Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:47]=[CH:46][C:27]4[C:28]([NH:31][C:32]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)=[O:33])=[N:29][O:30][C:26]=4[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>C(Cl)Cl>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:47]=[CH:46][C:27]4[C:28]([NH:31][C:32]([C@@H:34]5[CH2:38][CH2:37][CH2:36][NH:35]5)=[O:33])=[N:29][O:30][C:26]=4[CH:25]=3)=[CH:22][CH:23]=2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1noc2cc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1noc2cc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)ccc12)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of (S)-tert-butyl 2-(6-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)benzo[d]isoxazol-3-ylcarbamoyl)pyrrolidine-1-carboxylate (0.115 mg, 0.178 mmol) in CH2Cl2 (3 mL) was treated with TFA (1 mL) and the solution was allowed to stir at rt for 2 h. The solvents were removed in vacuo and the residue was purified by prep HPLC (CH3CN—H2O-TFA) to give the TFA salt of the title compound (74.8 mg, 53%) as a colorless glass. 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 9.53-9.58 (m, 1H), 9.30-9.36 (m, 1H), 8.97-9.04 (m, 1H), 8.79-8.84 (m, 1H), 8.10 (d, J=8.6 Hz, 1H), 8.06 (s, 1H), 7.93 (AB doublet of AB quartet 2H), 7.86 (AB doublet of AB quartet 2H), 7.78-7.83 (m, 1H), 4.73-4.78 (m, 2H), 4.51-4.54 (m, 2H), 3.28-3.38 (m, 4H), 1.95-2.22 (m, 6H). LCMS: Anal. Calcd. for C25H26N6O2: 442; found: 443 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[O:10][CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:3].[NH2:11][C:12]1[CH:19]=[C:18](F)[C:15]([C:16]#[N:17])=[CH:14][N:13]=1.C(N(CC)CC)C>>[NH2:11][C:12]1[CH:19]=[C:18]([N:7]2[CH2:8][CH2:9][O:10][CH:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH2:6]2)[C:15]([C:16]#[N:17])=[CH:14][N:13]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CN(C)CC1CNCCO1
Solvent: CCN(CC)CC
Product: CN(C)CC1CN(c2cc(N)ncc2C#N)CCO1
Temperature: 60 °C

Procedure:
A mixture of racemic 2-dimethylaminomethylmorpholine (670 mg, 4.65 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 637 mg, 4.65 mmol) and triethylamine (2.59 ml, 18.6 mmol) was heated at 60° C. in a septum sealed reaction vessel under argon for 10 h. The reaction mixture was evaporated, partitioned between aq. hydrochloric acid (2 M) and DCM (2×), the aqueous layer basified with aqueous NaHCO3, extracted a further 10× with DCM containing 10% MeOH, the combined DCM layers from the basic extraction, dried over Na2SO4 and evaporated. The residue was applied to a 24 g RediSep® silica column as a DCM solution and purified by normal phase chromatography, eluting with a gradient from DCM to 20% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as a beige foam. (UPLC-MS 6) tR 0.28; ESI-MS 262.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:8][CH2:9][C:10]=1[C:11]1[CH:12]=[N:13][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:15][CH:16]=1)=[O:4].Cl>CO>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:22]([Cl:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=3[Cl:27])=[CH:15][CH:16]=2)[CH2:9][CH2:8][N:7]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)nc1
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Compound A2 (7.00 g, 13.0 mmol) was dissolved in MeOH (130 mL). Mg (500 mg, 20.6 mmol) was added slowly. The mixture was stirred for 1 h, and Mg (608 mg, 25.0 mmol) was added again. The mixture was stirred 3 h. Aq. 1M HCl was added slowly, and the mixture was stirred 1 h at rt. The solvents were evaporated under reduced pressure, and the mixture was extracted with EtOAc. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the raw title compound (4.92 g, 70%). LC-MS: tR=1.16 min, ES+=539.43.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>[Cu]I.O.O1CCOCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:28]2[CH2:29][CH2:30][N:26]([CH3:25])[C:27]2=[O:31])[CH:7]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)c(C)c1
Reaction time: 8 h
Yield: 38.6 %

Procedure:
To a mixture of (2-bromo-4-chlorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (817 mg) described in Preparation Example 167, 1-methylimidazolidin-2-one (300 mg), cesium carbonate (1.30 g) and copper(I) iodide (191 mg) were added 1,4-dioxane (4 mL) and N,N′-dimethylethylenediamine (0.22 mL), and the mixture was stirred for 8 hr under refluxing. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (330 mg).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]3[CH2:18][CH2:19][CH2:20][CH:21]([NH:24][C:25](=O)[CH2:26][CH3:27])[C:22]=3[CH:23]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.B.C1COCC1>C1COCC1>[CH2:25]([NH:24][CH:21]1[CH2:20][CH2:19][CH2:18][C:17]2[N:16]=[CH:15][C:14]([NH:13][S:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:30])([F:29])[F:1])=[CH:9][CH:8]=3)(=[O:12])=[O:11])=[CH:23][C:22]1=2)[CH2:26][CH3:27]
Reactant: CCC(=O)NC1CCCc2ncc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc21
Agent: B
Solvent: C1CCOC1
Product: CCCNC1CCCc2ncc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc21
Yield: 56.9 %

Procedure:
Following the same procedure as described previously, N-[3-(4-trifluoromethoxy-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinolin-5-yl]-propionamide (120 mg, 0.27 mmol) in THF (10 ml) was treated with 1M BH3.THF (2.7 ml). Purification of the crude product by flash column chromatography (heptane:ethyl acetate, 1:2) provides the title compound (66 mg, 57%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:13])[O:9][C:10](=O)[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1>CO>[NH2:11][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([OH:1])[C:7]=1[C:8]([O:9][CH3:10])=[O:13]
Reactant: O=c1[nH]c2cccc(O)c2c(=O)o1
Solvent: CO
Product: COC(=O)c1c(N)cccc1O

Procedure:
A mixture of Example 386A (1.0 g, 5.6 mmol) and methanol (40 mL) was heated to reflux for 6 hours, concentrated, and purified on a silica gel column eluting with 30% ethyl acetate in hexanes to provide the desired product, 0.81 g, 86.6%. 1H NMR (DMSO-d6) δ 3.88 (s, 3H), 5.95 (d, 1H), 6.20 (d, 1H), 6.34 (s, 214), 7.02 (t, 1H), 10.88 (s, 1H); MS (DCI/NH3): m/e 168 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][C:5](Cl)=[O:6].[NH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:25])=[N:21][CH:22]=2)[CH:13]=[CH:12][N:11]=1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl>[CH3:2][N:3]([CH3:8])[CH2:4][C:5]([NH:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])=[O:25])=[N:21][CH:22]=2)[CH:13]=[CH:12][N:11]=1)=[O:6]
Reactant: CN(C)CC(=O)Cl
Reactant: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(N)c2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A suspension of 2-(dimethylamino)acetyl chloride hydrochloride (0.101 g, 0.638 mmol) in THF (5 mL) was added to a 0° C. solution of Example C1 (0.15 g, 0.455 mmol) and DIEA (0.239 mL, 1.366 mmol) in THF (5 mL), allowed to warm to RT and stirred overnight. Additional 2-(dimethylamino)acetyl chloride hydrochloride (0.200 g), DIEA (0.239 mL, 1.366 mmol) and DCM (5 mL) were added and the mixture stirred at RT overnight. The mixture was treated with 10% K2CO3, extracted with DCM (4×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via preparative TLC (MeOH/DCM/TEA) to afford N-((5-((2-(2-(dimethylamino)acetamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (86 mg, 46%). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 10.44 (s, 1H), 9.95 (s, 1H), 8.26 (d, J=2.9 Hz, 1H), 8.20 (d, J=5.8 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 6.73 (dd, J=5.8, 2.4 Hz, 1H), 3.07 (s, 2H), 2.25 (s, 6H), 1.21 (s, 9H); MS (ESI) m/z: 415.2 (M+H+).
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([C:18](O)=[O:19])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1>[CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][OH:19])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cc(C(=O)O)on1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cc(CO)on1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred, chilled (+3° C.) solution of 3-dodecyl -5-isoxazole carboxylic acid (24.27 g, 0.08625 mol) and triethylamine (12.0 mL, 0.0861 mol) in dry tetrahydrofuran (600 mL) under nitrogen was added in one portion a chilled (+3° C.) solution of ethyl chloroformate (8.25 mL, 0.0863 mol) in dry tetrahydrofuran (30 mL). A white precipitate formed immediately. The suspension was stirred for 1.25 hours before sodium borohydride (6.54 g, 0.173 mol) was added in portions over 10 minutes. The mixture was stirred for 1.5 hours while warming to room temperature. The mixture was rechilled and carefully quenched with water (350 mL). The organic layer was diluted with dichloromethane. The aqueous layer was washed with THF-CH2Cl2. The organic solutions were combined, dried (Na2SO4), and rotoevaporated. The residue was chromatographed on silica gel (1.5 kg, 70-230 mesh) using petroleum ether-acetone (9:1, 20×1 L) eluent. Fractions 10 to 14 were rotoevaporated from dichloromethane and dried in vacuo to give a white solid; yield 11.1 g (48%); mp 57°-59° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:19]=2[CH:18]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][CH2:37][N:38]([CH3:40])[CH3:39]>C(OCC)(=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])=[CH:25][C:19]=2[CH:18]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(O)ccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc2sc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Yield: 79 %

Procedure:
To a solution of 77 mg (0.20 mmol) {2-[(5-Hydroxy-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (4) in 3 ml ethyl acetate was added 120 mg potassium carbonate and 36 mg (0.25 mmol) (2-chloro-ethyl)-dimethyl-amine hydrochloride. The reaction mixture was heated at reflux for 16 h and poured into brine. The aqueous phase was extracted with ethyl acetate and the organic phase was dried over sodium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (dichloromethane/methanol 19:1 and then 9:1). (2-{[5-(2-Dimethylamino-ethoxy)-benzo[b]thiophene-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (5) (72 mg, 0.158 mmol) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:6](=[O:18])[CH2:5][CH2:4][NH:3]1.I[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=1>>[CH3:1][C@@H:2]1[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:6](=[O:18])[CH2:5][CH2:4][N:3]1[C:24]1[CH:25]=[CH:20][CH:21]=[C:22]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=1
Reactant: C[C@@H]1CN(CCCN2CCCCC2)C(=O)CCN1
Reactant: FC(F)(F)Oc1cccc(I)c1
Product: C[C@@H]1CN(CCCN2CCCCC2)C(=O)CCN1c1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared from (R)-2-methyl-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (Example 39E) and 1-iodo-3-trifluoromethoxy-benzene in analogy to example 33. MS: 414.4 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[ClH:24]>C(O)C>[ClH:24].[ClH:24].[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(N3CCNCC3)cc2)CC1
Agent: Cl
Solvent: CCO
Product: CC(=O)N1CCC(Cc2ccc(N3CCNCC3)cc2)CC1

Procedure:
In 100 ml of ethanol was dissolved 4.8 g of the 1-acetyl-4-(4-piperazinobenzoyl)piperidine (Compound No. 2) prepared in Example 4, followed by addition of 3.5 ml of concentrated hydrochloric acid. The reaction mixture was worked up in the same manner as Examples 15 and 17 to give a solid, which was recrystallized from ethanol-ethyl acetate. The procedure gave 3.0 g of a hygroscopic colorless solid melting at 136°-137° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[N:28][NH:29]2)=[CH:25][CH:24]=1.C(N(CC)CC)C.O>C(O)CCC.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[N:28][NH:29]3)=[CH:25][CH:24]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Temperature: 80 °C
Yield: 95.4 %

Procedure:
A mixture of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 1.17 mmol), 6-aminoindazole (171 mg, 1.29 mmol) and triethylamine (0.400 mL, 2.88 mmol) in n-butyl alcohol (10 mL) was heated at 80° C. overnight. After cooling down, H2O and CH2Cl2 were added. The organic phase was separated, washed with 1N HCl, followed by 5% NaHCO3, before it was dried over Na2SO4 and concentrated in vacuo to give 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (490 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS[C:34]([NH:46][C:47](=[O:56])[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[N:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>CN(C)C=O.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:49]([O:48][C:47](=[O:56])[NH:46]/[C:34](/[N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])=[CH:18][CH:17]=2)[CH:12]1[C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11]1)=[N:35]\[C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)NCC2
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)CC2
Reaction time: 3 h

Procedure:
N-[2-({1-[1-(4-Fluorophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide (100 mg, 0.224 mmol, cf. example 65) and dibenzyl [(methylsulfanyl)methylylidene]biscarbamate (104 mg, 0.291 mmol) were dissolved in dry dimethylformamide (1 mL). Triethylamine (0.094 mL, 0.672 mmol) was added followed by silver trifluoromethanesulfonate (81 mg, 0.313 mmol). A yellow precipitate was formed and the reaction mixture turned dark brown. Stirring was continued at room temperature for 3 h. The solvent was evaporated in vacuo. Dichloromethane (15 mL) was added, the solid was removed by filtration and washed with dichloromethane. The combined dichloromethane phases were concentrated in vacuo and the crude product was purified by flash chromatography (silica, dichloromethane then dichlorometane:methanol=100:1). Yield: 100 mg (0.132 mmol, 59%).
Reaction SMILES: C([O:4][C:5](=[O:69])[C@@H:6]([NH:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:7][C:8]1[CH:60]=[CH:59][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:48]([NH2:50])=[O:49])[CH2:27][S:28][C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:24])=[O:20])=[O:14])=[CH:10][CH:9]=1)C=C.C(N(CC)CC)C.C(O)=O>O1CCCC1.O>[C:55]([O:54][C:52]([NH:51][C@@H:18]([CH2:17][CH2:16][NH:15][C:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:6]([NH:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C:5]([OH:69])=[O:4])=[CH:60][CH:59]=1)=[O:14])[C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:48]([NH2:50])=[O:49])[CH2:27][S:28][C:29]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:24])=[O:20])=[O:53])([CH3:58])([CH3:57])[CH3:56]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
860 mg (0.89 mmol) of the compound from example 19A was dissolved in approx. 20 ml tetrahydrofuran. 620 μl (4.45 mmol) Triethylamine, 168 μl (4.45 mmol) formic acid and 103 mg (0.089 mmol) tetrakis(triphenylphosphin)palladium(0) were added. The reaction mixture was stirred over night at room temperature. The reaction was diluted with approx. 50 ml water and twice extracted with approx. 50 ml dichloromethane. The combined organic phases were extracted with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water/methanol gradient to yield 329 mg (38% of theory) product.
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].[CH3:21][N:22]1[C:26]([NH2:27])=[CH:25][CH:24]=[N:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][C:26]2[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Cn1nccc1N
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: Cn1nccc1NC(=O)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-methylpyrazol-3-amine (9.7 mg, 0.12 mmol). The title compound was obtained as a solid (10.0 mg, 23% yield). MS m/z: 429.96, 431.96 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:6](=[O:7])[C:5]2=[CH:17][CH:18]=1.[F:19][C:20]([F:33])([F:32])C1C=C2C(=O)OC(=O)C2=CC=1>C(OCC)(=O)C>[F:19][C:20]([F:33])([F:32])[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:6](=[O:7])[C:5]2=[CH:17][CH:18]=1
Reactant: O=C1OC(=O)c2cc(C(F)(F)F)ccc21
Reactant: O=C1c2ccc(Cl)cc2C(=O)N1CCC(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1c2ccc(C(F)(F)F)cc2C(=O)N1CCC(F)(F)F

Procedure:
4-Trifluoromethyl-N-(3,3,3-trifluoropropyl)phthalimide is prepared in a similar manner to 4-chloro-N-(3,3,3-trifluoropropyl)phthalimide described in Example 26, starting with 4-trifluoromethylphthalic anhydride, Rf=0.12, (thin layer chromatography on silica gel, eluent: ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N+:6]([O-])[CH:5]=1.O=P(Cl)(Cl)[Cl:26]>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:6][C:5]=1[Cl:26]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc(-c2c(CC)cccc2CC)[n+]([O-])cc1C(=O)OC
Product: CCc1cc(-c2c(CC)cccc2CC)nc(Cl)c1C(=O)OC
Temperature: 80 °C

Procedure:
A mixture of 6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester N-oxide (1.7 g) and POCl3 (10 mL) is heated at 80° C. for 2 hours. The volatile material is removed in vacuo. Ice water and ether is added to the residue. The organic layer is separated and the aqueous layer is extracted with ether. The combined extract is washed with brine, dried, and concentrated to give 2-chloro-6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester. 1H NMR (CDCl3) 7.26 (t, 1H), 7.12 (d, 3H), 4.02 (s, 3H), 2.69 (q, 2H), 2.32 (m, 4H), 1.25 (t, 3H), 1.07 (t, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([CH:16]([CH3:18])[CH3:17])[CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)=[C:24]([CH:34]=1)[CH2:25][NH:26][C:27](=[O:33])[C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([CH:16]([CH3:18])[CH3:17])[C@H:9]1[C:10]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:27]([NH:26][CH2:25][C:24]1[CH:34]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=1[N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)=[O:33])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C1CCN(C(=O)OC(C)(C)C)C1C(=O)O
Reactant: O=C(NCc1cc(Cl)ccc1-n1cncn1)[C@@H]1CCCN1
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)C1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1
Temperature: 25 °C

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-3-isopropyl-dl-proline, (77 mg, 0.30 mmol), N-[5-chloro-2-(1H1,2,4-triazol-1-yl)benzyl]-L-prolinamide (Example 27, Step B, 113 mg, 0.30 mmol), HOAt (20 mg, 0.15 mmol), EDC (86 mg, 0.45 mmol) and Et3N (80 μL, 0.60 mmol) in 1.5 mL DMF was stirred at room temperature. The diastereomeric products were separated by reverse phase HPLC (30 min gradient elution with 95:5 H2O/0.1% TFA:CH3CN/0.1% TFA to 5:95 H2O/0.1% TFA:CH3CN/0.1% TFA) and carried on directly to deprotection.