Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:34][C:35]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[NH:37][CH:36]=3)[C:20]([NH:22][C@H:23]([CH2:27][S:28][S:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([OH:26])=[O:25])=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O>[NH2:18][C@@H:19]([CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)[C:20]([NH:22][C@H:23]([CH2:27][S:28][S:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:24]([OH:26])=[O:25])=[O:21]
Reactant: CC(C)(C)SSC[C@@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)SSC[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A solution of ((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (Fmoc-Trp-D-Cys(StBu)-OH) (Compound SP642) (1.93 g, 3.12 mmol) in N,N-dimethylformamide (6.3 mL) was mixed with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (706 μL, 4.69 mmol) with stirring at room temperature, and the reaction solution was stirred at room temperature for 1 hour. 1 N hydrochloric acid was added to the reaction solution, and the organic layer was extracted with ethyl acetate, washed with brine and then dried over sodium sulfate. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((S)-2-amino-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (H-Trp-D-Cys(StBu)-OH) (Compound SP643) (870 mg, 2.20 mmol, 70%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:12]([C@H:16]1[C:43](=[O:44])[N:42]2[CH2:45][C@@H:39]([CH2:40][C@H:41]2[C:46]([O:48][CH3:49])=[O:47])[O:38][C:28]2=[N:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[C:36]([OH:37])=[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[CH2:50][CH2:51][CH2:52][C@H:20]2[O:19][C:18](=[O:53])[NH:17]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C@H:16]1[C:43](=[O:44])[N:42]2[CH2:45][C@@H:39]([CH2:40][C@H:41]2[C:46]([O:48][CH3:49])=[O:47])[O:38][C:28]2=[N:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[C:36]([O:37][CH2:3][CH2:4][CH2:5][N:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[CH2:50][CH2:51][CH2:52][C@H:20]2[O:19][C:18](=[O:53])[NH:17]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: ClCCCN1CCCCC1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1OCCCN1CCCCC1)O2

Procedure:
The title compound was prepared using the same method as described in Example 42 using 1-(3-chloropropyl)piperidine hydrochloride as the alkylating agent with the product of Step 1. LRMS (ES+) m/z 707.5 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])=[O:13])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])=[O:13]
Reactant: COc1ccc(C(=O)N2CCCC2=O)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(=O)N2CCCC2=O)cc1O

Procedure:
2.0 g of 1-(3-benzyloxy-4-methoxybenzoyl)-2-pyrrolidinone are hydrogenated in 60 ml of absolute methanol with 0.5 g of 5% palladium/carbon under atmospheric pressure and at room temperature. The catalyst is filtered off and the filtrate is concentrated and stirred with diethyl ether. After filtration, there is obtained 1-(3-hydroxy-4-methoxybenzoyl)-2-pyrrolidinone of melting point 123°-125° C.
Reaction SMILES: [C:1]1([CH:7]2[C:12]3[CH:13]=[C:14]([CH:16]=O)[S:15][C:11]=3[C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[O:8]2)[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.C(O)(=O)[CH2:23][C:24]([OH:26])=[O:25].N1C=CC=CC=1.N1CCCCC1>O>[C:1]1([CH:7]2[C:12]3[CH:13]=[C:14]([CH:16]=[CH:23][C:24]([OH:26])=[O:25])[S:15][C:11]=3[C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[O:8]2)[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc2c(s1)-c1ccccc1OC2C1=CCCC=C1
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc2c(s1)-c1ccccc1OC2C1=CCCC=C1

Procedure:
A stirred solution of 17.6 g 4H-4-phenyl-thieno[3,2-c][1]benzopyran-2-carboxaldehyde, 12.5 g malonic acid and 24 ml pyridine is slightly heated until a clear solution is obtained. Subsequently, 1 ml piperidine is added and the solution slowly heated to reflux. After 3 h reflux, the solution is cooled and poured into water. After acidification with hydrochloric acid, the crude product is filtered off, dried, recrystallized from ethyl acetate and dried in vacuo. Pure 3-(4H-4-phenyl-thieno[3,2-c][1]benzopyran-2yl)propenoic acid is obtained; m.p. 235° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12](Cl)(=[O:14])=[O:13])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].CCN(C(C)C)C(C)C.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>O1CCOCC1.O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:14])=[O:13])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(Br)c(F)c(S(=O)(=O)Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc(Br)c(F)c(S(=O)(=O)N2CCOCC2)c1
Reaction time: 2 h

Procedure:
To a solution of 3-Bromo-5-chlorosulfonyl-4-fluoro-benzoic acid (3.0 g) in dioxane/water (9/1 (v/v), 30 ml) was added DiPEA (5 ml) and morpholine (1.65 ml). After stirring for 2 h, the mixture was diluted with EtOAc and washed with 2 M aq. HCl. The organic layer was dried (Na2SO4) and concentrated in vacuo. Yield: 2.6 g.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)[S:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:42]1([S:48]([N:51]2[C:59]3[CH:58]=[CH:57][N:56]=[C:55](Br)[C:54]=3[CH:53]=[CH:52]2)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+]>[C:42]1([S:48]([N:51]2[C:59]3[CH:58]=[CH:57][N:56]=[C:55]([C:11]4[N:12]=[C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[C:8]5[N:28]=[C:27]([CH2:29][N:30]6[CH2:35][CH2:34][N:33]([C:36]([CH3:40])([CH3:41])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]6)[S:26][C:9]=5[N:10]=4)[C:54]=3[CH:53]=[CH:52]2)(=[O:50])=[O:49])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)nccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C(N)=O)CC3)sc2n1
Agent: [Cu+]
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4nccc5c4ccn5S(=O)(=O)c4ccccc4)nc3s2)CC1
Temperature: 25 °C

Procedure:
A degassed solution of 2-[4-(7-morpholin-4-yl-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidin-2-ylmethyl)piperazin-1-yl]isobutyramide (250 mg, 0.36 mmol), 1-benzenesulfonyl-4-bromo-1H-pyrrolo[3,2-c]pyridine (130 mg, 0.39 mmol), PdCl2{PtBu2(Ph-p-Nme2)}2 (26 mg, 0.036 mmol) and copper(I) thiophene-2-carboxylate (14 mg, 0.07 mmol) in 1,4-dioxane (4 mL) was subjected to microwave irradiation at 140° C. for 20 minutes. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated to give 2-{4-[5-(1-benzenesulfonyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperazin-1-yl}isobutyramide as a crude oil. Aqueous NaOH (12.5 M, 0 4 mL) was added to a solution of 2-{4-[5-(1-benzenesulfonyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl]-piperazin-1-yl}isobutyramide in 1,4-dioxane (4 mL) and IMS (4 mL). The reaction mixture was stirred at ambient temperature for 45 min, then concentrated in vacuo. The residue was dissolved in MeOH then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated to afford a solid. The solid was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 98:2 to 96:4) followed by reversed phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 169 as a yellow solid (43 mg, 23%). LCMS (method E): RT=5.03 min, [M+H]+=522.2. 1H NMR (CDCl3, 400 MHz) δ 8.55 (d, J=5.6 Hz, 1 H), 7.45-7.40 (m, 2 H), 7.38 (d, J=3.3 Hz, 1 H), 7.11 (d, J=5.3 Hz, 1 H), 5.25 (d, J=5.3 Hz, 1 H), 4.53-4.42 (m, 4 H), 3.90 (m, 6 H), 2.68 (m, 4 H), 2.62 (m, 4 H), 1.25 (s, 6 H)
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]1(/[CH:10]=[CH:11]/[C:12](=O)[CH3:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH3:13][C:12]1[CH2:11][CH:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:3][N:2]=1
Reactant: NN
Reactant: CC(=O)/C=C/c1ccccc1
Solvent: O
Solvent: CO
Product: CC1=NNC(c2ccccc2)C1
Yield: 74.8 %

Procedure:
17.1 g (342 mmol) of hydrazine monohydrate was dissolved in 500 ml of methanol. Then, 50 g (342 mmol) of trans-4-phenyl-3-buten-2-one dissolved in 100 ml of methanol was gradually dropwise added thereto under stirring within a range of from 5° C. to 15° C. Then, the mixture was stirred at room temperature for 30 hours, and methanol was distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain 41.0 g of the desired 3-methyl-5-phenyl-2-pyrazoline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[C@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[O:9]2)=[CH:4][CH:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H]1OC(c2ccc(Br)cc2)OC1=O
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(Br)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Zinc chloride (1.12 l of 1M solution in ether, 1120 mmol) was added to 500 ml ether at −40° C. (5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one (3:2 mixture of cis/trans) (56 g, 187 mmol) was then added dropwise in 200 ml ether (over 15 min), followed by phenylmagnesium bromide (125 ml of a 3M solution in ether, 374 mmol) (dropwise over 45 min). The solution was stirred at 0° C. for 2 hours. The reaction was quenched at 0° C. with 800 ml of a saturated solution of NH4Cl, the phases were separated and the aqueous layer extracted with 800 ml ether. The organic layers were combined, washed with brine, dried with MgSO4 and the solvent was removed. (2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid (de=86%) was obtained after purification on silica gel (5% ethyl acetate/toluene).
Reaction SMILES: [I-].[CH:2]1([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=O)[CH3:38]>O1CCCC1.O>[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=[CH:7][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:38]
Reactant: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Reactant: c1ccc([P+](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC1CCCC1)c1ccc(SC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
A solution of cylcopentylmethyl triphenylphosphonium iodide (prepared in Example 33, 725 mg, 1.53 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was treated with a 1.0M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.14 mL, 2.14 mmol). The reaction was stirred at 0° C. for 45 min. At this time, the reaction was treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (355 mg, 1.37 mmol) in tetrahydrofuran (5 mL). The reaction was then warmed to 25° C. and stirred at 25° C. for 20 h. The reaction was then diluted with water (50 mL) and extracted with diethyl ether (3×25 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-acrylic acid ethyl ester (267 mg, 60%, 2:1 mixture of E:Z isomers) as a yellow oil and taken on without characterization.
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.C(C1C=C(C=CC=1)N)#N.C[O:35][C:36]1[CH:37]=[C:38]([C:42]2[C:43]3[CH2:56][CH2:55][N:54]([C:57]4[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=4)[C:60]#[N:61])[C:44]=3[N:45]=[C:46]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[N:47]=2)[CH:39]=[CH:40][CH:41]=1>>[OH:35][C:36]1[CH:37]=[C:38]([C:42]2[C:43]3[CH2:56][CH2:55][N:54]([C:57]4[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=4)[C:60]#[N:61])[C:44]=3[N:45]=[C:46]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[N:47]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccc(C#N)c2)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Agent: N#Cc1cccc(N)c1
Product: N#Cc1cccc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 3-cyanoaniline, 3-[4-(3-methoxy-phenyl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-benzonitrile was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[CH3:22][C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15]
Reactant: [H][H]
Reactant: CC(C)(c1ccccc1)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(c1ccccc1)N1CCNCC1

Procedure:
1-Benzyl-4-(1-methyl-1-phenyl-ethyl)-piperazine (290 mg, 1.0 mmol) was dissolved in ethanol (3 ml), and the solution was mixed with 10% palladium-carbon (60 mg) and stirred at room temperature for 15 hours in an atmosphere of hydrogen. The catalyst was removed by filtering the reaction solution, and the solvent was removed by evaporation under a reduced pressure to obtain crude 4-(1-methyl-1-phenyl-ethyl)-piperazine. The thus obtained crude 4-(1-methyl-1-phenyl-ethyl)-piperazine, 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (310 mg, 1.0 mmol) and potassium carbonate (210 mg, 1.5 mmol) were stirred at room temperature for 14 hours in anhydrous N,N-dimethylformamide (3 ml). The reaction solution was mixed with ethyl acetate and washed with water and saturated brine, the solvent was removed by evaporation under a reduced pressure and then the thus obtained residue was dissolved in dichloromethane. The dichloromethane solution was washed with water and saturated brine and dried with anhydrous sodium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 33 mg (0.076 mmol, 7.7% in yield) of the title compound.
Reaction SMILES: FC(F)(F)C1C=C(C=C([NH:18][C:19]([CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25](OC4C=CN=C(C5NC(C(F)(F)F)=CN=5)C=4)=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])C=1)CNC(=O)OC(C)(C)C.Cl>O1CCOCC1>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][CH:21]1[C:19]([NH2:18])=[O:20]
Reactant: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5ncc(C(F)(F)F)[nH]5)c4)cc3C2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C1CCc2ccccc2C1
Reaction time: 1 h

Procedure:
tert-Butyl [3-(trifluoromethyl)-5-({[7-({2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbonyl}amino)benzyl]carbamate (45.0 mg, 0.07 mmol) was treated with a solution of 4.0M HCl in dioxane (12.0 mL) and stirred for 1 h. The solvents were evaporated to give N-[3-(aminomethyl)-5-(trifluoromethyl)phenyl]-7-({2-5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-332 as the HCl salt (41.0 mg, 94.9%). 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 10.58 (s, 1H), 8.54 (d, 1H), 8.31 (br s, 2H), 8.02 (d, 2H), 7.87 (s, 1H), 7.57 (s, 1H), 7.38 (d, 1H), 7.26 (d, 1H), 7.08-7.09 (m, 1H), 7.05 (d, 1H), 6.99-7.02 (m, 1H), 4.09 (q, 2H), 2.85-2.98 (m, 5H), 2.09-2.16 (m, 1H), and 1.79-1.89 (m, 1H). LCMS: (FA) ES+576.3, ES−574.4.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)[CH2:3]1.[CH3:32][C:33]1[S:37][C:36]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)=[N:35][CH:34]=1.CCN(CC)CC>C1COCC1>[CH3:32][C:33]1[S:37][C:36]([NH:38][C:39](=[O:40])[NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]3[CH:16]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][CH:19]=4)[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)[CH2:3]2)=[N:35][CH:34]=1
Reactant: Cc1cnc(NC(=O)Oc2ccccc2)s1
Reactant: NC(=O)c1cnc(N2CCC[C@@H](N)C2)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cnc(NC(=O)N[C@@H]2CCCN(c3cc(Nc4ccc(C(=O)N5CCOCC5)cc4)c(C(N)=O)cn3)C2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
A mixture of (R)-6-(3-aminopiperidin-1-yl)-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (34 mg, 0.080 mmol) and phenyl 5-methylthiazol-2-ylcarbamate (24.39 mg, 0.104 mmol) in THF (2 mL) was added Et3N (0.015 mL, 0.104 mmol) and capped in a vial and stirred at rt overnight. The reaction mixture was chromatographed (ISCO Companion 40 g silica gel column and eluted with NH4OH/MeOH/CH2Cl2 gradient (4-10%) to give 20 mg of (R)-6-(3-(3-(5-methylthiazol-2-yl)ureido)piperidin-1-yl)-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a white solid. LCMS: (M+H)+=565.19. 1H NMR (400 MHz, CDCl3) δ ppm 10.35 (1H, s), 8.36 (1H, br. s.), 7.40 (2H, d, J=8.35 Hz), 7.24 (2H, d, J=8.57 Hz), 6.83 (1H, s), 6.35 (1H, s), 3.31-4.02 (13H, m), 2.30 (3H, s), 1.94 (1H, br. s.), 1.53-1.80 (3H, m).
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[OH:34][CH:35]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:34][CH:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:20]2[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[CH2:36]1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: OC1CCCNC1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CNS(=O)(=O)c1ccc(N2CCCC(O)C2)c(C(=O)O)c1
Yield: 15 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example S) from 2-Chloro-5-methylsulfamoyl-benzoic acid and rac-3-hydroxy-piperidine and obtained in 15% yield. MS (m/e): 312.9 (MH− 100%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:29](O)=[O:30])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:21][CH2:20][C:19]4[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=4[NH:17][C:16]3=[O:28])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].Cl.Cl.[CH3:34][C:35]1([CH3:44])[CH2:40][NH:39][CH2:38][C:37]2[CH:41]=[N:42][NH:43][C:36]1=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:34][C:35]1([CH3:44])[CH2:40][N:39]([C:29]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][N:7]=[C:6]([N:9]3[CH2:14][CH2:13][CH:12]([N:15]4[CH2:21][CH2:20][C:19]5[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=5[NH:17][C:16]4=[O:28])[CH2:11][CH2:10]3)[CH:5]=2)=[O:30])[CH2:38][C:37]2[CH:41]=[N:42][NH:43][C:36]1=2
Reactant: CC1(C)CNCc2cn[nH]c21
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)c(C#N)cn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5cn[nH]c5C(C)(C)C4)c(C#N)cn3)CC1)C(=O)N2

Procedure:
100 mg (0.24 mmol) 5′-cyano-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid, 53.2 mg (0.24 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride, 137 μL (0.97 mmol) TEA and 83.8 mg (0.26 mmol) TBTU were stirred in 2 mL DMF overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [Na].CO.Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl.[Cl:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:14]=1)=[O:12]>COCCOC>[ClH:10].[NH:7]([C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:14]=1)=[O:12])[C:6]([NH2:8])=[NH:5]
Reactant: O=C(Cl)c1cn(-c2ccc3ncccc3c2)c2ccccc12
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: COCCOC
Product: N=C(N)NC(=O)c1cn(-c2ccc3ncccc3c2)c2ccccc12
Temperature: 22 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
0.256 g (11.1 mmol) of sodium is added at 22° C. under an argon atmosphere to 40 cm3 of methanol. After complete dissolution, 1 g (10.5 mmol) of guanidine hydrochloride is added. After stirring at 22° C. for 3 hours, the reaction mixture is filtered under an argon atmosphere. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is dissolved in 10 cm3 of 1,2-dimethoxyethane. 1 g of 3-chlorocarbonyl-1-(quinol-6-yl)-1H-indole hydrochloride, suspended in 40 cm3 of 1,2-dimethoxyethane, is subsequently added at 22° C. under an argon atmosphere. After stirring at 22° C. for 48 hours and after 2 hours at reflux, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 15 cm3 of water. After stirring at 22° C. for 1 hour, a few drops of 10N hydrochloric acid solution are added. After stirring at 22° C. for 12 hours, the suspension is filtered and dried to give 0.52 g of 3-guanidinocarbonyl-1-(quinol-6-yl)-1H-indole hydrochloride in the form of a yellow solid melting at 268° C. IR spectrum (KBr): 3343, 3168, 2174, 1693, 1597, 1543, 1502, 1454, 1236, 1199, 772 and 751 cm−1.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:4][N:5]1[CH2:13][CH2:12][CH2:11][C@H:6]1[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:32][S:33]([O:1][CH2:2][C@@H:3]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:4][N:5]1[CH2:13][CH2:12][CH2:11][C@H:6]1[C:7]([O:9][CH3:10])=[O:8])(=[O:35])=[O:34]
Reactant: COC(=O)[C@@H]1CCCN1C[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Methyl 1-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate (200 mg, 0.594 mmol) was dissolved in dichloromethane (5 mL) followed by the addition of 4-(dimethylamino)pyridine (3.6 mg, 0.039 mmol) and triethylamine (0.125 mL, 0.891 mmol) and the resulting mixture was cooled to 0° C. Methanesulfonyl chloride (0.060 mL, 0.773 mmol) was added dropwise and the reaction mixture was stirred for 1 h at 0° C. The mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford methyl 1-[(2S)-3-[(methylsulfonyl)oxy]-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate (246 mg, 100%) as a clear and colorless oil. MS (EI) for C18H27N2O7S: 415 (MH+).