Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[C:25]([F:45])=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[C:25]([F:45])=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C)-c1cccc(c1)-c1cccc(F)c1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 7.14 %

Procedure:
Prepared in 7.14% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-19-fluoro-4,5,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.08 (s, 1H), 8.02 (d, J=7.7 Hz, 1H), 7.94 (s, 1H), 7.60-7.54 (m, 1H), 7.43 (d, J=7.3 Hz, 1H), 7.33-7.26 (m, 2H), 7.22-7.15 (m, 1H), 5.87 (br. s., 1H), 4.32 (br. s., 1H), 4.01-3.92 (m, 1H), 3.58-3.38 (m, 4H), 2.70 (d, J=9.9 Hz, 1H), 2.47 (s, 3H), 2.31 (s, 3H), 1.94-1.54 (m, 10H), 1.20 (s, 3H), 1.15 (s, 9H), 0.78 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 657.4.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]([O:15]CC)=[CH2:14])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>C1COCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13](=[O:14])[CH2:15][Br:18])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: C=C(OCC)c1cc(=O)oc2cc(Br)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1cc(=O)oc2cc(Br)ccc12
Reaction time: 0.5 h

Procedure:
To a solution of 7-bromo-4-(1-ethoxyvinyl)-2H-chromen-2-one (2.0 g, 6.8 mmol) in THF and H2O is added N-bromosuccinimide (1.3 g, 14.2 mmol) with stirring for 30 min. Toluene is added and the solvent is evaporated. The residue is chromatographed on silica gel (hexane/EtOAc; 80:20) to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[CH:13][CH:14]=2)([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: Nc1ccccc1
Reactant: C=C(C)c1ccc(O)cc1
Agent: Cl
Product: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of 13.4 g (0.1 mole) of p-isopropenyl phenol monomer and 18.6 g (0.2 mole) of aniline was stirred at 150° C. To the mixture was added 0.50 g of a solution obtained by adding 1.28 g of 35% hydrochloric acid to 93 g of aniline and stirring the mixture well (to be referred to as a catalyst solution) (0.0018 mole of catalyst per mole of p-isopropenyl phenol), and the reaction was carried out for 3 hours. Gas-chromatographic analysis of the reaction mixture showed that 21.3 g (yield 94%) of 2-(4'-hydroxyphenyl)-2-(4'-aminophenyl)-propane of the formula ##STR11## was formed.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:5]=[CH:4][C:3]=1[NH:15]CC1C=CC(OCC)=C(OC)C=1.Cl>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:5]=[CH:4][C:3]=1[NH2:15]
Reactant: CCOC(=O)Cn1ncc(NCc2ccc(OCC)c(OC)c2)c(Br)c1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1ncc(N)c(Br)c1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
Ethyl 2-[5-bromo-4-(4-ethoxy-3-methoxybenzylamino)-6-oxopyridazin-1(6H)-yl]acetate (570 mg, 1.29 mmol) in ethanol (11 mL) was stirred with concentrated hydrochloric acid (3.4 mL) at 90° C. for 4 hours. After cooling, the solvent was removed by distillation, and the residue was stirred with ethanol (10 mL) and 4 M hydrogen chloride-1,4-dioxane (1 mL) at 90° C. for 1 hour. After cooling, the solvent was removed by distillation. Toluene was added, and the resulting crystals were collected by filtration as the desired product (184 mg, 52% yield).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:33]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of [6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]acetic acid (0.200 g) in N,N-dimethylformamide (5 mL) were added morpholine (0.053 mL), triethylamine (0.169 mL), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (116 mg) and 1-hydroxybenzotriazole (93 mg), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=40:60-100:0, volume ratio) and recrystallized from hexane-acetone to give the title compound (0.174 g, yield 76%) as pale-yellow crystals. MS: 564 (MH+). melting point 202-203° C.
Reaction SMILES: C1([C:4]([C:13]([C:15]([CH:24]2[CH2:26]C2)=CC2C=CC=C(O)C=2)=O)=[CH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=2)CC1.O.[NH2:28][NH2:29]>O>[CH:15]1([C:13]2[CH2:4][CH:5]([C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=3)[NH:29][N:28]=2)[CH2:24][CH2:26]1
Reactant: O=C(C(=Cc1cccc(O)c1)C1CC1)C(=Cc1cccc(O)c1)C1CC1
Reactant: NN
Solvent: O
Product: Oc1cccc(C2CC(C3CC3)=NN2)c1
Yield: 67.6 %

Procedure:
To a 500 ml round bottom flask equipped with magnetic stirrer and reflux condenser was charged 13.2 g (0.0702 moles) of cyclopropyl 3-hydroxystyrylketone 150 mls of water and 3.5 g (0.0702 moles) of hydrazine monohydrate. The reaction was refluxed for a total of 2 hours, after which it was cooled and diluted with an additional 200 mls of water. The resulting solid was collected by vacuum filtration, washed with water and hexane, and dried in vacuuo at 40° C. overnight to afford 9.6 g of 3-cyclopropyl-5-(3-hydroxyphenyl)-2-pyrazoline as a tan solid at a 68% isolated yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][C:3]=1[NH2:11].[CH3:12][O:13][C:14]([N:16]=[C:17]=[S:18])=[O:15]>CC(C)=O>[CH3:12][O:13][C:14]([NH:16][C:17](=[S:18])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][C:3]=1[NH:11][C:17]([NH:16][C:14]([O:13][CH3:12])=[O:15])=[S:18])=[O:15]
Reactant: N#CSc1ccc(N)c(N)c1
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(SC#N)cc1NC(=S)NC(=O)OC

Procedure:
2.6 G. 1,2-diamino-4-thiocyanatobenzene in 48 ml. acetone is treated overnight with 8 g. methoxy carbonyl isothiocyanate at room temperature. The solution is concentrated and the residue triturated with methanol and recrystallized from methanol-chloroform, yielding pure 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-thiocyanatobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[O:9][C:10]([C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=O)=[CH:5][CH:4]=1.[NH3:21]>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[NH:21][C:10](=[O:9])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cc2cc3ccccc3c(=O)o2)cc1
Reactant: N
Product: COc1ccc(Cc2cc3ccccc3c(=O)[nH]2)cc1
Temperature: 150 °C
Yield: 12 %

Procedure:
A stirred suspension of 3-(4-methoxybenzyl)isocoumarin (0.35 g, 1.3 mmol) in 15% methanolic ammonia solution (100 ml) was heated at 150° C. in a 300 ml autoclave for 5 hours then cooled to ambient temperature. The resulting solid was collected by filtration, washed with a little cold methanol and dried in vacuo to give 3-(4-methoxybenzyl)-1-isoquinolinone (0.04 g, 12%) as a solid; m.pt. 216-218° C.; δH 3.80 (3H, s), 3.85 (2H, s), 6.25 (1H, s), 6.90 (2H, d, J=8.2 Hz), 7.30 (2H, d), 7.30-7.60 (3H, m), 8.20 (1H, d), 11.20 (1H, br s); m/z (M+H)+. 266 (100% purity).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([C@@H:33]1[O:35][C@H:34]1[CH2:36]O)[CH2:30][CH2:31][CH3:32]>C(Cl)(Cl)Cl>[CH2:29]([C@@H:33]1[O:35][C@H:34]1[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCC[C@@H]1O[C@H]1CO
Reactant: CCCCCCCCOc1ccc(-c2ncc(-c3cccc(O)c3)cn2)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2ncc(-c3cccc(OC[C@@H]4O[C@H]4CCCC)c3)cn2)cc1

Procedure:
The synthesis is carried out analogously to Example 1 from 5-(3-hydroxyphenyl)-2-(4-octyloxyphenyl)pyrimidine and (2S, 3S )-3-butyloxiran-2-ylmethanol. ##STR44## [α]D20 (CHCl3)=-14.27
Reaction SMILES: [Cl-].[NH4+].C(O)(C)C.[C:7]([NH:10][C:11]1[S:15][N:14]=[C:13]([CH2:16]C(=O)C2C=CC(Cl)=CC=2)[C:12]=1[N+:26]([O-:28])=[O:27])(=[O:9])[CH3:8]>O>[C:7]([NH:10][C:11]1[S:15][N:14]=[C:13]([CH3:16])[C:12]=1[N+:26]([O-:28])=[O:27])(=[O:9])[CH3:8]
Reactant: CC(=O)Nc1snc(CC(=O)c2ccc(Cl)cc2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)Nc1snc(C)c1[N+](=O)[O-]
Yield: 70.3 %

Procedure:
Reduced iron (2.94 grams, 50.0 mmol) and 0.30 gram of ammonium chloride were introduced into 20 ml of isopropyl alcohol and 3 ml of water, and the mixture was heated under reflux for 20 minutes. 5-Acetylamino-3-(4-chlorobenzoylmethyl)-4-nitroisothiazole (2.04 grams, 6.00 mmol) was added little by little, and the mixture was heated under reflux for 2 hours. The iron was removed by suction filtration, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt water and then dried over anhydrous sodium sulfate. After filtration, the solvent was removed by distillation under reduced pressure. The residue was dissolved in 20 ml of acetic acid and heated under reflux for 2 hours. The mixture was then poured into water and extracted with ethyl acetate. The extract was washed with aqueous bicarbonate and then with saturated salt water, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed by distillation and the material was crystallized from ethyl acetate. Recovery was 1.23 gram (4.22 mmol); Yield was 70.3%; and Melting Point was 210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[CH2:18]([O:25][CH2:26][C:27](Cl)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:12]1([N:11]2[C:10]3[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=3[N:1]=[C:27]2[CH2:26][O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Nc1cc(C(=O)O)ccc1Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc2c(c1)nc(COCc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.8 %

Procedure:
A 4-neck flask equipped with a reflux condenser was charged with 3-amino-4-phenylaminobenzoic acid (see Synthesis Example 1-2) (3.09 g, 13.54 mmol) and anhydrous toluene (45 mL) and this was refluxed. To this was added dropwise benzyloxyacetyl chloride (5 g, 27.08 mmol) in toluene solution (approx. 3 mL) over approx. 10 minutes. This was stirred under these conditions for 15 hours. This was allowed to cool to room temperature, and was extracted with dilute aqueous sodium hydroxide solution (10%, 100 mL). This was washed with toluene, and after separating the dark orange aqueous layer, this was cooled (5 to 10° C.), and concentrated hydrochloric acid (12 M) was added to the liquid to give pH 4. The precipitated crystals were filtered off, washed with distilled water, and dried under reduced pressure with heating to yield the title compound (4.21 g, 86.8% yield) as a light purple powder.
Reaction SMILES: [Na+].[F:2][C:3]1[CH:4]=[C:5]([CH:37]=[CH:38][CH:39]=1)[CH2:6][N:7]([CH3:36])[C:8]([C:10]1[C:11]([CH:33]([CH3:35])[CH3:34])=[C:12]([CH2:22][CH2:23][CH:24]([OH:32])[CH2:25][CH:26]([OH:31])[CH2:27][C:28]([O-:30])=O)[N:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:14]=1)=[O:9].C(O)(C(F)(F)F)=O>CC#N.CCOC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([CH:37]=[CH:38][CH:39]=1)[CH2:6][N:7]([CH3:36])[C:8]([C:10]1[C:11]([CH:33]([CH3:35])[CH3:34])=[C:12]([CH2:22][CH2:23][CH:24]2[CH2:25][CH:26]([OH:31])[CH2:27][C:28](=[O:30])[O:32]2)[N:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:14]=1)=[O:9]
Reactant: CC(C)c1c(C(=O)N(C)Cc2cccc(F)c2)nn(-c2ccc(F)cc2)c1CCC(O)CC(O)CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)N(C)Cc2cccc(F)c2)nn(-c2ccc(F)cc2)c1CCC1CC(O)CC(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a 7-[5-[(3-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt (270 mg, 0.49 mmol) in MeCN (50 ml) was slowly added TFA (1.0 mL, 1.23 mmol). The reaction mixture was stirred at 25° C. and monitored by HPLC. After 2 hrs, the reaction was completed. The reaction mixture was diluted with EtOAc (150 ml) and washed with H2O, saturated NaHCO3, and brine. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (70% EtOAc/Hex) to afford 1-(4-fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylic acid (3-fluoro-benzyl)-methyl-amide (210 mg, 84%): MS(APCI+) 512.2 m/z (M+H); H-NMR (CDCl3) [Mixture of rotamers at 25° C.] δ 7.40-7.21, 7.18-6.88, 4.72, 4.611, 4.58-4.48, 4.33-4.24, 2.98-2.93, 2.80-2.68, 2.63, 2.63 2.62, 2.61, 2.57, 2.56, 2.55, 2.17-2.14, 1.80-1.63, 1.61-1.58, 1.31-1.29.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[CH2:13][C@H:12]([OH:14])[C@H:11]([CH2:15][OH:16])[CH2:10]2)[CH:3]=1.ClC1N=CN=C(N[C@H]2C[C@@H]3OC(C4C=CC(OC)=CC=4)OC[C@@H]3C2)C=1.[NH2:42][C@@H:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44]1>C(O)CCC>[C@@H:43]1([NH:42][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]3[CH2:13][C@H:12]([OH:14])[C@H:11]([CH2:15][OH:16])[CH2:10]3)[CH:3]=2)[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: OC[C@@H]1C[C@@H](Nc2cc(Cl)ncn2)C[C@@H]1O
Agent: COc1ccc(C2OC[C@@H]3C[C@@H](Nc4cc(Cl)ncn4)C[C@@H]3O2)cc1
Solvent: CCCCO
Product: OC[C@@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Temperature: 180 °C
Yield: 168 %

Procedure:
A mixture of (1S,2S,4R)-4-[(6-chloropyrimidin-4-yl)amino]-2-(hydroxymethyl)cyclopentanol (33.1 mg, 0.136 mmol), 6-chloro-N-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]pyrimidin-4-amine (81.6 mg, 0.226 mmol), (S)-(+)-1-aminoindan (0.222 mL, 1.73 mmol) and 1-butanol (1.00 mL) was heated to 180° C. for 6 h in a sealed tube using MWI. The reaction was purified via silica gel chromatography eluting with a gradient of 0 to 15% MeOH in DCM to afford the title compound (77.8 mg, 63%). LC/MS: Rt=1.29 min, ES+ 341 (AA standard).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([NH:44][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCc1ccccc1
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4ccccc4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and benzylamine, m.p. 138-141° C. MS [(+)ESI, m/z]: 524 [M+H]+
Reaction SMILES: [O:1]=[C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].F[C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1.[NH4+].[OH-]>CS(C)=O.CCOC(C)=O.CO>[C:40]([C:39]1[CH:42]=[CH:43][C:36]([N:26]2[CH2:25][CH2:24][CH:23]([N:20]3[CH2:21][CH2:22][C@@H:18]([NH:17][C:2](=[O:1])[CH2:3][NH:4][C:5](=[O:16])[C:6]4[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=4)[CH2:19]3)[CH2:28][CH2:27]2)=[CH:37][CH:38]=1)#[N:41]
Reactant: N#Cc1ccc(F)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CO
Product: N#Cc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a solution of N-(2-oxo-2-{[(3R)-1-piperidin-4-ylpyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide (33 mg, 0.083 mmol) in DMSO (3 mL) was added K2CO3 (17.2 mg, 0.124 mmol) followed by 4-fluorobenzonitrile (10 mg, 0.83 mmol). The mixture was heated to 120° C. for 16 hours. The crude mixture was subjected to column chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford N-[2-({(3R)-1-[1-(4-cyanophenyl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (0.031 g, 75%) as a white solid. 1H-NMR (CDCl3) δ: 1.48-1.70 (m, 3H), 1.82-1.96 (m, 2H), 2.20-2.42 (m, 3H), 2.58-2.76 (m, 2H), 2.84-3.00 (m, 3H), 3.70-3.82 (m, 2H), 4.08 (d, J=4.8 Hz, 2H), 4.38-4.51 (m, 1H), 6.45 (d, J=7.5 Hz, 1H), 6.82 (d, J=9.0 Hz, 2H), 7.18-7.27 (m, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.54 (t, J=7.8 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 8.07 (s, 1H). MS m/z: 500 (M+1).
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]([C:12]2[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@@H:19]3[CH2:27][C@:22]4([O:26][CH2:25][CH2:24][CH2:23]4)[CH2:21][C@@H:20]3[C:28](OC)=[O:29])=[O:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].Cl.[NH2:43][OH:44]>CO.C[O-].[Na+]>[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].[O:34]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]([C:12]2[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@@H:19]3[CH2:27][C@:22]4([O:26][CH2:25][CH2:24][CH2:23]4)[CH2:21][C@@H:20]3[C:28]([NH:43][OH:44])=[O:29])=[O:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@]2(CCCO2)C[C@H]1NC(=O)c1ccc(C2CCS(=O)(=O)c3ccccc32)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)NO)c1ccc(C2CCS(=O)(=O)c3ccccc32)cc1
Reaction time: 1 h
Yield: 37 %

Procedure:
Methyl (5R,7S,8R)-8-{[4-(1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxylate from reaction 33f (0.165 mmol) was dissolved in a solution of hydroxylamine hydrochloride, methanol and sodium methoxide, (2 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 1 h, made neutral with TFA, concentrated and purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient, to give the title compound (0.03 g, 37%) as a white solid. MS found: (M+H)+=485, (2M+H)+=969.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)[CH:19]=[N:20][C:15]4=[N:14][N:13]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CO>[CH:30]1([NH:33][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([C:18]3[CH:19]=[N:20][C:15]4[N:16]([C:12]([C:9]5([C:6]6[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=6)[CH2:10][CH2:11]5)=[N:13][N:14]=4)[N:17]=3)=[CH:22][CH:23]=2)[CH2:32][CH2:31]1
Reactant: COc1ccc(C2(c3nnc4ncc(-c5ccc(C(=O)O)cc5)nn34)CC2)cc1
Reactant: NC1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(C2(c3nnc4ncc(-c5ccc(C(=O)NC6CC6)cc5)nn34)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoic acid (isomer-I from step 2, 14.0 mg, 0.0361 mmol), cyclopropylamine (3.76 μL, 0.0542 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16.0 mg, 0.0361 mmol) and N,N-diisopropylethylamine (25.2 μL, 0.145 mmol) in DMF (1.0 mL) was stirred at RT for 3 h. The mixture was diluted with methanol and purified by RP-HPLC (pH=10) to give the desired product. Analytical LCMS: (M+H)+=427.3.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1)[CH3:2].[CH2:16]([O:18][C@H:19]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=O)=[CH:23][CH:22]=1)[CH3:17].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:16]([O:18][C@@H:19]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][CH:6]=2)=[O:29])=[CH:30][CH:31]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:17]
Reactant: CCNCc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(OC(F)(F)F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of N-ethyl-N-[4-(trifluoromethoxy)benzyl]amine (0.438 g, 2.00 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (40 mL) and the organic phase was washed with 5% HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methylene chloride/ethyl acetate 10:1 as the eluent yielded 0.57 g (58%) of a colourless oil.