Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[O:10][CH2:9][C:8]1([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH3:19].[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>N1C=CC=CC=1.ClCCl>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:34]([C:31]3[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=3)(=[O:36])=[O:35])[C:8]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)([CH3:19])[CH2:9][O:10]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C2(C)COc3cc(OC)ccc3C2CCCCCO)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C2(C)COc3cc(OC)ccc3C2CCCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
(3RS,4RS)-4-(5-Hydroxypentyl)-7-methoxy-3-(4-methoxyphenyl)-3-methylchroman (430 mg, 1.2 mmol) was dissolved in a solvent mixture of pyridine (12 ml) and dichloromethane (4 ml), which was then cooled down to 0° C. p-Toluenesulfonylchloride (460 mg, 2.3 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. Water was then added, and the organ layer was extracted with ethyl acetate. The organic extract was washed with 2N hydrochloric acid solution, dried over magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (315 mg, yield 53%) as a colorless oil.
Reaction SMILES: C(CCCC[C:8]1[CH:9]=[C:10](/[C:14](=[CH:48]\[CH:49]=[C:50]2/[C:51]([CH3:69])([CH3:68])[C:52]3[C:53](=[N:67]/2)[N:54]([CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[CH:55]=[C:56]([Cl:58])[CH:57]=3)/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:38])=[O:37])[CH:30]=[C:31]([S:32]([O-:35])(=[O:34])=[O:33])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][CH2:43][S:44]([O-:47])(=[O:46])=[O:45])[CH:11]=[CH:12][CH:13]=1)(O)=O.[Na+:70].[Na+].[Na+].[OH:73][CH2:74][CH2:75][CH2:76][CH2:77][O:78]C1C=C(B(O)O)C=CC=1>>[Cl:58][C:56]1[CH:57]=[C:52]2[C:51]([CH3:69])([CH3:68])/[C:50](=[CH:49]\[CH:48]=[C:14](/[C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:73][CH2:74][CH2:75][CH2:76][CH2:77][OH:78])[CH:9]=3)\[CH:15]=[CH:16]\[C:17]3[C:25]([CH3:26])([CH3:27])[C:24]4[C:23]5[CH:28]=[C:29]([S:36]([O-:39])(=[O:37])=[O:38])[CH:30]=[C:31]([S:32]([O-:35])(=[O:33])=[O:34])[C:22]=5[CH:21]=[CH:20][C:19]=4[N+:18]=3[CH2:40][CH2:41][CH2:42][CH2:43][S:44]([O-:47])(=[O:45])=[O:46])/[N:67]=[C:53]2[N:54]([CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[CH:55]=1.[Na+:70].[Na+:70].[Na+:70]
Reactant: OCCCCOc1cccc(B(O)O)c1
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(OCCCCO)c1

Procedure:
Compound 51 is prepared analogously to compound 28, except with 3-(4-hydroxybutoxy)phenylboronic acid as a starting material.
Reaction SMILES: FCC(CF)(CF)[C:4]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[C:18]([CH3:24])[CH:17]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[OH:5].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:23][N:22]([C:19]1[CH:20]=[CH:21][C:16]([C:4]([OH:5])([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=2)[C:12]([F:15])([F:14])[F:13])=[CH:17][C:18]=1[CH3:24])[S:35]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:37])=[O:36]
Reactant: CNc1ccc(C(O)(c2cccc(C(F)(F)F)c2)C(CF)(CF)CF)cc1C
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cc1cc(C(O)(c2cccc(C(F)(F)F)c2)C(F)(F)F)ccc1N(C)S(=O)(=O)c1ccccc1

Procedure:
The title compound was prepared from 2,2,2-trifluoromethyl-1-(3-methyl-4-methylaminophenyl)-1-(3-trifluoromethyl-phenyl)-ethanol (Step A) and benzenesulfonyl chloride using the procedure described in Example 1, Step D. 1H-NMR (CDCl3) δ 2.41 (s, 3H), 3.15 (s, 3H), 6.64 (d, J=8.4 Hz, 1H), 7.18 (brs, 1H), 7.42 (brs, 1H), 7.52-7.56 (m, 3H), 7.63-7.67 (m, 3H), 7.73 (d, J=8.5 Hz, 2H), 7.82 (s, 1H). Mass Spectrum (CI+) m/e 526.0 (M+23).
Reaction SMILES: [CH:1]#[CH:2].[C:3]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O1CCCC1>[C:4]1([C:3]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)([OH:10])[C:1]#[CH:2])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccncc1
Reactant: C#C
Agent: Cl
Solvent: C1CCOC1
Product: C#CC(O)(c1ccccc1)c1ccncc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Acetylene was passed into a suspension of 174 g (1.55 mol) of potassium tert.-butylate in 750 ml of tetrahydrofuran for about 30 minutes. 198 g (1.08 mol) of 4-benzoylpyridine in 400 ml of tetrahydrofuran were added dropwise to this reaction mixture, acetylene being simultaneously passed in for about a further hour. The mixture was subsequently stirred for 30 minutes, dilute hydrochloric acid was added, the salt which had precipitated was filtered off and the organic phase of the filtrate was separated off. This phase was concentrated in vacuo. The solid residue was triturated with water and the solid was filtered off and washed with methanol/water (1:1). 170 g (75% of theory) of 3-phenyl-3-pyridin-4-yl-1-propyn-3-ol of melting point 165°-66° C. were obtained.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[CH2:22][CH3:23].CCN(C(C)C)C(C)C.O>CC(O)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)([NH:31][C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:21][CH2:22][CH3:23])=[CH:30][CH:29]=3)[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: CCCOc1ccc(N)cc1
Solvent: O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from example 1c supra), 4-propoxy-phenylamine (61 mg, 0.41 mmol) and DIPEA (104.5 mg, 0.81 mmol) in propan-2-ol (10 mL) was stirred at room temperature for 2 h. Then water (10 mL) was added and the desired product was precipitated out, then filtrated and dried to give 98 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one as a white solid. MS: 441 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[N:8]=[C:7]([Cl:9])[C:6]([S:10][CH3:11])=[C:5](Cl)[N:4]=1.C1C=CC=CC=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>C(N(CC)CC)C>[CH3:21][CH2:20][N:22]([CH2:23][CH2:24][NH:25][C:5]1[N:4]=[C:3]([N:2]([CH3:1])[CH3:13])[N:8]=[C:7]([Cl:9])[C:6]=1[S:10][CH3:11])[CH2:26][CH3:27]
Reactant: CCN(CC)CCN
Reactant: CSc1c(Cl)nc(N(C)C)nc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCNc1nc(N(C)C)nc(Cl)c1SC

Procedure:
23.8 parts of 2-dimethylamino-4,6-dichloro-5-methylthio-pyrimidine are placed in 300 parts by volume of benzene and a solution of 12.2 parts of N,N-diethylethylenediamine and 16 parts of triethylamine is added. The mixture is heated under reflux for three hours. After filtering off the triethylamine hydrochloride, the mixture is concentrated, extracted with ether/water, and the organic phase is concentrated and recrystallised from ethyl alcohol. 2-dimethylamino-4-(2'-diethylamine)ethylamino-5-methylthio-6-chloropyrimidine having a melting point of 56°C. is obtained.
Reaction SMILES: [C:1]([N:11]([CH2:13][C:14](O)=[O:15])[CH3:12])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:17]([O:19][CH3:20])=[O:18].[H-].[Na+]>CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([N:11]([CH3:12])[C:13](=[CH:14][OH:15])[C:17]([O:19][CH3:20])=[O:18])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC=O
Reactant: CN(CC(=O)O)C(=O)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)N(C)C(=O)C=Cc1ccccc1
Reaction time: 0.25 h
Yield: 49 %

Procedure:
A solution of the methyl ester of E-N-cinnamoylsarcosine (2.03 g) and methyl formate (ca. 11 ml) in dry DMF (15 ml) was added to a stirred suspension of sodium hydride (0.42 g) in dry DMF (20 ml). Only gentle effervescence was observed at first, but after 40 minutes brisk effervescence began [further methyl formate (3 ml) added], subsiding after about 15 minutes and continuing gently until the mixture was carefully diluted with aqueous sodium carbonate after 7.5 hours. The mixture was extracted with ether, and the extracts were washed with aqueous sodium carbonate then water, dried and concentrated under reduced pressure to give recovered E-N-cinnamoylsarcosine methyl ester (0.975 g). The original basic aqueous layer was acidified with concentrated hydrochloric acid and extracted with ether. The extracts were washed with water, dried and concentrated under reduced pressure to give methyl N-cinnamoyl-N-methyl-2-amino-3-hydroxypropenoate (1.108 g, 49% yield, or 94% based on recovered starting material) as a pale red glass, used without further purification for the next step. The proton n.m.r. spectrum recorded using deuteriochloroform as solvent showed duplication of some signals (presumably due to restricted rotation about the amide bond). However, with deuterated dimethylsulphoxide as solvent, the following single set of signals was seen:
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[S:22][C:21]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:20][N:19]=1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[S:22][C:21]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[N:20][N:19]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3O)s1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl ((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)methyl)carbamate (400 mg, 0.89 mmol) in THF (60 mL) was added 10% Pd(OH)2/C (3 g). The mixture was stirred under H2 atmosphere at it for 3 hrs. The reaction mixture was filtered and concentrated to afford tert-butyl ((5-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)methyl)carbamate as a yellow solid, which was directly used in the next step. ESI-MS (EI+, m/z): 356.1 [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]([NH:17][C:18]3[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[Cl:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35]([NH:24][C:19]3[C:18]([NH:17][C:15]([O:14][CH2:13][CH:10]4[CH2:9][CH2:8][N:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH2:12][CH2:11]4)=[O:16])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1
Reactant: Nc1ccccc1NC(=O)OCC1CCN(c2ccncc2)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: O=C(Nc1ccccc1NC(=O)c1ccc2c(Cl)c[nH]c2c1)OCC1CCN(c2ccncc2)CC1

Procedure:
Using the procedure described in Example 23, Part C, and purifying with preparative RPHPLC method A, N2-[1-(4-pyridyl)piperidin-4-yl]methoxycarbonyl-1,2-benzenediamine (326 mg, 1.0 mmol) and 3-chloroindole-6-carboxylic acid (195 mg, 1.0 mmol) yielded the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:10]([NH:16][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: Cc1cc(C)cc(Br)c1
Product: CCCCCCNc1cc(C)cc(C)c1
Yield: 91.1 %

Procedure:
Using the general procedure, 5-bromo-m-xylene (136 μL, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (20:1) as eluent afforded the desired product as a colorless oil (187 mg, 91% yield).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[C:20]([CH:24]([NH:26]C(=O)OC(C)(C)C)[CH3:25])[CH:21]=[CH:22][CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:26][CH:24]([C:20]1[CH:19]=[C:18]([NH:17][C:14]2[N:15]=[C:16]3[C:8]([C:6]([NH:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:9][NH:10][C:11]3=[N:12][CH:13]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:25]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1cccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 1-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)ethylcarbamate (150 mg, 257 mol) in dichloromethane (4 mL) was added trifluoroacetic acid (587 mg, 397 μL, 5.15 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (4 mL), methanol (2 mL) and ammonium hydroxide (0.7 mL) and the mixture stirred at room temperature for 1 h. The reaction mixture was concentrated then purified by chromatography (silica, 6-10% methanol/dichloromethane) to give 2-(3-(1-aminoethyl)phenylamino)-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (64 mg, 182 mol, 71%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 9.44 (s, 1H), 8.01 (s, 1H), 7.99 (d, J=7.9, 1 H), 7.98 (s, 1H), 7.77 (s, 1H), 7.22 (t, J=7.8, 1 H), 7.20 (s, 1H), 6.98 (d, J=7.8, 1 H), 4.05 (q, J=6.1, 1 H), 1.43 (s, 9H), 1.32 (d, J=6.5, 3 H); MS (EI/CI) m/z: 353.2 [M+H].
Reaction SMILES: Cl[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[C:10](=[S:15])([O:12]CC)[NH2:11]>O>[O:9]=[C:3]1[C:2]2[S:15][C:10](=[O:12])[NH:11][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(N)=S
Reactant: O=C1CCCC(=O)C1Cl
Solvent: O
Product: O=C1CCCc2[nH]c(=O)sc21
Temperature: 140 °C
Yield: 36.1 %

Procedure:
A mixture of 29.3 g of 2-chloro-1,3-cyclohexanedione [Muehlstaedt et al, J. Prakt Chem., Vol. 20 (1963), p. 285] and 21 g of ethyl thiocarbamate was heated at 140° C for 15 minutes and was then poured into water. The precipitate formed was recovered by vacuum filtering and was crystallized from isopropyl alcohol to obtain 12.2 g of 7-oxo-2,3,4,5,6,7-hexahydrobenzothiazoline-2-one melting at 262° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1.[NH3:21]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:10]=[C:11]([S:15]([NH2:21])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(C(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
3-(4-Methoxy-benzoyl)-benzenesulfonyl chloride is dissolved in dichloromethane (10 ml) and treated with 1.7 mL of a 2 M solution of ammonia in methanol. The reaction is stirred at ambient temperature for 2 hours and quenched with 1N HCl. The organic phase is separated and evaporated under reduced pressure to give the crude sulfonamide. Purification by silica gel chromatography (gradient of ethyl acetate in hexanes 5-25%) yielded 100 mg (50% yield) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 8.3 (t, 1H, J=1.6 Hz), 8.1 (m, 1H), 7.95 (m, 1H), 7.8 (d, 2H, J=6.98 Hz), 7.65 (t, 1H, J=7.8 Hz), 7.0 (d, 2H, J=6.98 Hz), 4.95 (s, 2H), 3.9 (s, 3H). MP: 119-122° C. LCMS Elution time 0.81 MS (m/z): 291 (M+1). CHN Calc C, 57.72; H, 4.50; N, 4.81. Found C, 57.65; H, 4.33; N, 4.69
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:29]([NH:28][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:30])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: c1ccncc1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)NC1CCCCC1
Reaction time: 18 h
Yield: 49.8 %

Procedure:
A solution of the compound of Example 45, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.50 mmol) in 30 ml of pyridine was chilled in an ice water bath. With vigorous stirring, the solution was treated with cyclohexyl isocyanate (0.45 mL, 3.50 mmol). After 18 h, the reaction was concentrated to yield an off white solid. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave 716 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-cyclohexylurea as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([NH:15][NH2:16])([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C([BH3-])#N.[Na+]>C(O)C>[C:5]([NH:15][NH:16][CH:2]([CH3:4])[CH3:1])([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: CC(C)=O
Reactant: NNC(=O)OCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)NNC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 87.2 %

Procedure:
Acetone (0.377 g; 0.477 ml; 6.50 mmol) was added to a solution of carbobenzyloxyhydrazine (1.00 g; 6.02 mmol) in absolute ethanol (6 ml). After one hour, the solution was concentrated to dryness and then ethanol (5 ml) and sodium cyanoborohydride (0.19 g; 3.0 mmol) were added. The mixture was stirred for 18 hours and then evaporated to a thick syrup. Hydrochloric acid (0.50 N; 5 ml) and ether (50 ml) were added and the two-phase mixture was stirred for one hour. The aqueous layer was neutralized by addition of solid NaHCO3 and extracted with ether (2×25 ml). The combined ether portions were washed with water and brine and dried (MgSO4) Removal of solvent gave a solid which was recrystallized from hexanes - ether, giving pure hydrazide 4 (1.09 g; 5.25 mmol; 87%), mp 61°-62°. TLC (silica gel; CH2Cl2 --CH3OH; 20:1) Rf=0.5. MS m/e 208 (M+). Analysis: Calculated for C11H16N2O2 : (C, 63.44; H, 7.44; N, 13.45). Found: C, 63.22; H, 7.67; N, 13.71; NMR (CDCl3);δ0.97 (6H,d,J=6); 3.15 (1H, septet, J=6); 3.8-4.6(1H, broad); 5.13(2H,S); 6.2-7.0(1H, broad); 7.33 (5H,S); IR(CHCl3) 3500, 1720 cm-1.
Reaction SMILES: [Na].C([O:4][C:5](=[O:8])[CH2:6][SH:7])C.Cl[C:10]([CH3:18])=[C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:12]=O>C(O)C.C1COCC1.C(OCC)C>[CH2:14]([C:11]1[CH:12]=[C:6]([C:5]([OH:4])=[O:8])[S:7][C:10]=1[CH3:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(Cl)=C(C=O)CC(C)C
Reactant: CCOC(=O)CS
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1CC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.3 %

Procedure:
Sodium (10.7 g, 467 mmol) is dissolved in ethanol (500 mL) and the resulting solution is diluted with THF (100 mL) before mercapto-acetic acid ethyl ester (33.7 g, 280 mmol) dissolved in THF (70 mL) is slowly added at 5° C. The mixture is stirred at rt for 1 h before a solution of 3-chloro-2-isobutyl-but-2-enal (30 g, 187 mmol) in THF (100 mL) is slowly added at 8° C. The resulting yellow suspension is stirred at rt for 16 h. The reaction mixture is diluted with diethyl ether (500 mL) and is washed with dilute aq. NaOCl solution, followed by aq. 1N HCl and water. The organic extract is dried over MgSO4, filtered and evaporated. The remaining orange oil is dissolved in ethanol (150 mL) and 2N aq. LiOH (50 mL) is added. The mixture is stirred for 16 h at 50° C., acidified with 2 N aq. HCl and extracted with EA. The organic extract is dried over MgSO4, filtered and evaporated. The crude product is recrystallized from EA/heptane to give 4-isobutyl-5-methyl-thiophene-2-carboxylic acid (10.5 g) as colourless crystals; LC-MS: tR=0.92 min, [M+1+CH3CN]=240.16; 1H NMR (CDCl3): δ 7.59 (s, 1H), 2.40-2.37 (m, 5H), 1.84 (hept, J=7.0 Hz, 1H), 0.90 (d, J=7.0 Hz, 6H).
Reaction SMILES: Cl.[CH:2]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([NH2:19])[C:7]=2[N:6]=1)([CH3:4])[CH3:3].[CH2:20]([O:22][CH2:23][CH2:24][C@H:25]1[CH2:30]N[CH2:28][CH2:27][NH:26]1)[CH3:21]>>[CH2:20]([O:22][CH2:23][CH2:24][C@@H:25]1[NH:26][CH2:27][CH2:28][N:19]([C:8]2[C:7]3[N:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[S:14][C:13]=3[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=2)[CH2:30]1)[CH3:21]
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Reactant: CCOCC[C@H]1CNCCN1
Agent: Cl
Product: CCOCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1

Procedure:
In a manner similar to that described in Example 300, combine 2-isopropyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine hydrochloride (0.523 g, 1.77 mmol) and (S)-2-(2-ethoxyethyl)piperazine (0.561 g, 3.54 mmol) to obtain the title compound: mass spectrum (APCI): m/z =400.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C:5]1[NH:9][C:8]([C:10]2[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=2)[C:15]([O:17]C)=[O:16])=[N:7][CH:6]=1)=[O:4].O1CCCC1>[Li+].[OH-]>[CH3:1][N:2]([CH3:22])[C:3]([C:5]1[NH:9][C:8]([C:10]2[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=2)[C:15]([OH:17])=[O:16])=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ncc(C(=O)N(C)C)[nH]2)c(C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2ncc(C(=O)N(C)C)[nH]2)cc1C(=O)O
Temperature: 25 °C
Yield: 52.7 %

Procedure:
Methyl 5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoate (compound 232.1, 113 mg, 0.37 mmol) was dissolved in 2N LiOH aqueous (1 ml) and tetrahydrofuran (THF) (5 ml) and heated to 50° C. for 16 hours. After cooling to ambient temperature, the organic solvent was removed in vacuo. The pH of the remaining aqueous layer was adjusted with 2N HCl to pH 3-4. The resulting precipitate was collected by filtration and dried to afford 56 mg of 5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoic acid (53%). m/z (ES+) 288 (M+H)+.