Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11](Br)[CH:12]=[CH2:13].[H-].[Na+]>CN(C=O)C>[CH2:13]([N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1ccc2ncnc(Cl)c21
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To a room temperature solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.2 g, 7.8 mmol,) and allyl bromide in 40 mL of DMF was added 60% sodium hydride (625 mg, 15.6 mmol, 2 equiv.) in several portions. After 20 minutes, the reaction was quenched with water and extracted with EtOAc. The combined organics were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexanes) to provide 1.3 g (88%) of 5-allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine as a yellow oil which was used without further purification.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].CCOCC.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1.C(=O)([O-])[O-].[Ca+2]>O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]=[C:1]=[S:2])=[N:15][CH:16]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOCC
Solvent: O
Product: S=C=Nc1ccc(Cl)cn1

Procedure:
A solution of 16.3 ml. of thiophosgene in 600 ml. of ether is added with rapid stirring to a suspension of 25.6 g. of 5-chloro-2-aminopyridine and 42 g. of calcium carbonate in 600 ml. of water. The reaction mixture is stirred for 11/2 hours and the ether layer separated and the water layer extracted with a 400 ml. portion of ether. The combined ether extracts are washed with water, dried over magnesium sulfate and evaporated to dryness in vacuo affording 29.9 g. of a dark red oil. The oil is distilled at 0.75 mm. of Hg. at a temperature 96° C. affording 5-chloro-2-pyridylisothiocyanate.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[N:12]([CH2:26][CH2:27][CH3:28])[C:13](=[O:25])[C:14]3[NH:15][C:16]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:17][C:18]=3[N:19]=2)[CH:5]=1.C[N:31]1CCCN2C1=NCCC2.N>C1COCC1>[CH:20]1([C:16]2[NH:15][C:14]3[C:13](=[O:25])[N:12]([CH2:26][CH2:27][CH3:28])[C:11]([O:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([NH2:31])=[O:2])=[N:19][C:18]=3[N:17]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CN1CCCN2CCCN=C12
Reactant: CCCn1c(Oc2cccc(C(=O)OC)c2)nc2nc(C3CCCC3)[nH]c2c1=O
Agent: N
Solvent: C1CCOC1
Product: CCCn1c(Oc2cccc(C(N)=O)c2)nc2nc(C3CCCC3)[nH]c2c1=O
Yield: 61.7 %

Procedure:
A mixture of 3-(8-Cyclopentyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-yloxy)-benzoic acid methyl ester (0.07 g, 0.17 mmol, 1.0 eq) and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.034 g, 0.247 m·mol, 1.4 eq) was taken in THF. To this was added Liq.NH3 (˜3 g) through septum in sealed tube at −78° C. and then heated at 50° C. overnight. Crude reaction mixture was purified by preparative TLC to give the product as a white solid (0.04 g) in 60% yield.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9][NH:10]C(=O)OC(C)(C)C)(=[NH:3])[CH3:2].Cl>O1CCOCC1.CCOCC>[NH2:10][CH2:9][C:8]1[CH:7]=[C:6]([CH:20]=[CH:19][CH:18]=1)[CH2:5][NH:4][C:1](=[NH:3])[CH3:2]
Reactant: CC(=N)NCc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=N)NCc1cccc(CN)c1
Temperature: 20 °C
Reaction time: 24 h
Yield: 137.5 %

Procedure:
Solid tert-butyl N-(3-((acetimidoyl)aminomethyl)benzyl)carbamate (3.0 g, 9.6 mmol) was suspended into 150 ml anhydrous dioxane. 4N Hydrochloric acid in dioxane solution (20 ml) was added at 20° C. The mixture was stirred for 24 hours at 20° C. After diluting with 200 ml ether, the white solids were collected by filtration and dried under vacuum at 100° C. to yield 2.34 g (98%) of N-(3-(aminomethyl)benzyl)-acetamidine. 1H NMR (200 MHz, D2O) δ 7.52-7.35 (m, 4H), 4.49 (s, 2H), 4.16 (s, 2H), 2.25 (s, 3H). Mass Spectrum (CI) 177.9 (MH+, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Br)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[CH3:27][NH:28][CH3:29].[I-].[Na+]>>[CH3:27][N:28]([CH2:17][C:14]1[N:13]2[C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:26][C:8]=3[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:10][CH2:11][C:12]2=[N:16][N:15]=1)[CH3:29]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CBr)n1-2
Agent: [I-]
Agent: [Na+]
Product: CN(C)Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 8-nitro-1-(bromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine was reacted with dimethylamine in the presence of sodium iodide to give 1-[(dimethylamino)methyl]-8-nitro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][CH:14]([NH:23][CH:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]1=[O:38])=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:9]([CH2:11][N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][CH:14]([NH:23][CH:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:13]1=[O:38])([OH:10])=[O:8]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2N(CC(=O)O)C1=O

Procedure:
A solution of 1-benzyloxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (isomer A of example 3; 1.2 g) in ethanol (125 ml) was hydrogenated at room temperature and atmospheric pressure, using 10% palladium on charcoal (0.5 g) as catalyst. After uptake of hydrogen had ceased, the catalyst was filtered off, and the solvent removed under reduced pressure to give a solid. This material was triturated with ether (8 ml) to give 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one melting at 126°-129°, and being the lower melting racemic isomer A.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH2:17]([O:19][C:20]([C:22]1[NH:23][N:24]=[C:25]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)=[O:21])[CH3:18].[CH3:35][C:36]1([CH3:50])[O:40][CH2:39][C@@H:38]([CH2:41]O)[N:37]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:46]([O:45][C:43]([N:37]1[C@H:38]([CH2:41][N:23]2[C:22]([C:20]([O:19][CH2:17][CH3:18])=[O:21])=[CH:26][C:25]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:24]2)[CH2:39][O:40][C:36]1([CH3:35])[CH3:50])=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)COC1(C)C
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(COc2ccccc2)nn1C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Di-tert-butyl azodicarboxylate (0.56 g, 2.43 mmol) was added portionwise to a mixture of 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.5 g, 2.0 mmol), (R)-1-boc-2,2-dimethyl-4-hydroxymethyl-oxazolidine (0.49 g, 2.1 mmol) and triphenylphosphine (0.64 g, 2.4 mmol) in THF (10 mL) at 0° C. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (silica; DCM in heptane 50/50 to 100/0). Desired fractions were collected and the solvent evaporated in vacuo to yield (R)-4-(5-ethoxycarbonyl-3-phenoxymethyl-pyrazol-1-ylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.91 g, 98% yield) as a clear oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CCO.[Pd]>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][OH:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: OCc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: OCc1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 100 %

Procedure:
To a solution of [4-(4-Benzyl-piperazin-1-yl)phenyl]-methanol in EtOH (50 ml) under a blanket of argon was added a suspension of 10% palladium on charcoal (1.5 g) in EtOH (150 ml). Hydrogen was bubbled through the suspension for 1 h and then the reaction mixture was stirred under a blanket of hydrogen for 60 h at RT. The catalyst was filtered off and the solvent removed in vacuo to yield the title compound as a white solid (4.8 g, 100%). 1H-NMR δ (CDCl3) 7.30–7.21 (2H, m, ArH), 6.94–6.88 (2H, m, ArH), 4.59 (2H, s), 3.18–2.98 (8H, m). HPLC: 0.5 min (37%@214 nm), 0.7 min (55%@214 nm), multiple peaks due to salt formation from TFA buffer; LRMS +ve: 193 (M+1, 70).
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])([CH3:8])([CH3:7])[CH3:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:29][C:30](=[O:65])/[C:31](/[CH3:64])=[CH:32]/[C@:33]34[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]3[C@@H:35]3[C@@:48]([CH3:51])([CH2:49][CH2:50]4)[C@@:47]4([CH3:52])[C@@H:38]([C@:39]5([CH3:56])[C@@H:44]([CH2:45][CH2:46]4)[C:43]([CH3:54])([CH3:53])[C@@H:42](O)[CH2:41][CH2:40]5)[CH2:37][CH2:36]3)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:16][C:11]([CH3:17])([CH2:12][C:13]([O:15][C@H:42]1[CH2:41][CH2:40][C@@:39]2([CH3:56])[C@@H:44]([CH2:45][CH2:46][C@:47]3([CH3:52])[C@@H:38]2[CH2:37][CH2:36][C@H:35]2[C@@:48]3([CH3:51])[CH2:49][CH2:50][C@@:33]3(/[CH:32]=[C:31](\[CH3:64])/[C:30]([NH:29][C:26]4([C:23]5[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=5)[CH2:27][CH2:28]4)=[O:65])[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]32)[C:43]1([CH3:53])[CH3:54])=[O:14])[C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:18]
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Reactant: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ccc(Cl)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a solution of DMAP (415 mg, 3.40 mmol), EDC (652 mg, 3.40 mmol) and 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid (425 mg, 2.039 mmol) in DCM (10 mL) stirred at 20° C. for 30 min was added (E)-N-(1-(4-chlorophenyl)cyclopropyl)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylamide (650 mg, 0.680 mmol). The reaction mixture was stirred at 20° C. for 2 h. The mixture was washed with saturated ammonium chloride, water, and saturated NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column eluting with petroleum ether/Ethyl acetate (3:1) to afford 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(4-chlorophenyl)cyclopropyl)amino)-2-methyl-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (300 mg, 52%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.30-7.22 (m, 2H), 7.22-7.14 (m, 2H), 6.59 (s, 1H), 6.32 (s, 1H), 4.51 (dd, J=5.4, 10.9 Hz, 1H), 3.28-3.10 (m, 1H), 2.72 (d, J=10.3 Hz, 1H), 2.55 (s, 3H), 2.41-2.21 (m, 2H), 2.12-0.71 (m, 61H).
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][CH2:6][CH:7]([NH2:20])[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[N:9]=1)C.[C:22]([O:26][C:27](=[O:43])[N:28]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH2:29][CH:30]=O)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:43])[N:28]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH2:29][CH2:30][N:20]1[C:4](=[O:21])[CH2:5][CH2:6][CH:7]1[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[N:9]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N(CC=O)Cc1ccc2c(c1)OCCO2
Reactant: CCOC(=O)CCC(N)c1cc(C)nc(-n2ccnc2)n1
Product: Cc1cc(C2CCC(=O)N2CCN(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)nc(-n2ccnc2)n1

Procedure:
(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-5-oxo-pyrrolidin-1-yl]-ethyl}-carbamic acid tert-butyl ester was prepared following the procedures described in the preparation of Example 77c using 4-amino-4-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-butyric acid ethyl ester and (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(2-oxo-ethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].O.S(=O)(=O)(O)O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([CH:4]([CH2:14][CH2:15][CH2:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCC(=O)CCCC(CCCCCCC(=O)O)C(C)=O
Reaction time: 0.5 h

Procedure:
A solution of 8-acetyl-12-hydroxyheptadecanoic acid (9.85 g., 0.03 mole) in acetone (29 ml.) is cooled to 5°-10° and treated, dropwise, over 21/4 hours with a solution prepared from a mixture of chromium trioxide (2.57 g., 0.0257 mole) water (7.5 ml.) and concentrated sulfuric acid (2.1 ml.). Stirring is continued for an additional 30 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([OH:13])[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH3:14][C:15]1[CH:20]=[C:19](O)[CH:18]=[C:17]([CH3:22])[C:16]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CO>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([O:13][C:19]2[CH:20]=[C:15]([CH3:14])[C:16]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=3)=[C:17]([CH3:22])[CH:18]=2)[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(C(C)O)s1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(C)Oc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of (±)-5-(1-hydroxy-ethyl)-thiophene-2-carboxylic acid ethyl ester (0.402 g, 2.01 mmol), 2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ol (0.593 g, 2.23 mmol), and PPh3 (0.798 g, 3.04 mmol) is dissolved in toluene (20 mL) and treated with 1,1′-(azodicarbonyl)dipiperidine (ADDP, 0.763 g, 3.02 mmol) and stirred overnight at rt. The mixture is diluted with MeOH until homogeneous and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 40% giving (±)-5-[1-(2,6-Dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid ethyl ester (0.638 g, 71%) as a clear syrup. MS (ES): 447.3 [M−H]−.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]([NH:21][C@@H:22]([CH2:28][OH:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[C:15]([O:14][C:12](=[O:13])[CH2:11][C@H:10]([C:19]1[O:29][CH2:28][C@@H:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=1)[CH2:9][CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CCOC(=O)[C@H](CO)NC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1COC([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)=N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.7 %

Procedure:
A solution of tert-butyl(3R)-6-cyclohexyl-3-({[(1S)-2-ethoxy-1-(hydroxymethyl)-2-oxoethyl]amino}carbonyl)hexanoate (preparation 151) (10.09, 24.2 mmol) in THF (80 ml) was treated with Burgess reagent (6.34 g, 26.6 mmol) and heated at reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and stored in a fridge for 3 days. The solvent was removed under reduced pressure. The crude material was ourififed on a silica column eluting with a solvent gradient of pentane:EtOAc (100:0) gradually changing to (80:20) to afford the title compound as a colourless oil (9.26 g, 97%).
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:9]([C:13]([O:15]C)=O)=[CH:10][S:11][CH:12]=1)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:9]([C:13]([NH2:2])=[O:15])=[CH:10][S:11][CH:12]=1)[CH3:5]
Reactant: COC(=O)c1cscc1N=NN(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N=Nc1cscc1C(N)=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 25 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (5 mL) was added a solution of methyl 4-[(dimethylamino)diazenyl]thiophene-3-carboxylate (110 mg) in THF (2 mL) for 5 min and stirred at rt for 36 h. The solution was poured into ice cooled water and extracted with chloroform. The combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product as a pale red color solid (25 mg, 25%), mp 168-172° C. IR (neat) νmax 3324, 3125, 2917, 2851, 1655, 1600, 1367, 1336, 1090 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.55 (1H, br s), 8.19 (1H, d, J=3.6 Hz), 7.15 (1H, d, J=3.6 Hz), 5.84 (1H, br s), 3.56 (3H, br s), 3.19 (3H, br s); LC-MS (positive ion mode): m/z 199 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[N:10][N:9]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=[C:8]2[C:7]=1[NH:21][C@@H:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([O:25]C)=[O:24])(=[O:5])[NH2:4]>CO.C1COCC1>[C:3]([C:6]1[CH:11]=[N:10][N:9]2[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=[C:8]2[C:7]=1[NH:21][C@@H:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([OH:25])=[O:24])(=[O:5])[NH2:4]
Reactant: COC(=O)[C@@H](Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1cnn2cc(-c3ccccc3)cc2c1N[C@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 105.3 %

Procedure:
Sodium hydroxide (11.200 ml, 11.20 mmol) added in one portion to a heterogeneous mixture of (S)-methyl 2-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-2-phenylacetate (Example 121, 900 mg, 2.248 mmol) in MeOH (30 ml) and THF (15 ml). The reaction was allowed to stir at rt for ca. 2.5 hrs before removing the solvent in vacuo and cooling the flask in an ice bath. 1N aq. HCl was added and the yellow precipitate was then filtered and allowed to dry overnight. This afforded the title compound (915 mg, 100%) as a pale yellow solid. HPLC (condition B): retention time=0.87 min. LCMS (condition B): MH+ m/z 387.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (1 H, d, J=7.04 Hz), 8.23 (1 H, s), 8.10 (1 H, d, J=1.54 Hz), 7.66 (2 H, d, J=7.26 Hz), 7.55 (2 H, d, J=7.48 Hz), 7.36 (5 H, q, J=7.92 Hz), 7.12-7.29 (4 H, m), 5.93 (1 H, br. s.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:15]([O:17][CH2:18][CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[N:29]1[CH2:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][C:38]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:42][CH2:41][NH:40][CH2:39]2)[CH2:31][CH2:30]1)[CH3:16]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:4]=1[C:5]([N:40]1[CH2:41][CH2:42][C:38]([CH2:37][CH2:36][N:32]2[CH2:33][CH2:34][CH2:35][N:29]([C:21]3[N:20]([CH2:19][CH2:18][O:17][CH2:15][CH3:16])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=3)[CH2:30][CH2:31]2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:39]1)=[O:7]
Reactant: COc1ccc(C#N)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(C#N)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-cyanobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [O:1]=[C:2]([CH3:29])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N:45]=[C:46]=[S:47])([CH3:38])[CH3:37].O>CN(C)C=O>[OH:1]/[C:2](/[CH3:29])=[C:3](/[C:46](=[S:47])[NH:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[CH:36]([CH3:37])[CH3:38])\[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:20][CH:19]=3)[N:14]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CC(=O)CC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1ccccc1N=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C(O)=C(/C(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=S)Nc1ccccc1C(C)C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
A portion of the solid from Step 1 (0.50 g, 1.24 mmol) was dissolved in 5 mL of dry N,N-dimethylformamide (DMF) and stirred at ambient temperature while potassium carbonate (0.25 g, 1.81 mmol) and 2-isopropylphenyl isothiocyanate (0.25 g, 1.41 mmol) were added. The solution was stirred for 18 h, then it was poured into 15 mL of water, extracted with ether, and the solvent evaporated. Chromatography of the crude product (0-70% EtOAc-hexanes) gave 350 mg of the title compound as an off-white solid. mp 141-144° C. 1H NMR (400 MHz, CDCl3) δ 15.35-14.58 (m, 1H), 10.93 (s, 1H), 8.57 (m, 3H), 8.31-8.11 (m, 6H), 7.71 (m, 12H), 7.56-7.30 (m, 15H), 5.35 (s, 1H), 3.02 (heptet, J=6.9 Hz, 1H), 2.52 (s, 3H), 1.35-1.11 (m, 6H); ESIMS m/z 582 ([M+H]+).