Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:15])[CH:4]=[CH:5][C:6]=1[S:7]([NH:10]C(C)(C)C)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[N:3]([CH3:15])[CH:4]=[CH:5][C:6]=1[S:7]([NH2:10])(=[O:8])=[O:9]
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(S(N)(=O)=O)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.4 %

Procedure:
To a solution of 7.11 g (24 mmol) of 2-bromo-N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 50 mL methylene chloride under a nitrogen atmosphere was added 50 mL of TFA. The reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the crude residue and was removed by evaporation to remove residual TFA, which yielded 1.23 g of the title compound as a light brown solid.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[N:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH:6]=1)C.[Li+].[OH-]>C1COCC1.O.CO.CO.Cl>[C:26]1([C:22]2[CH:21]=[C:20]([C:17]3[N:14]4[N:15]=[CH:16][C:11]([C:7]5[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=5)[C:4]([OH:32])=[O:3])=[CH:12][C:13]4=[N:19][CH:18]=3)[CH:25]=[CH:24][N:23]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[3-(2-Phenyl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid ethyl ester (1 eq, 0.119 mmol, 50 mg) (Ex. 42) is dissolved in THF/H2O/MeOH (0.5/0.25/0.25 ml) and LiOH (20 eq, 2.38 mmol, 57 mg) is then added and the reaction is stirred at room temperature for 1 h. The reaction mixture is then diluted with MeOH and HCl (1M) is added. The precipitate is filtered and dried to afford 3-[3-(2-Phenyl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid as a yellow solid which did not require further purification; [M+H]+=393
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:10]2[C:23]3[O:22][CH2:21][CH2:20][N:19]4[C:15](=[C:16]([CH:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[C:17]5[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[CH:24][C:18]=54)[C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[N:40]1([CH2:39][CH2:38][N:9]([CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:10]2[C:23]3[O:22][CH2:21][CH2:20][N:19]4[C:15](=[C:16]([CH:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[C:17]5[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:18]=54)[C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c-3cccc1N(CCN1CCCCC1)CCN1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c-3cccc1N(CCN1CCCCC1)CCN1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (401 mg, 0.65 mmol) in tetrahydrofuran (4.0 ml) and methanol (4.0 ml) was added 4N aqueous sodium hydroxide solution (4.0 ml), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was adjusted to pH 6 with 2N hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The precipitated solid was collected by filtration to give 4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid. To a solution of the obtained 4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid in chloroform was added 4N HCl-ethyl acetate solution (4.0 ml). The reaction mixture was concentrated under reduced pressure and ethyl acetate was added. The precipitated solid was collected by filtration and dried in vacuo to give 4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid trihydrochloride (338 mg, yield 73%).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH3:17]O>>[ClH:1].[CH3:17][NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:16][CH:15]=1
Reactant: CO
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Product: CN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 18 h

Procedure:
Dry methanol (200 ml) was saturated with HCl(g) in a two-necked round bottom flask cooled to -10° C. p-Nitrophenylalanine (10.0 g, 47.6 mmol) was added in one portion and left to stir for about 18 hours, the solution was evaporated to near dryness on a rotary evaporator and the precipitated product collected in a Buchner funnel. After drying under vacuum at about 50° C., the yield was 10.97 grams (88.3%). A TLC (thin layer chromatography) of the free amino ester run in CHCl3 :MeOH (4:1) revealed and Rf =0.85-0.88. 1H NMR (220 MHz, D2O, pH 1.5) 8.20 (d,2 J=10.0), 7.53 (d,2,J=10.0), 4.55 (t,1,J=5.00), 3.84 (s,3), 3.43 (m,2); CI-MS 225 ((M+1)/z). Anal. Calcd. for C10H13N2O4Cl: C, 46.07; H, 5.03; N, 10.74; Cl, 13.60. Found: C, 45.87; H, 5.08; N, 10.48; Cl, 13.58.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:3][CH:2]=1.C1C(=O)N([Br:31])C(=O)C1.O>C1COCC1>[Br:31][C:13]1[CH:14]=[CH:15][C:9]2[C:8]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:23])=[CH:2][CH:3]=3)[S:11][C:10]=2[CH:12]=1
Reactant: Cc1ccc(-c2sc3ccccc3c2-c2ccc(C)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2sc3cc(Br)ccc3c2-c2ccc(C)cc2)cc1
Reaction time: 6 h
Yield: 80.5 %

Procedure:
2.5 g (1 eq, 7.9 mmol) of 2,3-di-p-tolyl-benzo[b]thiophene and 14 g (10 eq, 79 mmol) of NBS were dissolved in 200 ml of THF in a 500 ml-round-bottomed flask and stirred for 6 hours. 50 ml of water was added to the solution to terminate the reaction, and the organic phase was extracted using brine and methylene chloride. The extracted organic phase was dried using anhydrous magnesium sulfate and filtered to remove the solvent. A resulting solid was recrystallized using methylene chloride and hexane, dissolved in a small amount of THF, and separated using column chromatography (silica and hexane) to obtain 2.5 g (71%) of a yellow solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[CH:13]\[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])/[CH:11]=[O:12])=[CH:6][CH:5]=1.O>[OH-].[Na+].C(O)(C)C>[F:3][C:4]1[CH:5]=[CH:6][C:7](/[C:10](=[CH:13]\[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])/[CH2:11][OH:12])=[CH:8][CH:9]=1
Reactant: O=C/C(=C/c1ccccc1Cl)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: OC/C(=C/c1ccccc1Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
7.3 g of sodium borohydride, which has been dissolved in a little 10% strength sodium hydroxide solution are added to a solution of 150 g of E-2-(4-fluorophenyl)-3-(2-chlorophenyl)-propenal (prepared as described in Example A) in 600 ml of isopropanol at 0° C. After the reaction mixture has been stirred for two hours at room temperature, 300 ml of water are added to the solution and the resulting emulsion is extracted by shaking with methylene chloride. The organic phase isolated is then dried over sodium sulfate and evaporated down. 150.7 g (100%) of E-2-(4-fluorophenyl)-3-(2-chlorophenyl)-prop-2-enol are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16](Br)[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.Cl[Pd]Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]2[C:15]=1[O:14][CH:13]([CH2:12][O:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH2:22][CH2:21]2
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3cc(F)cc(Br)c3O2)cc1
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2CCc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Yield: 71.2 %

Procedure:
To a solution of (8-bromo-6-fluoro-3,4-dihydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (0.33 g, 0.795 mmol) and 2-chlorophenylboronic acid (249 mg, 1.589 mmol) in dioxane (9 mL) was added a solution of potassium carbonate (329 mg, 2.38 mmol) in water (3 mL) and the mixture purged with nitrogen for 20 minutes. Trans-dichlorobis(tri-o-tolylphosphine)palladium (II) (31.2 mg, 0.0397 mmol) was added and the reaction mixture heated to reflux for 18 hours. The cooled reaction mixture was then partitioned between ethyl acetate (100 mL) and 2.0 M aqueous sodium hydroxide (100 mL). The organic layer was separated, washed with water (100 mL) and saturated brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 5 to 20% ethyl acetate in hexane gave 253 mg (71%) of toluene-4-sulfonic acid 8-(2-chloro-phenyl)-6-fluoro-chroman-2-ylmethyl ester as a colorless syrup. MS (ESI) m/z 464 ([M+NH4]+).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([NH2:27])[C:24]([NH2:28])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:30]C1C=CC(S(O)(=O)=O)=CC=1.O.C(OC)(OC)OC>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]([F:29])=[CH:23][C:24]4[N:28]=[CH:30][NH:27][C:25]=4[CH:26]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(N)c(N)cc3F)CC2)CC1
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc4[nH]cnc4cc3F)CC2)CC1
Reaction time: 16 h

Procedure:
The crude 60b was combined with TsOH.H2O (50 mg) in 2 mL of DMF and treated with HC(OMe)3 (1 mL). The mixture was stirred for 16 h then concentrated and purified on preparative HPLC to afford 60-1: LC-MS 418.4 (MH+), tR=4.64 (Method 4).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[CH:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)=[C:8]([CH3:23])[C:6]=3[N:7]=2)=[CH:39][CH:40]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3ccc(N)nc3)nc12
Yield: 99.2 %

Procedure:
(S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 50 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to give 67.3 mg of 202. MS (Q1) 498.3 (M)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Cc1cc(-c2ccc(F)c(F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (42 mg, 76%), MS (ISP) m/z=327.4 [(M+H)+], mp 231° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 11) (50 mg, 0.17 mmol) and commercially available 3,4-difluoro-phenylboronic acid (35 mg, 0.22 mmol).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:17])=[CH:5][C:6](=[O:16])[C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].II.[I:20](O)(=O)=O>C(O)C.O.S([O-])([O-])=O.[Na+].[Na+]>[I:20][C:5]1[C:6](=[O:16])[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:2]([CH3:1])[NH:3][C:4]=1[CH3:17]
Reactant: CCCCCCCCc1c(C)[nH]c(C)cc1=O
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCc1c(C)[nH]c(C)c(I)c1=O
Reaction time: 0.5 h
Yield: 205.8 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-octylpyridin-4(1H)-one (1.17 g) and iodine (0.63 g) in ethanol (15 ml) at 70° was added dropwise a solution of iodic acid (0.22 g) in water (1 ml). After 30 min the mixture was allowed to cool and a few drops of an aqueous sodium sulphite solution added to remove excess iodine. The precipitate was filtered, washed with ethanol and recrystallised from DMF to give the title compound (0.93 g), m.p. 224°-226°, NMR δH (d6 -DMSO) 2.42 (3H, s), 2.3-2.5 (2H, m), 2.2 (3H, s), 1.1-1.45 (12H, m), 0.85 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([C:16]([NH2:18])=[O:17])[CH:3]=1.C1COCC1.CC[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:18][C:16]2=[O:17]
Reactant: CCOC(=O)C(=O)Nc1ccc(N)cc1C(N)=O
Agent: CC[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2ccc(N)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.6 %

Procedure:
To a solution of ethyl {[4-amino-2-(aminocarbonyl)phenyl]amino}(oxo)acetate (1.96 g) in a mixed solvent of THF (60 ml)-ethanol (30 mL) was added dropwise sodium ethylate (20% ethanol solution, 2.82 g), and the mixture was stirred at room temperature for 12 hr. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, and the obtained crude crystals were washed with diisopropyl ether to give the title compound (738 mg).
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:9][N:10]=1)(=[O:4])[CH2:2][CH3:3].[Cl-].[NH4+].O.O1CCCC1>C(O)C.[Fe]>[C:1]([NH:5][C:6]1[S:7][C:8]([S:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[CH:9][N:10]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCC(=O)Nc1ncc(Sc2ccc(N)cc2)s1
Yield: 96 %

Procedure:
To a mixture of 2-propionylamino-5-(4-nitrophenylthio)thiazole (3 g), and ammonium chloride (1 g) in a mixture of ethanol (100 ml), water (30 ml) and tetrahydrofuran (70 ml) was portionwise added the iron powder at 80° C. with stirring. The mixture was refluxed for 2hours with stirring. The reaction mixture was filtered by suction and the filtrate was concentrated under reduced pressure. The residue was triturated with water, the precipitates were collected by filtration and washed with water to give solid. The solid was recrystallized from ethanol to give 2-propionylamino-5-(4-aminophenylthio)thiazole (2.6 g, yield: 96.3%).
Reaction SMILES: [CH:1]([C:3]1([CH2:16][CH2:17][CH3:18])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[NH3:19]>CO.[Ni]>[CH2:8]1[C:3]2([CH2:16][CH2:17][CH2:18][NH:19][CH2:1]2)[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7]1
Reactant: N
Reactant: CCCC1(C=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Temperature: 110 °C

Procedure:
Tert-butyl 4-formyl-4-propylpiperidinecarboxylate (30 g) was dissolved in a saturated solution of ammonia in methanol, and 15 g of Raney Ni was added. The reaction mixture was heated to 110° C. at 80 atmospheres pressure in a 2 L high-pressure autoclave. The mixture was filtered to remove the catalyst and the filtrate was concentrated to give residue which was purified by column chromatography to afford tert-butyl 3,8-diazaspiro[5,5]undecane-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>N1C=CC=CC=1>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:1][C:2]2[N:7]=[CH:6][C:5]([O:8][C:9]3[CH:10]=[C:11]([NH:15][C:16](=[O:27])[C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=4)[CH:12]=[CH:13][CH:14]=3)=[CH:4][CH:3]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2)cc1
Temperature: 80 °C
Yield: 97.3 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (2.00 g, 5.36 mmol) in pyridine (60 mL) was added 4-methylbenzenesulfonyl chloride (1.12 g, 5.89 mmol) under ice-cooling, and the mixture was stirred with heating at 80° C. for 2 days. After cooling the reaction mixture to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (2.75 g, 99%) as a yellow oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][C:26]([N:28]([CH:37]([CH3:39])[CH3:38])[C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)=[O:27]>CN(C=O)C.O>[CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[N:13]([CH2:25][C:26]([N:28]([CH:37]([CH3:39])[CH3:38])[C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[O:27])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cn1
Reactant: O=C1Cc2nnc(C3CCCCC3)n2-c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(C4CCCCC4)n3-c3ccccc32)C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-cyclohexyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(B) (100 mg, 0.354 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in oil, 15 mg, 0.372 mmol). The reaction was stirred at 0° C. for 30 minutes, was cooled to −10C and 2-bromo-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (Preparation 1(B) (107 mg, 0.372 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature for 24 h and was diluted with water. The aqueous solution was washed with EtOAc (3×). The combined organic solutions were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (1% EtOAc in hexanes to 100% EtOAc) to provide 861.8 mg of 2-(1-cyclohexyl-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CDCl3) δ 8.11-7.48 (m, total 3H), 7.36 (m, 3H), 6.79 (dd, 1H), 4.99 (m, 1H), 4.12 (m, 2H), 3.92 (d, 3H), 3.65 (d) and 3.82 (d, total 1H), 3.46 (dd, 1H), 2.83 (m, 1H), 2.20 (d, 1H), 2.03-1.86 (m, 3H), 1.68 (m, 2H), 1.54 (m, 2H) 1.31-1.41 (m, 2H), 1.07 (m, 6H); MS 489.4 (M+1), 487.4 (M−1).
Reaction SMILES: [C:1]([NH:4][CH:5](OCC)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].B(Br)(Br)Br.[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([NH:4][CH:5]([NH:30][NH:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Reactant: NNc1ccccc1
Agent: BrB(Br)Br
Product: CC(=O)NC(NNc1ccccc1)C(=O)NCc1ccccc1

Procedure:
Using 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol), BBr3 (1M in CH2Cl2, 10.0 mL, 10.0 mmol), and phenylhydrazine (2.60 g, 24.0 mmol) gave a pale yellow oily residue which was purified by flash column chromatography on SiO2 gel (2% MeOH/CHCl3) to give the desired product. The product was recrystallized from chloroform/hexane as a light yellow solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:21]1[N:22]=[C:23]([NH2:39])[C:24]2[N:25]=[CH:26][N:27]([C:37]=2[N:38]=1)[C@@H:28]1[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]1[OH:30]>>[F:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:21]3[N:22]=[C:23]([NH2:39])[C:24]4[N:25]=[CH:26][N:27]([C:37]=4[N:38]=3)[C@@H:28]3[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]3[OH:30])[CH2:5][CH2:6]2)=[O:11])=[CH:18][CH:17]=1
Reactant: C#CCC1CCN(C(=O)Oc2ccc(F)cc2)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(C#CCC2CCN(C(=O)Oc3ccc(F)cc3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Batch: AB-9-147. 4-fluorophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-97 (0.700 g, 2.68 mmol) was added to a solution of 2-iodoadenosine (0.812 g, 2.065 mmol) according to general procedure 2. Yield: 0.902 g, 83%. 1H NMR (CD3OD) δ 8.34 (s, 1H), 7.11 (m, 4H), 5.98 (d, 1H), 4.76 (m, 2H), 4.37-4.19 (2×m, 3H), 3.95-3.75 (2×d, 2H), 3.07-2.93 (2×bt, 4H), 2.47 (d, 5H), 1.98-1.44 (2×m, 5H). m/z MH+=527.19. HPLC rt=7.6 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[C:33]([O:41][CH2:42][CH3:43])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[C:33]([O:41][CH2:42][CH3:43])[CH:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:44])=[C:16]([F:22])[CH:17]=1
Reactant: CCOc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O
Temperature: 70 °C

Procedure:
In a manner similar to the method described in Example 380, a solution of the above methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-ethoxybenzoate (89.7 mg, ˜0.13 mmol) in THF (8 ml) was treated with lithium hydroxide hydrate (40.9 mg, 0.974 mmol) in water (4 mL) and heated at 70° C. for 3 hrs and then stirred at room temperature to give rac 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-ethoxy-benzoic acid as a white lyophilized solid (33.5 mg., 38%) after HPLC purification.