant: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](CF)[C@H]3CSC(NC(=O)OC(C)(C)C)=N4)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](CF)[C@H]3CSC(N)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl ((4aS,5S,7aS)-7a-(2-fluoro-5-(5-methoxypyrazine-2-carboxamido)phenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate, synthesized in preparation example 2-(2), (6.71 g, approx. purity 90%) was dissolved in DCM (20 mL) and TFA (10 mL) was added. After stirring at RT for 2 h, the reaction mixture was evaporated and sodium bicarbonate (sat., aq., 50 mL) was added. The mixture was extracted with EtOAc (2×100 mL), and the combined organic portions dried over MgSO4, evaporated, and purified by silica gel chromatography (0% to 50% EtOAc in DCM) to afford the title compound as a white solid (3.26 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.81 (dd, J=13.4, 3.8 Hz, 1H), 3.08 (dt, J=7.7, 3.7 Hz, 1H), 3.18 (dd, J=13.4, 3.3 Hz, 1H), 3.88 (dd, J=8.6, 2.5 Hz, 1H), 4.09 (s, 3H), 4.43-4.73 (m, 6H), 7.10 (dd, J=11.9, 8.8 Hz, 1H), 7.55 (dd, J=7.1, 2.8 Hz, 1H), 7.91-8.00 (m, 1H), 8.17 (d, J=1.3 Hz, 1H), 9.04 (d, J=1.0 Hz, 1H), 9.51 (s, 1H)
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([C:6]([O:8][CH3:9])=[O:7])[NH:4][C:3]1=[O:10].C(=O)([O-])O.[Na+].Cl.[Cl:17][CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:31]/[O:32][CH2:33][CH:34]=[CH2:35])/[C:28](Cl)=[O:29])[N:26]=1)=[O:20]>O1CCCC1.O>[Cl:17][CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:31][O:32][CH2:33][CH:34]=[CH2:35])[C:28]([NH:1][C@H:2]2[C@@H:5]([C:6]([O:8][CH3:9])=[O:7])[NH:4][C:3]2=[O:10])=[O:29])[N:26]=1)=[O:20]
Reactant: C=CCO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C(=O)OC)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a mixture of 2 ml of tetrahydrofuran and 2 ml of water is dissolved 185.5 mg of methyl cis-3-amino-2-oxoazetidine-4-carboxylate and under ice-cooling and stirring 469.6 mg of sodium hydrogen carbonate and successively, 600 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-allyloxyiminoacetyl chloride hydrochloride is added. The mixture is stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue is added 20 ml of water and the insolubles are collected by filtration, washed with aqueous sodium hydrogen carbonate, water, hexane and ether in this order, and dried to give methyl cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-allyloxyiminoacetamido]-2-oxoazetidine-4-carboxylate (syn isomer) as light-yellow granules, m.p. 270°-280° C. (decomp.).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>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.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC(O)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (54.5 mg, 0.65 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (30 mg) and Cul (5 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 56 mg, 64%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Br:23]Br>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:15])([F:16])[F:14])=[C:8]([Br:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc(C(F)(F)F)nc1N
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Int. E) (30 mg, 0.13 mmol) in acetic acid (5 ml), sodium carbonate (15 mg, 0.14 mmol) was added. To this mixture, half the contents of a solution of bromine (7 μL, 0.13 mmol) in acetic acid (5 ml) was added, followed by the addition of sodium carbonate ((15 mg, 0.14 mmol). The remaining solution of bromine in acetic acid was added and the reaction mixture was left to stir at RT for 2 hours. The mixture was diluted with water and the resulting yellow precipitate was filtered under vacuum to afford the title compound.
Reaction SMILES: C[Mg+].[Br-].CCOCC.[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].[C:16](#[N:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH:9]([N:12]([CH:13]([CH3:15])[CH3:14])[C:16](=[NH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:11])[CH3:10]
Reactant: N#Cc1ccccc1
Reactant: CC(C)NC(C)C
Agent: C[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)N(C(=N)c1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.9 %

Procedure:
A solution of MeMgBr in ether (50.0 mL, 3.0 M, 0.15 mol) was added to a solution of diisopropylamine (16.17 g, 0.16 mol) in toluene (250 mL) at 50° C. The mixture was stirred for 1.5 h and a white precipitate formed. Next, the mixture was cooled to 0° C. and benzonitrile (15.4 g, 0.15 mol) was added. The mixture was allowed to warm to room temperature and stirred for 16 h subsequently. The conversion, determined by GC, appeared to be 90%. The mixture was quenched with water (100 mL). The organic phase was separated from the aqueous phase and the latter was extracted with diethylether (50 mL) twice. The combined organic phases were dried over Na2SO4, filtered and the solvents were removed under reduced pressure. The crude product was distilled at 145° C. at reduced pressure (0.52 mbar) resulting in 15.3 g (50%) of pure product. The ligand was characterized by 1H NMR (300 MHz) (CDCl3) δ (ppm): 7.2 (m, 5H), 5.7 (bs, 1H), 3.5 (p, 2H), 1.2 (d, 12H) and by 13C-NMR (75.5 MHz) (CDCl3) δ (ppm) 168.4, 141.8, 128.8, 128.5, 126.2, 48.6, 21.2.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[NH2:22][C:23]1[CH:24]=[N:25][C:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:27][CH:28]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:29]1([C:26]2[N:25]=[CH:24][C:23]([NH:22][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([I:1])=[CH:10][CH:9]=4)=[O:21])=[CH:28][CH:27]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Nc1ccc(N2CCCC2)nc1
Reactant: O=C(O)c1cc2cc(I)ccc2n1Cc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCCC2)nc1)c1cc2cc(I)ccc2n1Cc1cccc(F)c1
Yield: 70.6 %

Procedure:
The compound was prepared according to a process similar to that described in stage 5.4, by reacting 0.3 g (0.76 mmol) of 5-iodo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared according to the protocol described in stage 8.2, with 148 mg (0.91 mmol) of 3-amino-6-(pyrrolidin-1-yl)pyridine in the presence of 145 mg (0.76 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and of 105 mg (0.76 mmol) of 1-hydroxybenzotriazole (HOBT) in 5 ml of dimethylformamide. 290 mg of the expected product are obtained.
Reaction SMILES: OC1C2C(=CC(C3C=CC(C(OC(C)(C)C)=O)=CC=3)=CC=2)N(C)C(=O)C=1C(=O)CCC=O.[O:33]1CCC[O:35][CH:34]1[CH2:39][CH2:40][C:41]([C:43]1[C:44](=[O:68])[N:45]([CH3:67])[C:46]2[C:51]([C:52]=1[OH:53])=[CH:50][CH:49]=[C:48]([C:54]1[CH:66]=[CH:65][C:57]([C:58]([O:60]C(C)(C)C)=[O:59])=[CH:56][CH:55]=1)[CH:47]=2)=[O:42]>CC(O)=O>[C:34]([CH2:39][CH2:40][C:41]([C:43]1[C:44](=[O:68])[N:45]([CH3:67])[C:46]2[C:51]([C:52]=1[OH:53])=[CH:50][CH:49]=[C:48]([C:54]1[CH:55]=[CH:56][C:57]([C:58]([OH:60])=[O:59])=[CH:65][CH:66]=1)[CH:47]=2)=[O:42])([OH:35])=[O:33]
Reactant: Cn1c(=O)c(C(=O)CCC2OCCCO2)c(O)c2ccc(-c3ccc(C(=O)OC(C)(C)C)cc3)cc21
Agent: Cn1c(=O)c(C(=O)CCC=O)c(O)c2ccc(-c3ccc(C(=O)OC(C)(C)C)cc3)cc21
Solvent: CC(=O)O
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2ccc(-c3ccc(C(=O)O)cc3)cc21
Temperature: 90 °C

Procedure:
tert-Butyl 4-(4-hydroxy-1-methyl-2-oxo-3-(4-oxobutanoyl)-1,2-dihydroquinolin-7-yl)benzoate. AcOH (80%, 15 mL) was added to tert-butyl 4-(3-(3-(1,3-dioxan-2-yl)propanoyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)benzoate (150 mg, 304 μmol), and the resulting mixture was heated at 90° C. for 1 hour. The reaction mixture was quenched with water and cooled to room temperature. A solid precipitated from solution and was filtered and stuck to the frit. The frit was washed with EtOAc (5×) to give the title compound as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][NH:36][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:16])[CH2:32][CH2:33]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCCN1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCN1CCN(Cc2ccccc2)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 2-(4-benzylpiperazin-1-yl)ethanamine (25.0 mg, 0.12 mmol). The title compound was obtained as a solid (12.0 mg, 22% yield). MS m/z: 552.08, 554.08 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][N:21]([C:25](=[S:27])[NH2:26])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[CH2:29](O)C.CI>CO>[CH3:29][S:27][C:25]([N:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][C:15]([O:14][CH2:13][CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:12][CH2:11]3)=[CH:16][CH:17]=2)[CH2:22]1)=[NH:26]
Reactant: CCO
Reactant: NC(=S)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Agent: Cl
Solvent: CO
Solvent: CI
Product: CSC(=N)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
7-[1-(Pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (200 mg) was treated with hydrogen chloride—ethanol solution. To a suspension of the obtained residue in methanol (6 ml) was added methyl iodide (0.1 ml), and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was dissolved in water and ethanol and neutralized with ion-exchange resin (IRA-410). This was filtrated and the filtrate was concentrated and dried under reduced pressure to give the title compound (200 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].[CH2:25](OC(=O)COC1C2CCCCC=2C(S)=CC=1)C.ClC1C=C(C=CC=1Cl)C=O>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:25])[C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)cc1C
Reactant: CCOC(=O)COc1ccc(S)c2c1CCCC2
Agent: O=Cc1ccc(Cl)c(Cl)c1
Product: CCOC(=O)COc1cc(C)c(Sc2ccc(C=O)cc2Cl)cc1C

Procedure:
The title compound was prepared according to the method described for preparing compound 10.4, using compound 22.3 and 3,4-dichlorobenzaldehyde as the starting materials. 1H NMR (400 MHz) (CDCl3) δ 9.85 (1H, s); 7.82 (1H, d, J=1.7 Hz); 7.49 (1H, dd, J=1.7, 8.2 Hz); 7.36 (1H, s); 6.70 (1H, s); 6.58 (1H, d, J=8.2 Hz); 4.71 (2H, s); 4.31 (2H, q, J=7.1 Hz); 2.31 (3H, s); 2.27 (3H, s); 1.33 (3H, t, J=7.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH3:9][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:24])[CH:20]=2)(=[O:18])=[O:17])[CH:15]=1)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: C1COCCN1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)O)c2)c1)C(=O)OC(C)(C)C
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)N3CCOCC3)c2)c1)C(=O)OC(C)(C)C
Yield: 95.3 %

Procedure:
Using 3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoic acid (150 mg) and morpholine (42 mg), a procedure as in Reference Example 284 was performed to give the title compound as a colorless oil (yield 164 mg, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][C:3]=1[O:19][CH3:20].O>O1CCCC1.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc(C=CC(=O)c2ccc(O)cc2)ccc1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCC(=O)c2ccc(O)cc2)ccc1O
Yield: 89.3 %

Procedure:
3-(4-Hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)-2-propene-1-one (10 g) is dissolved in 100 g tetrahydrofuran, 0.2 g of Pd on activated carbon (Pd content: about 5% by weight, water content approx. 50% by weight, based on the total mass of the catalyst) is added and a hydrogenation is carried out at normal pressure and room temperature (approx. 20° C.). After removal of the catalyst and the solvent, 9 g of 3-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)-propane-1-one is obtained. Yield: 89% of the theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 65.4 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (91.0 g), 2-iodopropane (103.4 g), potassium carbonate (146 g) and N,N-dimethylformamide (600 mL) was stirred at 50° C. for 3.5 h. The mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=0/100 to 30/70, volume ratio) to give the title compound (75.4 g, 65%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:21]=[C:20]([I:22])[C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.O>ClCCl>[CH3:23][N:17]1[CH2:16][CH2:15][C:14]2[C:20]([I:22])=[CH:21][C:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:12][C:13]=2[CH2:19][CH2:18]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=S(=O)(c1ccc(F)cc1)c1cc(I)c2c(c1)CCNCC2
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN1CCc2cc(S(=O)(=O)c3ccc(F)cc3)cc(I)c2CC1
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 7-(4-fluorophenylsulfonyl)-9-iodo-1,2,4,5-tetrahydro-3-benzazepine (2.4 g, 5.5 mmol) in dichloromethane (20 ml) were added sodium triacetoxyborohydride (1.8 g, 8.5 mmol) and formalin (1 ml, 37%, 12 mmol). The mixture was stirred for 2 h without cooling then poured into water (100 ml) and extracted with more dichloromethane (100 ml). The resulting organic layer was washed with brine (100 ml), dried (MgSO4), and evaporated to give the subtitle compound as a white foam (2.4 g).