Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[N:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:13]=2)[S:9][CH:10]=1)=[O:5])C.[OH-].[K+]>CO>[CH3:21][C:18]([C:16]1[C:15]([OH:22])=[C:14]([C:23]([CH3:24])([CH3:25])[CH3:26])[N:13]=[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[N:17]=1)([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1csc(Nc2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1nc(Nc2nc(C(=O)O)cs2)nc(C(C)(C)C)c1O
Reaction time: 3.5 h

Procedure:
A solution of 2-([4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]amino)-4-thiazolecarboxylic acid ethyl ester (0.5 g, 1.3 mmol) in 20 mL of methanol is treated with 10 mL of 1.0N KOH (aq) at room temperature. After 3.5 hours, the methanol is removed under reduced pressure, and the aqueous solution is acidified to pH 4 with concentrated HCl. The resulting precipitate is collected by filtration and recrystallized from MeOH/water. Yield of 2-([4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]amino)-4-thiazolecarboxylic acid is 0.09 g (26%); mp 251°-253° C.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[C:5]([O:9][C:10]([N:12]([CH3:17])[CH2:13][CH2:14][NH:15][CH3:16])=[O:11])([CH3:8])([CH3:7])[CH3:6]>>[C:5]([O:9][C:10]([N:12]([CH3:17])[CH2:13][CH2:14][N:15]([CH2:3][CH2:2][C:1]#[N:4])[CH3:16])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Reactant: C=CC#N
Product: CN(CCC#N)CCN(C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
530 mg of acrylonitrile were slowly added to 1.88 g of N-(tert-butoxycarbonyl)-N,N'-dimethyl-ethylenediamine, while cooling with ice. The mixture was stirred at 0° C. for 1 hour, at RT for 14 hours and at 60° C. for 2 hours. The volatile constituents were removed in vacuo and the residue was purified by chromatography over silica gel (EA:MeOH 9:1). 1.92 g of product were obtained. MS(Cl): 242 (M+H)⊕, 186, 142
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:37][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][CH:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:38][CH3:39].[ClH:40]>O1CCOCC1>[ClH:40].[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:37][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:38][CH3:39]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNCC4CCN(C(=O)OC(C)(C)C)CC4)ccnc3[nH]1)cn2C
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCC4CCNCC4)ccnc3[nH]1)cn2C

Procedure:
The product is prepared by following the procedure described in example 51 starting with 0.115 g of tert-butyl 4-({[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}methyl)piperidine-1-carboxylate instead of the tert-butyl (2-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}ethyl)carbamate used in example 51 and 1.3 cm3 of 5N hydrochloric acid in dioxane. 0.101 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-piperidin-4-ylmethylamine hydrochloride is obtained with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N12CCCN=C1CCCCC2.[F:23][CH:24]([F:43])[O:25][C:26]1[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33](C2C=CC=CC=2)[C:34](=O)[O-:35])[N:27]=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([S:8]([NH:11][C:34]([NH:33][C:28]2[N:27]=[C:26]([O:25][CH:24]([F:43])[F:23])[CH:31]=[C:30]([CH3:32])[N:29]=2)=[O:35])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(OC(F)F)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: NS(=O)(=O)c1cccnc1Cl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(OC(F)F)nc(NC(=O)NS(=O)(=O)c2cccnc2Cl)n1
Reaction time: 2 h
Yield: 90 %

Procedure:
To a mixture of 0.652 g of 2-chloro-3-pyridinylsulfonamide and 0.55 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene in 10 ml of absolute dioxan is added, at 25° C., 1 g of N-(4-difluoromethoxy-6-methylpyrimidin-2-yl)phenylcarbamate. The reaction mixture is stirred for another 2 hours at the same temperature and then concentrated. The residue is taken up in ice/water and neutralised with 1.86 ml of 2N hydrochloric acid. The precipitate is isolated, washed with water and dreid, affording 1.2 g (90%) of N-(2-chloro-3-pyridinylsulfonyl)-N'-(4-difluoromethoxy-6-methylpyrimidin-2-yl)urea (compound 1.15) with a melting point of 161°-162° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=[CH:12][C:11]=2[NH:21]C(=O)OC(C)(C)C)=[O:8])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:21][C:11]1[CH:12]=[CH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:15][C:10]=1[NH:9][C:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)C1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cccs2)cc1NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a stirred solution of tert-butyl (2-(tetrahydro-2H-pyran-4-carboxamido)-4-(thiophen-2-yl)phenyl)carbamate in dichloromethane (20 mL) was added trifluoroacetic acid (7 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. the solvents were then removed under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added. The product was extracted with EtOAc, washed with water and brine, dried, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, MeOH/CH2Cl2) to afford N-(2-amino-5-(thiophen-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide as a beige solid (1.1 g, 86% yield). ESI+ MS: m/z 303 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 9.12 (s, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.34 (d, J=5.0 Hz, 1H), 7.24-7.18 (m, 2H), 7.03 (dd, J=5.5; 3.5 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 5.05 (s, 1H), 3.91 (dd, J=11.0; 2.0 Hz, 2H), 3.36 (dt, J=11.0; 2.0 Hz, 2H), 2.68-2.62 (m, 1H), 1.80-1.64 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18](Br)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(N(CC)CC)C.[C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1)#[CH:34]>C1(C)C=CC=CC=1.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.[Cu]I>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:34]#[C:33][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:37][CH:36]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(Br)c2)Cc2ccccc2C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(C#Cc3ccc(C(F)(F)F)cc3)c2)Cc2ccccc2C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
300 mg (0.74 mmol) of the compound of step 1 and 90.1 mg (0.89 mmol) of triethylamine were dissolved in 10 ml of dry toluene. 171.5 mg (148 μmol) of tetrakis(triphenylphosphine)palladium(0) and 14.1 mg (74 μmol) of copper(I) iodide were added, and the mixture was stirred for 30 min. Subsequently 126.2 mg (0.74 mmol) of 1-ethynyl-4-trifluoromethyl-benzene were added and the mixture was heated to 100° C. for 10 h. The mixture was filtered, the solvent was evaporated and the residue was purified by preparative RP HPLC (water/ACN gradient) to give 40 mg of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]2[CH2:13][CH2:14][CH2:15][C:16](=[O:17])[C:4]=12.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:15]1[CH2:14][CH2:13][C:5]2=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:7][C:3]([S:2][CH3:1])=[C:4]2[C:16]1=[O:17]
Reactant: CCOC(=O)c1oc(SC)c2c1CCCC2=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc(SC)c2c1CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
Ethyl 4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]furan-1-carboxylate (4.26 g) was dissolved in chloroform (75 ml); a solution of bromine (2.73 g) in chloroform (5 ml) was added dropwise at room temperature over a period of 10 minutes. After the reaction mixture was stirred at room temperature for 30 minutes, it was washed with a 2% aqueous solution of sodium sulfite (100 ml), water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]furan-1-carboxylate (5.01 g, 89.8%), which was then recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 130-131° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([S:23][C:24]2[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: Cc1ccc(Sc2cccc(O)c2)c(N)c1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3cccc(O)c3)ccnc2n1

Procedure:
The product from Example 2g (275 mg, 1.33 mmol) was reacted with the product from Example 52b (307 mg, 1.33 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (305 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.75-1.94 (m, 2H) 2.38 (s, 3H) 2.98 (t, J=7.35 Hz, 2H) 6.30 (d, J=6.99 Hz, 1H) 6.49-6.66 (m, 3H) 6.91-7.04 (m, 1H) 7.29-7.44 (m, 3H) 7.79 (d, J=8.82 Hz, 1H) 8.39 (d, J=7.35 Hz, 1H) 8.96 (d, J=8.46 Hz, 1H) 9.57 (s, 1H) 10.95 (s, 1H) 14.34 (s, 1H); MS (ESI+) m/z 402 (M+H−TFA)+.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[NH:11][C:12]([C:14]1[NH:18][C:17]2[C:19]([Cl:23])=[C:20]([Cl:22])[S:21][C:16]=2[CH:15]=1)=[O:13].CCN(CC)CC.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>C(Cl)Cl>[Cl:22][C:20]1[S:21][C:16]2[CH:15]=[C:14]([C:12]([NH:11][C@H:3]3[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]3[NH:1][C:33]([N:32]([CH3:36])[CH3:31])=[O:34])=[O:13])[NH:18][C:17]=2[C:19]=1[Cl:23]
Reactant: N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
To a solution of N-[(1S,2S)-1-amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 9, 240 mg, 0.5 mmol) and Et3N (101 mg, 1.0 mmol) in DCM (4 mL) was added a solution of dimethylcarbamoyl chloride (54 mg, 0.5 mmol) in DCM (1 mL). The reaction was stirred at ambient temperature for 2 hours, washed with saturated NaHCO3 (1 mL), water (1 mL), brine (1 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (50 mg, 23%) as a foam.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].C[Sn]([N:28]=[N+:29]=[N-:30])(C)C.Cl>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:30][N:29]=[N:28][N:23]=3)=[CH:12][CH:11]=2)[N:4]=1)[CH3:2]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=N)s1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Yield: 16 %

Procedure:
In 10 ml of toluene, 1.6 g of 5-ethyl-2-imino-3-(2'-cyanobiphenyl-4-yl)methyl-1,3,4-thiadiazoline and 1.1 g of trimethyltin azide were suspended, followed by heating under reflux for 4 hours. After cooling, the reaction mixture was subjected to column chromatography on a silica gel and eluted using chloroform:methanol (20:1)→chloroform:methanol:acetic acid (20:10:1). The eluate fractions thus obtained were distilled off under reduced pressure. To the resulting residue, 40 ml of 2N sodium hydroxide and 40 ml of ethyl acetate were added. The aqueous layer so obtained was neutralized with 12N hydrochloric acid and powders so precipitated were collected by filtration. The powders were successively washed with water, ethanol and diethyl ether and then dried, whereby 290 mg of the title compound was obtained.
Reaction SMILES: [C:1]([CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)(=O)C>O1CCCC1>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[O:23])[CH2:2][C:1]([CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[O:3])[CH3:22]
Reactant: CC(=O)C1COc2ccccc2C1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)C1COc2ccccc2C1=O
Temperature: -40 °C

Procedure:
A solution of 3-acetyl-4-chromanone (1.8 g, 9.5 mmoles, described in Example 5) in dry tetrahydrofuran (20 ml) is added dropwise to a suspension of 57% sodium hydride (1.17 g, 28.5 mmoles) in tetrahydrofuran (30 ml) and the mixture is heated at reflux temperature for 15 min. A solution of diethyl oxalate (1.39 g, 9.5 mmoles) is added dropwise under an atmosphere of nitrogen. The reaction mixture is heated at reflux temperature overnight and cooled to -40° C. A solution of 50% aqueous acetic acid (4 ml) is added and the reaction mixture evaporated. The residue is partitioned between chloroform and water, the organic phase is separated and the aqueous phase is re-extracted with chloroform. The combined chloroform extracts are dried and evaporated. The residue is subjected to chromatography on silica gel. Elution with chloroform affords 4-(4-chromanon-3-yl)-2,4-dioxobutyric acid ethyl ester (VII; R1, R2, R3R4 and R17 = H, R19 = C2H5 and X = O), which is crystallized from ether, m.p. 117°-119° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Na].[N+:7]([C:10](=[C:15]1[NH:20][CH2:19][CH2:18][CH2:17][S:16]1)[C:11]([O:13][CH3:14])=[O:12])([O-:9])=[O:8]>C1COCC1>[CH3:14][O:13][C:11](=[O:12])[C:10](=[C:15]1[N:20]([C:2]([O:4][CH3:5])=[O:3])[CH2:19][CH2:18][CH2:17][S:16]1)[N+:7]([O-:9])=[O:8]
Reactant: COC(=O)Cl
Reactant: COC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)C(=C1SCCCN1C(=O)OC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° a solution of 16.0 g of methyl chloroformate in THF was added dropwise to a solution of the sodium derivative of 32.7 g of methyl nitro(tetrahydro-2H-1,3-thiazin-2-ylidene)acetate (3A; Example 2, Ser. No. 554,371) in THF. The stirred solution was then allowed to warm to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the residue was poured into ether. The ether phase was washed with water, dried (MgSO4) and the solvent evaporated under reduced pressure. The resulting oil was mixed with pentane to give 3, as yellow crystals, m.p.: 71°-2°.
Reaction SMILES: [CH2:1]([CH:3]([CH2:29][CH3:30])[CH:4]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:2].[Li+].[OH-]>O.O1CCOCC1>[CH2:29]([CH:3]([CH2:1][CH3:2])[CH:4]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:30]
Reactant: CCC(CC)C(c1ccc2nc(-c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(CC)C(c1ccc2nc(-c3ccc(C(=O)O)cc3)sc2c1)n1ccnc1
Reaction time: 8 h

Procedure:
A solution of methyl 4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate (74 mg, 0.176 mmol) and LiOH (37 mg, 0.882 mmol) in water (1.5 mL) and dioxane (3 mL) was heated to 50° C. and stirred overnight. The solvent was evaporated, water was added and neutralized to pH 7 using 1 N HCl and evaporated. The crude product was purified by preparative TLC using 30% MeOH in DCM as eluent to afford to 4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoic acid as white solid. MS (ES+): m/z 406.28 (MH+).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:15])[CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=O.[CH3:22][C:23]1[S:24][CH:25]=[C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH:31]=O)[N:27]=1>>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:15]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([C:26]3[N:27]=[C:23]([CH3:22])[S:24][CH:25]=3)[CH:29]=2)[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Reactant: COC(=O)CCCC(N)c1ccccc1-c1ccccc1
Product: Cc1nc(-c2cccc(CN3C(=O)CCCC3c3ccccc3-c3ccccc3)c2)cs1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-([1,1′-biphenyl]-2-yl)-5-aminopentanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 439.10 g/mol.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH:15]1[CH:19]([O:20][Si](C(C)(C)C)(C)C)[CH2:18][N:17]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:16]1)[C:11](=[O:14])[CH2:12][Cl:13])(C)(C)C>Cl.O1CCOCC1>[NH2:7][CH2:8][CH2:9][N:10]([CH:15]1[CH:19]([OH:20])[CH2:18][N:17]([C:28](=[O:36])[C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:16]1)[C:11](=[O:14])[CH2:12][Cl:13]
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)CCl)C1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: NCCN(C(=O)CCl)C1CN(C(=O)c2ccc(Cl)cc2)CC1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
{2-[[4-(tert-Butyl-dimethyl-silanyloxy)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-(2-chloro-acetyl)-amino]-ethyl}-carbamic acid tert-butyl ester (260 mg, 0.45 mmol) was dissolved in 1 mL of 4M HCl in dioxane solution. The mixture was stirred at RT for 1.5 h. After concentrating, a white solid was formed (200 mg). The LC-Mass showed two products as showed above. MS: (ESI), M/Z, 360 (M+1). Retention time: 1.31 min (FA-polar). MS: (ESI), M/Z, 474 (M+1). Retention time: 2.20 min (FA-polar).
Reaction SMILES: [F:1][S:2]([F:15])([F:14])([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[Br-:16].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>C1COCC1>[Br:16][CH2:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([S:2]([F:12])([F:13])([F:14])([F:15])[F:1])=[CH:8][CH:7]=1)=[O:11]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(S(F)(F)(F)(F)F)cc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[4-(pentafluoro-λ6-sulfanyl)phenyl]ethanone (Preparation 41, 0.6 g, 2.44 mmol) in THF (20 mL) at 0° C. was added trimethylphenylammonium tribromide (0.962 g, 2.56 mmol). After stirring for 2 hours at 0° C. the reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate. The reaction was extracted with ethyl acetate and dried over MgSO4 before concentrating in vacuo to afford the title compound that was used without further purification.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[CH:13][CH:12]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: Clc1ccc(OCCCCCCCBr)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCCCCCCCOc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium (2.5 g., 0.11 M) was dissolved in absolute ethanol (50 ml) and ethyl 4-hydroxybenzoate (16.6 g., 0.10 M) in ethanol (50 ml) was added at room temperature. The mixture was stirred at room temperature for 15 min, 1-bromo-7-(4-chlorophenoxy)-heptane (0.10 M) in ethanol (50 ml) was added in one portion and the mixture was boiled under reflux with stirring for 24 hours. The hot solution was filtered to remove sodium bromide, the ethanol removed under vacuum, the product dissolved in dichloromethane (100 ml) and washed with 5% sodium hydroxide solution (2×100 ml) and water (2×100 ml). The dichloromethane solution was dried (MgSO4), filtered, evaporated and the product purified by crystallisation, from ethanol m.p. 70°-71°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[N:14]=1>CN(C=O)C.CCN(CC)CC.[Pd]>[CH3:1][O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C
Temperature: 25 °C
Reaction time: 44 h

Procedure:
A suspension of 10% Pd/C (53% water; 30 mg) and tert-butyl 4-(5-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A17) (125 mg, 0.231 mmol) in DMF (5 mL) and Et3N (1 mL) was stirred under a hydrogen atmosphere at room temperature for 44 hours. The resulting mixture was filtered through Celite, washing with EtOAc (200 mL). The combined filtrates were evaporated in vacuo and the resulting oil purified by silica gel chromatography (Biotage Isolera, 12 g SiO2 cartridge, 0-100% EtOAc in hexanes) to give the title compound A18 as a yellow foam (115 mg, 91%); 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J=2.5 Hz, 1H), 8.16 (dd, J=8.5, 2.7 Hz, 1H), 8.11 (d, J=0.5 Hz, 1H), 7.25-7.16 (m, 5H), 7.11 (d, J=8.5 Hz, 1H), 4.25 (br. s, 2H), 3.71 (s, 2H), 3.67 (s, 3H), 3.09 (dd, J=9.6, 6.1 Hz, 2H), 2.93 (dd, J=9.4, 6.0 Hz, 2H), 2.88-2.76 (m, 3H), 2.08 (s, 3H), 1.91 (d, J=11.8 Hz, 2H), 1.75-1.61 (m, 2H), 1.47 (s, 9H). LCMS-A: rt 5.401 min; m/z 546 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C:4]2([CH2:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][Br:17])[C:8](=[O:18])[CH2:7]2)[CH2:3]1.[C:19](Cl)(=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CC#N>[C:19]([O:1][CH:2]1[CH2:6][CH2:5][C:4]2([CH2:7][C:8](=[O:18])[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][Br:17])[C:10](=[O:12])[CH2:11]2)[CH2:3]1)(=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C1CC2(CCC(O)C2)CC(=O)N1CCCCBr
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CC#N
Product: CCCCCCCCCC(=O)OC1CCC2(CC(=O)N(CCCCBr)C(=O)C2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
2-Hydroxy-8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9dione (2.55 g, 1.00 equiv) was dissolved in 100 mL of anhydrous CH3CN and cooled in an ice-water bath to 0° C. Decanoyl chloride (1.80 mL, 1.08 equiv) was added dropwise neat. The ice-water bath was removed and the reaction was stirred an additional 18 h. The solvent was removed in vacuo and the resultant oil was flash chromatographed with 20% EtOAc/hexane to yield the title compound (3.03 g, 80%) as a clear liquid.