Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C:16]1([C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]1=[O:25])[CH2:15]2.Cl[C:31]1[N:36]=[CH:35][N:34]=[C:33]([C:37]([C:39]2[CH:40]=[C:41]([CH3:48])[C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)=[O:38])[CH:32]=1>C(O)CCCC>[CH3:48][C:41]1[C:42]2[O:46][CH2:45][CH2:44][C:43]=2[CH:47]=[C:39]([C:37]([C:33]2[N:34]=[CH:35][N:36]=[C:31]([NH:11][C:12]3[CH:13]=[C:14]4[C:27](=[CH:28][CH:29]=3)[CH2:26][C:16]3([C:24]5[C:19](=[N:20][CH:21]=[CH:22][CH:23]=5)[NH:18][C:17]3=[O:25])[CH2:15]4)[CH:32]=2)=[O:38])[CH:40]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1OCC2
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCCCCO
Product: Cc1cc(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)cc2c1OCC2
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A spatula tip of benzenesulphonic acid was added to 70 mg (0.28 mmol) 5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one and 0.10 g (0.26 mmol) (6-chloro-pyrimidin-4-yl)-(7-methyl-2,3-dihydro-benzofuran-5-yl)-methanone in 2 mL 1-pentanol and the mixture was stirred at 85° C. for 1 h. The reaction mixture was evaporated down, taken up in DMF, acidified with a few drops of hydrochloric acid and purified by preparative HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])[C:6](=[O:22])[C:5]2([C:24]1[CH:29]=[C:28]([CH2:30][O:31]COC)[CH:27]=[CH:26][C:25]=1[Cl:35])[OH:23].CO.Cl>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])[C:6](=[O:22])[C:5]2([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[CH:27]=[CH:26][C:25]=1[Cl:35])[OH:23]
Reactant: COCOCc1ccc(Cl)c(C2(O)C(=O)N(Cc3ccc(OC)cc3OC)c3ccc(Cl)cc32)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2C(=O)C(O)(c3cc(CO)ccc3Cl)c3cc(Cl)ccc32)c(OC)c1

Procedure:
A mixture of 0:307 g of the compound of Example 19, 15 ml of methanol and 1 ml of 10N hydrochloric acid is heated at 50° C. for 2 hours. The solvent is evaporated under reduced pressure and the residue obtained is taken up in dichloromethane and water. The organic phase is washed twice with water and then dried over anhydrous sodium sulphate. The solvents are evaporated under reduced pressure. The expected product is isolated after solidifying in cyclohexane, filtering and drying at 30° C. under reduced pressure for 6 hours; M.p.=107° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5](C(OC(C)(C)C)=O)[CH2:4]1.[N+:25]([O-])([O-:27])=[O:26].[K+].N>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=3[C:8]([N+:25]([O-:27])=[O:26])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1ccc1cc(C#N)ccc21
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.6 %

Procedure:
Powdered carbamate 143 (1.00 g, 2.9 mmol) was added portionwise to stirred conc. H2SO4 (10 mL) at 0° C., and the mixture was warmed to room temperature for 10 min. The resulting solution was cooled to −5° C. and treated dropwise with a solution of KNO3 (324 mg, 3.2 mmol) in cone. H2SO4 (2 mL). After siting for a flirter 5 min at 0° C., the mixture was poured into ice/water and neutralized with dilute aqueous NH3. The resulting solid was purified by chromatography on silica gel, eluting with CH2Cl2, followed by recrystallization from CH2Cl2, then EtOAc, to give 1-(chloromethyl)-7-cyano-5-nitro-1,2-dihydro-3H-benzo[e]indole (144) (522 mg, 62%) as a red solid: mp 237-238° C.; 1H NMR [(CD3)2SO] δ 8.55 (d, J=1.4 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 7.74 (dd, J=8.8, 1.5 Hz, 1H), 6.87 (s, 1H), 4.29-4.21 (m, 1H), 3.94-3.85 (m, 2H), 3.80 (dd, J=11.1, 8.1 Hz, 1H), 3.75 (dd, J=10.6, 3.1 Hz, 1H). Anal. (C14H10ClN3O2) C, H, N, Cl.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([Cl:16])[CH:9]=2)=[CH:6][N:5]=[CH:4][C:3]=1[CH:17]([CH:24]1[CH2:26][CH2:25]1)[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:16][C:10]1[CH:9]=[C:8]([C:7]2[CH:6]=[N:5][CH:4]=[C:3]3[C:2]=2[CH2:22][S:19](=[O:21])(=[O:20])[N:18]([CH3:23])[CH:17]3[CH:24]2[CH2:26][CH2:25]2)[CH:13]=[CH:12][C:11]=1[C:14]#[N:15]
Reactant: CN(C(c1cncc(-c2ccc(C#N)c(Cl)c2)c1Cl)C1CC1)S(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CN1C(C2CC2)c2cncc(-c3ccc(C#N)c(Cl)c3)c2CS1(=O)=O
Temperature: 65 °C

Procedure:
To a solution of N-((4-chloro-5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)-N-methylmethanesulfonamide (51 mg, 0.124 mmol) in THF (10 mL) and DMSO (0.1 mL) was added 1M KOtBu in THF (0.37 mL, 0.37 mmol), and the mixture was heated to 65° C. for 10 min under microwave irradiation. The mixture was quenched with MeOH (2 mL) and concentrated. The residue was purified by Xbridge C18 eluting with 20-100% ACN-water to give 2-chloro-4-(4-cyclopropyl-3-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2-thia-3,6-diaza-naphthalen-8-yl)-benzonitrile
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C(Cl)Cl.C(#N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:10](=[O:11])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(F)ccc1O
Solvent: CC#N
Solvent: ClCCl
Product: O=c1[nH]c2cc(F)ccc2o1

Procedure:
A solution of 2-amino-4-fluorophenol (4.0 g), carbonyldiimidazole (1.7 g) in DCM (100 ml) and acetonitrile (30 ml) was stirred at RT for 5 h. The solvent was removed under reduced pressure and the residue purified by chromatography on silica eluting with 30% ethylacetate/isohexane, yield 4.0 g.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:40][C:41]1[C:42]([O:59][C@H:60]([CH2:62][CH:63]=[CH2:64])[CH3:61])=[C:43](B2OC(=O)CN(C)CC(=O)O2)[CH:44]=[C:45]([F:47])[CH:46]=1.C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=C(F)C(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C(C)=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:43]5[CH:44]=[C:45]([F:47])[CH:46]=[C:41]([F:40])[C:42]=5[O:59][C@H:60]([CH2:62][CH:63]=[CH2:64])[CH3:61])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1c(F)cc(F)cc1B1OC(=O)CN(C)CC(=O)O1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)cc(F)c5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 99 %

Procedure:
Prepared from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate and (S)-2-(3,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione in 99% yield following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′,5′-difluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 716.9.
Reaction SMILES: [F:1][CH2:2][C@H:3]([N:11]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.NN.C(O)C>[F:1][CH2:2][C@H:3]([NH2:11])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H](CF)Cc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: N[C@@H](CF)Cc1ccccc1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A mixture of (R)-2-(1-fluoromethyl-2-phenylethyl)isoindol-1,3-dione (52 mg) and hydrazine hydrate (two drops) and ethanol (1 mL) was heated to reflux for 2 hours. The reaction solution was allowed to be cooled to room temperature, and the deposited crystal was separated by filtration and concentrated under reduced pressure. The residue was purified by LC-MS and 6.0 mg of the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([N:22]([CH3:24])[CH3:23])=[N:17][N:16]=[C:15]3I)=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:28]([Cu])#[N:29]>N1C=CC=CC=1>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([N:22]([CH3:24])[CH3:23])=[N:17][N:16]=[C:15]3[C:28]#[N:29])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: N#C[Cu]
Reactant: CN(C)c1nnc(I)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
Solvent: c1ccncc1
Product: CN(C)c1nnc(C#N)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
Temperature: 85 °C
Yield: 44.3 %

Procedure:
A mixture of 1-dimethylamino-4-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (40 mg, 0.082 mmol), pyridine (3 mL) and CuCN (22 mg, 0.247 mmol) was heated to 85° C. for 2 h and concentrated. Column chromatography (Hexanes/EtOAc) afforded the desired compound (14 mg, 44.2%) as a yellow solid. 1H-NMR (CDCl3) δ: 3.45 (s, 6H), 7.40-7.44 (m, 1H), 7.49 (t, 1H), 8.01 (d, 1H), 8.12 (s, 1H), 8.23 (d, 1H), 8.31 (s, 1H), 8.38 (d, 1H), 9.13 (s, 1H). m/z (M+1) 386.20.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:4].I[CH2:14][CH2:15][CH3:16]>O>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:14][CH2:15][CH3:16])[CH3:4]
Reactant: CCCI
Reactant: CCOc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCOc1ccccc1OCC
Temperature: 80 °C

Procedure:
The reaction was conducted in a 500-ml 3-neck flask equipped with a reflux condenser, an addition funnel, and a magnetic stirring bar. Into the flask was introduced 75 ml water, 11.5 grams of 50% aqueous sodium hydroxide, 19.3 grams (0.14 moles) 2-ethoxyphenol, and 23.8 grams (0.14 moles) 1-iodopropane. The flask contents were maintained at 80° C. for a period of 7 hours and were then cooled to room temperature. After the addition of 100 ml of water the reaction mixture was transferred to a 250-ml separatory funnel and washed twice with 100-ml quantities of hexane. The organic layer was washed twice with 10 ml of 15% aqueous sodium hydroxide and dried over anhydrous magnesium sulfate. Most of the solvent was removed by simple distillation. A liquid was isolated which boiled at 63-67° C. @ 0.05 mm. It was labeled example 8, and the structure confirmed by glpc and NMR analysis.
Reaction SMILES: [OH-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[N+:10]([C:7]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1
Temperature: 60 °C
Yield: 302.4 %

Procedure:
A solution of sodium hydroxide (7.1 g) in water (7.1 g) and benzyltriethylammonium chloride (0.4 g) was added to a mixture of 4-fluoronitrobenzene (14.1 g) and 1,1,7-trihydryl-F-heptanol (36 g). The whole was stirred and heated at about 60° C. for about 6 hours. The product was recrystallized from an ethanol/petroleum ether mixture to give 4-(1,1,7-trihydryl-F-hepyloxy) nitrobenzene (37.2 g), having a melting point of 51°-53° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([NH:37]C(=O)OC(C)(C)C)[CH2:32]1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:31]5[CH2:36][CH2:35][CH2:34][C@@H:33]([NH2:37])[CH2:32]5)[N:7]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccnc(Cl)n2)c2cc(-c3cccnc3)ncc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Product: N[C@@H]1CCCN(c2nccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)C1
Yield: 63 %

Procedure:
Following the procedure of Example 144, 3-(2-chloropyrimidin-4-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl piperidin-3-ylcarbamate were reacted. The product was deprotected by the procedure of Example 225 and purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 32 mg (63%) of 300. ESI MS m/z 373.2 (M+1). 1H NMR (400 MHz, DMSO): 9.30 (s, 1H), 9.25 (s, 1H), 8.91 (s, 1H), 8.59 (dd, J=4.7, 1.2 Hz, 1H), 8.45 (t, J=8.1 Hz, 2H), 7.53 (dd, J=7.9, 4.7 Hz, 1H), 7.32 (d, J=5.0 Hz, 1H), 4.71 (d, J=10.8 Hz, 1H), 4.61 (d, J=12.5 Hz, 1H), 3.15-3.06 (m, 1H), 2.91-2.83 (m, 1H), 2.82-2.73 (m, 1H), 1.96 (d, J=11. Hz, 1H), 1.81 (d, J=13.4 Hz, 1H), 1.55 (d, J=12.1 Hz, 1H), 1.36 (td, J=12.2, 3.8 Hz, 1H)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH2:10][C@@H:11]([NH:22][C:23](OC(C)(C)C)=O)[C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[C:38]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:43]=[CH:42][C:41]([CH:44]2[CH2:48]C(OC)O[CH:45]2OC)=[CH:40][CH:39]=1>ClCCCl>[CH2:1]([O:8][C:9](=[O:30])[CH2:10][C@@H:11]([N:22]1[CH:23]=[CH:45][C:44]([C:41]2[CH:42]=[CH:43][C:38]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:39][CH:40]=2)=[CH:48]1)[C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:17])[CH3:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(C)(C)O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)[C@H](CO)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 11 %

Procedure:
According to the procedure described in Example 1(c) for N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17]-octa-deca-11(18),12,14,16-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-t-butoxycarbonylamino-N-(2-hydroxy-1(S)-hydroxymethyl-2-methyl-propyl)succinamic acid benzyl ester was deprotected with trifluoroacetic acid. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to give in 11% yield 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-(hydroxymethyl)-2-methylpropyl]succinamic acid benzyl ester as an amorphous solid. 1H NMR (acetone-d6): δ 7.67-7.61 (m, 6H), 7.48 (t, 2H, J=7.7 Hz), 7.39 (t, 1H, J=1.8 Hz), 7.37-7.27 (m, 6H), 7.09 (bd, 1H, J=9.2 Hz), 6.96 (t, 1H, J=2.6 Hz), 6.53 (dd, 1H, J=1.7, 2.8 Hz), 5.35 (t, 1H, J=7.4 Hz), 5.11 (s, 2H), 3.81-3.62 (m, 3H), 3.39 (dd, 1H, J=6.8, 16.4 Hz), 3.12 (dd, 1H, J=7.7, 16.6 Hz), 1.24 (s, 3H), 1.21 (s, 3H). Anal. Calculated for C32H34N2O5: C, 72.98; H, 6.51; N, 5.32. Found: C, 72.83; H, 6.60; N, 5.24.
Reaction SMILES: [N:1]1([CH2:5][C:6]2[S:14][C:13]3[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=3[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[ClH:22]>CO>[ClH:22].[ClH:22].[N:1]1([CH2:5][C:6]2[S:14][C:13]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CN3CCC3)cc2C1
Agent: Cl
Solvent: CO
Product: c1c(CN2CCC2)sc2c1CNCC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
tert-Butyl 2-(azetidin-1-ylmethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (0.28 g, 0.908 mmol) was dissolved in methanol (1 ml) and HCl in methanol (1.25 M, 3.63 ml, 4.54 mmol) was added. The reaction mixture was heated at reflux for 1 h. After cooling to room temperature the solvent was removed in vacuo. The crude product was re-dissolved in ethanol, diethylether was added and the mixture was stirred at 0° C. for 20 min. The solid was collected by filtration, washed with diethylether and dried in vacuo. Yield: 0.2 g (78%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:20][CH:19]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C(O)(=O)C>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:22][CH:23]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: CCc1nc(Cl)cc(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCc1nc(Nc2ccc(CC(N)=O)cc2)cc(-c2cccc(Cl)c2)n1
Temperature: 85 °C
Yield: 38.3 %

Procedure:
A mixture of 4-chloro-6-(3-chlorophenyl)-2-ethylpyrimidine (0.080 g, 0.32 mmol) and 2-(4-aminophenyl)acetamide (0.057 g, 0.38 mmol) and 4M HCl in dioxane (2 drops) in acetic acid (2.5 mL) was heated for 2.5 h at 85° C. After this time, the mixture was cooled to 0° C., neutralized with NaHCO3, extracted with CH2Cl2 (2×30 mL) and EtOAc, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with methylene chloride and methanol to afford the title compound (0.045 g, 40%) as a white solid. MW=366.84. 1H NMR (DMSO-d6, 500 MHz) δ 9.60 (s, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.95-7.93 (m, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.58-7.54 (m, 2H), 7.42 (br s, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.05 (s, 1H), 6.85 (br s, 1H), 2.81 (q, J=7.6 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H); ESI MS m/z 367 [M+H]+.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:6])[CH2:4][Cl:5].[P:7]([O:14]CC)([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]>>[Cl:5][CH2:4][CH:3]([CH3:6])[CH2:2][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CC(CCl)CBr
Product: CCOP(=O)(CC(C)CCl)OCC
Yield: 57.2 %

Procedure:
A mixture of 1-bromo-3-chloro-2-methylpropane (95 g.) and triethyl phosphite (61.4 g.) was heated to reflux for 5.5 hours with stirring and then excess 1-bromo-3-chloro-2-methylpropane was distilled off under reduced pressure to give oily diethyl 3-chloro-2-methylpropylphosphonate (48.3 g.).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCCC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCCC[C@H]1C(N)=O
Yield: 87.4 %

Procedure:
2.1 g (4.32 mmoles) of Z-Glp-Leu-Pip-NH2 are dissolved in 40 ml of methanol. 0.2 g of a 10% palladium-on-carbon catalyst are added, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the residue is triturated with ether. The resulting crude product (1.48 g) is dissolved in 20 ml of water, the solution is decolourized, filtered, and 4 g of sodium chloride are dissolved in the clear filtrate. The aqueous solution is extracted thrice with 10 ml of chloroform, each. The chloroform solutions are combined, dried over anhydrous sodium sulfate, evaporated, and the amorphous residue is triturated with a mixture of ethyl acetate and ether. 1.33 g (87.5%) of Glp-Leu-Pip-NH2 are obtained; Rf5 =0.60, [α]D25 =-86.4° (c=1%, in acetic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:17])([F:16])[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:9]([F:17])([F:16])[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(F)(F)c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(F)(F)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the preparation of N-Aryl-benzenesulfonamides using 4-chloro-2-(difluoro-pyridin-4-yl-methyl)-phenylamine and 4-tert-butyl-benzenesulfonyl chloride. MS: (M+H)=451.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:16]([O:18][C:19]1[CH:27]=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[C:20]=1B1OC(C)(C)C(C)(C)O1)[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:20]3[C:21]4[O:25][CH2:24][O:23][C:22]=4[CH:26]=[CH:27][C:19]=3[O:18][CH2:16][CH3:17])[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOc1ccc2c(c1B1OC(C)(C)C(C)(C)O1)OCO2
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3c(OCC)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 5-ethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole (example A31) the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:21])[CH2:19][CH3:20])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:22]1([C:26]([C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][N:29]=2)=[O:27])[CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br>[N:22]1([C:26]([C:28]2[N:29]=[CH:30][C:31]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:21])[CH2:19][CH3:20])[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[CH:32][CH:33]=2)=[O:27])[CH2:25][CH2:24][CH2:23]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: CC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A mixture of 3-hydroxy-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.116 g, 0.4 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (116 mg, 0.48 mmol), cesium carbonate (392 mg, 1.2 mmol) and bromotris(triphenylphosphine)copper(I) (38 mg, 0.04 mmol) in DMA (5 mL) was stirred in the microwave reactor at 160° C. for 4 hours. The product was dissolved in ethyl acetate (20 mL) and water (15 mL) and the layers separated. The organic layer was washed with brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a brown oil which was chromatographed on silica, eluting with a gradient of 0-5% methanol in ethyl acetate, and then re-columned on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound as a white foam which crystallised on standing. The material was triturated with 50% ethyl acetate in hexane to give the required product as a white solid (95 mg). 1H NMR δ (CDCl3): 0.90 (t, 3H), 1.23 (d, 3H), 1.51-1.72 (m, 2H), 2.28 (quin, 2H), 3.73 (s, 3H), 4.18 (t, 2H), 4.28 (q, 1H), 4.64 (t, 2H), 6.67 (t, 1H), 6.72 (d, 1H), 6.99 (s, 1H), 7.15 (s, 1H), 7.22 (d, 1H), 7.31 (d, 1H), 8.04 (d, 1H), 8.26 (s, 1H), 8.41 (s, 1H); m/z 450 (M+H)+