Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:48]=[CH:47][C:24]([C:25]([C:27]2[CH:28]=[CH:29][C:30]3[N:36]([CH3:37])[C:35](=[O:38])[CH2:34][NH:33][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=4)[C:31]=3[CH:46]=2)=[O:26])=[CH:23][CH:22]=1>CCCCCC.C1COCC1>[Cl:45][C:41]1[CH:40]=[C:39]([CH:32]2[C:31]3[CH:46]=[C:27]([C:25]([C:24]4[CH:47]=[CH:48][C:21]([Cl:20])=[CH:22][CH:23]=4)([OH:26])[C:11]4[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=4)[CH:28]=[CH:29][C:30]=3[N:36]([CH3:37])[C:35](=[O:38])[CH2:34][NH:33]2)[CH:44]=[CH:43][CH:42]=1
Reactant: CN1C(=O)CNC(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1C(=O)CNC(c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
BuLi 1.6M in hexane (27.4 ml) was added dropwise at −70° C. under N2 flow to a mixture of 1-methyl-1H-imidazole (0.0439 mol) in THF (140 ml). The mixture was stirred for 30 min. ClSiEt3 (0.0439 mol) was added. The mixture was brought slowly to room temperature and cooled again to −70° C. BuLi 1.6M in hexane (27.4 ml) was added dropwise. The mixture was stirred for 1 hour, brought quickly to −15° C. and cooled to −70° C. A solution of intermediate (8) (0.02 mol) in THF (90 ml) was added dropwise. The mixture was stirred at −50° C. for 30 min, then hydrolyzed and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (17.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 94/6/0.1 and 93/7/0.1; 20–45 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN, EtOAc and 2-propanone. The precipitate was filtered off and dried, yielding 0.8 g (8.5%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,3,4,5-tetrahydro-1-methyl-2H-1,4-benzodiazepin-2-one, mp. 208° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].N1C=CC=CC=1.[C:15]([CH2:20][CH2:21][C:22](Cl)=[O:23])([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[CH2:20][CH2:21][C:22]([NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:23])[CH3:19]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: CCN(CC)CCN
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCC(=O)NCCN(CC)CC
Yield: 16.4 %

Procedure:
First, 20 milliliters (0.05 mole) N,N-diethylethylene diamine, 50 milliliters dry methylene chloride, and 5.2 milliliters (0.065 mole) pyridine were combined in a flask. Next, 9.03 grams (0.06 mole) 3-carboethoxy-propionyl chloride was added at -60° C. with stirring. The temperature was allowed to rise to 0° C. The reaction mixture was then washed with a 200 milliliter portion of water and a 100 milliliter portion of saturated sodium carbonate solution. The organic solution was stripped in vacuum to yield 2.0 grams of the desired product. nD30 1.4500.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([CH2:25][CH3:26])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[C:5]1=[O:27])[CH:2]=C.[BH4-].[Na+].C[OH:31]>>[CH2:25]([C:6]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)[CH2:7][CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH2:2][OH:31])[C:5]1=[O:27])[CH3:26]
Reactant: C=CCN1CCCCC(CC)(c2cccc(OCc3ccccc3)c2)C1=O
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CCC1(c2cccc(OCc3ccccc3)c2)CCCCN(CCO)C1=O
Temperature: -40 °C
Reaction time: 0.42 h

Procedure:
A solution of 1-allyl-3-ethyl-3-(3-benzyloxy-phenyl)-azepan-2-one, as described in Step B above, (0.87 g, 2.4 mmol) in MeOH (20 mL) at −78° C. was saturated with 03 for 25 min. The solution was warmed to −40° C. for 10 min then NaBH4 (0.363 g, 9.6 mmol) was added and the reaction mixture was stirred at 25° C. for 1 hr. The MeOH was removed in vacuo , and the residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound after chromatography on silica gel eluting with hexane/EtOAc, 1/1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:35]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[S:8]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:35]
Reactant: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(c1ccc2ccccc2c1)c1ccc(NS(=O)(=O)c2ccc(Cl)nc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 6-Chloro-pyridine-3-sulfonic acid [3-chloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-amide (94, 55 mg, 0.12 mmol) in CH2Cl2 (2 mL), was added dropwise a solution of m-chloroperoxybenzoic acid (mCPBA, Aldrich, 36 mg, 0.12 mmol) in CH2Cl2 (1 mL). The resulting mixture was stirred at ambient temperature for 1 hour and diluted with EtOAc (60 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (50 mL), twice with brine solution (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (10-25% EtOAc in hexane) to yield 17 mg (30%) of 103 as an off white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][Se:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.C(N(CC)CC)C.[I-].[Cl:26]C1C=CC=C[N+]=1C.[NH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>ClCCl>[ClH:26].[ClH:26].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][Se:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)=[O:13]
Reactant: C[n+]1ccccc1Cl
Reactant: Nc1ccncc1
Reactant: O=C(O)c1ccccc1[Se]Cc1ccccn1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl
Product: O=C(Nc1ccncc1)c1ccccc1[Se]Cc1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 g (0.0137 mol) 2-(2-picolylseleno)benzoic acid from Example 1 and 2 ml triethylamine in 40 ml dichloromethane is treated with 3.5 g (0.0137 mol) 2-chloro-1-methylpyridinium iodide and stirred at room temperature for 1 hour. Then a solution of 1.29 g (0.0137 mol) 4-aminopyridine and 2 ml triethylamine in 30 ml dichloromethane are added dropwise within 15 min and after stirring for 2 hours the reaction mixture is extracted once with 100 ml 1 N sodium hydroxide solution and twice with 100 ml portions of water. The organic phase is dried, the solvent removed and the residue taken up in 2-propanol (80 ml)/15% HCl (10 ml). After filtration the solid crude product is dissolved in 100 ml methanol and diethyl ether is added dropwise until the solution remains turbid. The crystals which then form are filtered off after 2 hours and dried.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21].C(Cl)Cl>CN1CCCC1=O.CO>[NH2:21][CH2:20][CH2:19][NH:22][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)ccc2c1=O
Reactant: NCCN
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CO
Product: NCCNc1ccc2c(=O)c(C(=O)O)cn(C3CC3)c2c1
Temperature: 130 °C
Yield: 41.8 %

Procedure:
To a solution of 7-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (2.0 g) in 1-methyl-2-pyrrolidinone (20 mL) was added ethylenediamine (2.3 g). The mixture was heated at 130° C. for 10 h. The reaction mixture was cooled and poured into DCM (20 mL). The precipitate obtained was dispersed in MeOH, filtered to give the title compound (910 mg).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[C:7]1([C:13]#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:20][C:21]1[CH:27]=[CH:26]C=[C:23]([OH:24])[C:22]=1O>CC(C)=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:13]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:4][C:1]2[CH:26]=[CH:27][C:21]([Cl:20])=[CH:22][C:23]=2[O:24]1)[CH3:19]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: Oc1cccc(Cl)c1O
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC1(c2ccccc2)Oc2ccc(Cl)cc2O1

Procedure:
78.5 g of anhydrous K2CO3 are added, in parts, to a solution of 40.5 g of ethyl phenylpropiolate and 43.5 g of chloropyrocatechol in 200 cc of anhydrous acetone. The mixture is heated for 15 h. It is subsequently filtered and the solvent eliminated at low pressure. The residue is treated as indicated in Example 2. The product has b.p. 150°-155°C/0.3 mm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](/[N:28]=[CH:29]/[N:30](C)C)[C:25]([C:33]#[N:34])=[CH:24][C:23]=2[O:35][CH2:36][CH2:37][O:38][CH3:39])[C:6]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:5][C:4]=1/[N:45]=[CH:46]/[N:47](C)C)#[N:2].[C:50]([C:52]1[CH:53]=[C:54]([CH:56]=[CH:57][CH:58]=1)N)#[CH:51].[CH3:59][C:60](O)=O>CCOCC>[C:50]([C:52]1[CH:53]=[C:54]([NH:2][C:1]2[C:3]3[C:4](=[CH:5][C:6]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:7]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[C:26]5[C:25]([C:33]([NH:34][C:3]6[CH:8]=[CH:7][CH:6]=[C:5]([C:60]#[CH:59])[CH:4]=6)=[N:30][CH:29]=[N:28]5)=[CH:24][C:23]=4[O:35][CH2:36][CH2:37][O:38][CH3:39])[CH:8]=3)[N:45]=[CH:46][N:47]=2)[CH:56]=[CH:57][CH:58]=1)#[CH:51]
Reactant: CC(=O)O
Reactant: C#Cc1cccc(N)c1
Reactant: COCCOc1cc(/N=C/N(C)C)c(C#N)cc1OCCOCCOCCOCCOc1cc(/N=C/N(C)C)c(C#N)cc1OCCOC
Solvent: CCOCC
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOCCOCCOCCOc4cc5c(Nc6cccc(C#C)c6)ncnc5cc4OCCOC)c(OCCOC)cc23)c1

Procedure:
(E)-N′-(2-cyano-4-(2-(2-(2-(2-(4-cyano-5-((E)-((dimethylamino)methylene)amino)-2-(2-methoxyethoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-5-(2-methoxyethoxy)phenyl)-N,N-dimethylformimidamide (0.2 g), 3-ethynylaniline (0.11 g) were added to AcOH (5 mL), the resulting mixture was heated at reflux for 3 h under N2 atmospheres. After reaction finished, the mixture was diluted with Et2O (30 ml) and solid was collected. The solid was washed with Et2O and air-dried to give N-(3-ethynylphenyl)-6-(2-(2-(2-(2-((4-((3-ethynylphenyl)-amino)-6-(2-methoxyethoxy)quinazolin-7-yl)-oxy)ethoxy)ethoxy)ethoxy)ethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine (0.14 g, dimer 3) as a brown solid. 1H-NMR (400 MHz, DMSO-d6): δ: 9.46 (br, 2H), 8.48 (s, 2H), 7.98 (s, 2H), 7.89-7.83 (m, 4H), 7.40-7.37 (m, 2H), 7.22-7.19 (m, 4H), 4.33-4.25 (m, 8H), 4.21 (s, 1H), 4.20 (s, 1H), 3.90-3.80 (m, 4H), 3.80-3.70 (m, 4H), 370-7.60 (m, 4H), 3.60-3.50 (m, 4H), 3.35 (s, 3H), 3.34 (s, 3H).
Reaction SMILES: [C:1]1([C@H:11]([NH:13][C@H:14]2[CH2:18][CH2:17][C@@H:16]([C:19]3[CH:28]=[CH:27][C:22]([O:23][CH2:24][C:25]#[N:26])=[CH:21][CH:20]=3)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-:29].[NH4+].[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[ClH:29].[C:1]1([C@H:11]([NH:13][C@H:14]2[CH2:18][CH2:17][C@@H:16]([C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]4[N:31]=[N:32][NH:33][N:26]=4)=[CH:27][CH:28]=3)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: [Cl-]
Reactant: C[C@@H](N[C@H]1CC[C@@H](c2ccc(OCC#N)cc2)C1)c1cccc2ccccc12
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(OCc3nn[nH]n3)cc2)C1)c1cccc2ccccc12
Product: Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
Under a nitrogen stream, {4-[(1R,3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}cyclopentyl]phenoxy}acetonitrile (150 mg, 0.40 mmol), ammonium chloride (325 mg, 6.1 mmol) and sodium azide (263 mg, 4.0 mmol) were suspended in N,N-dimethylformamide (3 mL), followed by stirring for 3 hours at 80° C. The reaction solution was cooled to room temperature, followed by addition of water, and the precipitated powder was collected by filtration and washed with ethyl acetate to give the free form of the title compound (100 mg, 60%). The free form obtained was converted to the hydrochloride using 0.5N hydrochloric acid/dioxane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[N:14]=[C:15]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25](N)[CH:24]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:5][CH:4]=1.N1C=CC=CC=1.C(#N)C.[CH3:39][N:40]([CH3:45])[S:41](Cl)(=[O:43])=[O:42]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:39][N:40]([CH3:45])[S:41]([C:25]1[CH:24]=[C:23]([NH:22][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]3=[N:11][N:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[N:13]3[N:14]=2)[CH:28]=[CH:27][CH:26]=1)(=[O:43])=[O:42]
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(N)c4)nn23)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(S(=O)(=O)N(C)C)c4)nn23)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of N-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,3-diamine (compound A2) (1.90 g) and DMAP (304 mg) in a 3:1:1 mixture of anhydrous pyridine, anhydrous acetonitrile and anhydrous dichloromethane (100 mL) is added dimethylsulfamoyl chloride (2.67 mL). The mixture is stirred at RT for 3 days and filtered. The filtrate is concentrated in vacuum and a non-saturated solution of NaHCO3 (250 mL) is added to the residue. The suspension is filtered and the solid washed with a minimum of MeOH and AcOEt. Purification of residue by column chromatography (CH2Cl2/MeOH, 98:2) gives 1.43 g of the title compound as white powder.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=1>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)NC(=O)c3cccnc3)cc1)n2C)c1ccccn1
Yield: 56 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and nicotinic acid chloride. Yield: 56% of theory, C34H33N7O4 (603.7); Rf value: 0.52 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=604; (M+Na)+=626.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].ClCCl.C(N(C(C)C)CC)(C)C.[CH2:19]1[CH:23]2[CH2:24][NH:25][CH2:26][CH:22]2[CH2:21][N:20]1[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=2)[N:32]=1>C1(C)C=CC=CC=1>[CH2:1]([S:3]([N:25]1[CH2:24][CH:23]2[CH2:19][N:20]([C:27]3[CH:28]=[CH:29][C:30]4=[N:35][N:34]=[C:33]([C:36]([F:39])([F:37])[F:38])[N:31]4[N:32]=3)[CH2:21][CH:22]2[CH2:26]1)(=[O:5])=[O:4])[CH3:2]
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)N1CC2CN(c3ccc4nnc(C(F)(F)F)n4n3)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
Ethanesulfonyl chloride (0.024 g, 0.19 mmol) and then dichloromethane (0.5 mL) were added sequentially to a mixture of diisopropylethylamine (0.044 g, 0.34 mmol) and 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.050 g, 0.17 mmol) in toluene (1.5 mL). The reaction mixture was stirred for 1 hour at ambient temperature and then for 1.5 hours at 50° C. and then evaporated to give an involatile residue. The residue was purified by preparative hplc using a Phenomenex Luna C18 100A column (10μ silica, 21 mm diameter, 150 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% trifluoroacetic acid) and acetonitrile as eluents to give 6-(5-ethylsulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (0.0143 g, 22%) as a white solid.
Reaction SMILES: [C:1]([Cl:4])(=O)C.[N+:5]([C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][C:19]=1[OH:20])[CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])([O-:7])=[O:6]>CO>[ClH:4].[CH3:1][O:15][C:14](=[O:16])[C@H:12]([CH2:11][C:10]1[CH:17]=[CH:18][C:19]([OH:20])=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=1)[NH2:13]
Reactant: N[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccc(O)c([N+](=O)[O-])c1
Product: Cl
Yield: 42.9 %

Procedure:
Acetyl chloride (8.9 ml, 125 mmol) was added slowly to methanol (100 ml) at 0°. 3-Nitro-L-tyrosine (5.65 g, 25 mmol) was added and the mixture refluxed for 2 h. The solvent was evaporated in vacuo and the yellow solid obtained recrystallised from methanol to give the title compound as yellow needles (2.97 g, 43%), m.p. 200-201°. (Found: C, 43.29;H, 4.69; N, 10.19. C10H12N2O5HCl requires C, 43.41;H, 4.74; N, 10.13%); δH (CD3OD) 8.00 (1H, d, J 2.2 Hz, ArH), 7.53 (1H, dd, J 2.3, 8.6 Hz, ArH), 7.17 (1H, d, J 8.6 Hz, ArH), 4.37 (1H, dd, J 6.4, 7.0 Hz, CHα), 3.83 (3H, s, CO2CH3), 3.29 (1H, dd, J 6.3, 14.6 Hz, CHAHBAr) and 3.20 (1H, dd, J 7.1, 14.6 Hz, CHAHBAr); m/z (ES, 27V) 241 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][C:12]3=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26](OCC)=[O:27])=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].NC1C=CC(CCO)=CC=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][C:12]3=[C:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][OH:27])=[CH:23][CH:24]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3ccc(Cl)c(Cl)c3)nc3c2CCC3)cc1
Agent: Nc1ccc(CCO)cc1
Product: Cl
Product: OCCc1ccc(Nc2cc(-c3ccc(Cl)c(Cl)c3)nc3c2CCC3)cc1
Yield: 33 %

Procedure:
Following General Procedure B2, ethyl 2-(4-((2-(3,4-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate (0.075 g, 0.25 mmol) was reacted with 4-aminophenethyl alcohol (0.052 g, 0.38 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.018 g, 25%) as an off-white solid. MW=435.77. 1H NMR (DMSO-d6, 500 MHz) δ 14.40 (s, 1H), 9.77 (s, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.77-7.73 (m, 1H), 7.32 (s, 4H), 7.04 (s, 1H), 4.67 (s, 1H), 3.63 (t, J=7.0 Hz, 2H), 3.14 (t, J=7.6 Hz, 2H), 2.91 (t, J=7.6 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.26-2.14 (m, 2H); APCI MS m/z 399 [M+H]+.
Reaction SMILES: N[C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH3:10])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[I:15]CI.[N+]([O-])(OCCC(C)C)=O.[N+]([O-])(OCCCCC)=O>C(#N)C>[C:7]([C:6]1[C:2]([I:15])=[C:3]([C:11]([O:13][CH3:14])=[O:12])[S:4][C:5]=1[S:9][CH3:10])#[N:8]
Reactant: COC(=O)c1sc(SC)c(C#N)c1N
Reactant: ICI
Agent: CC(C)CCO[N+](=O)[O-]
Agent: CCCCCO[N+](=O)[O-]
Solvent: CC#N
Product: COC(=O)c1sc(SC)c(C#N)c1I
Temperature: 38 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a suspension of methyl 3-amino-4-cyano-5-(methylthio)thiophene-2-carboxylate (4.0 g, 17.5 mmol) in acetonitrile (20 mL) was added diiodomethane (4.94 mL, 61.3 mmol). The reaction mixture was heated at 38° C. Isoamyl nitrate (5.13 g, 43.8 mmol) was added dropwise over five minutes. After the addition of amyl nitrate, the reaction mixture was allowed to cool to room temperature and stirred for two hours. The reaction mixture was cooled in an ice bath and hexanes (20 mL) were added. The resultant precipitate was filtered and washed with a solution of 90% hexanes in acetonitrile (10 mL), 75% hexanes in diethyl ether (10 mL) and 100% hexanes (20 mL) to give methyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (3.4 g, 57%) as a light orange solid. 1H NMR (400 MHz, CDCl3) δ: 3.91 (s, 3H), 2.70 (s, 3H)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[NH:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([NH2:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:5][CH2:4][CH2:3][CH2:2][N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([NH2:13])=[O:12]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)[C@@H]1CCCN1CCCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.6 %

Procedure:
3-Bromo-1-propanol (584 mg, 4.2mmol) was added to a mixture of (S)-pyrrolidine-2-carboxamide (399 mg, 3.5 mmol) and potassium carbonate (966 mg, 7 mmol) in acetonitrile (10 ml). The mixture was heated at reflux for 5 hours and the mixture was stirred for 18 hours at ambient temperature. The insolubles were removed by filtration and the solvent was removed from the filtrate by evaporation The residue was purified by column chromatography on silica eluting with methylene chloride/methanol (9/1 followed by 8/2) to give (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (365 mg, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[N:10]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O.NN>CO.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:27])[N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N(Cc1ccc([N+](=O)[O-])cc1)C1CCCCC1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1
Yield: 101 %

Procedure:
The compound (1.24 g) obtained in Example 87-1 was dissolved in methanol (12 ml) and THF (6.2 ml) and added with activated carbon (124 mg) and iron trichloride hexahydrate (12.4 mg), followed by thermal reflux for 0.5 hour. After standing to cool, the solution was added with hydrazine monohydrate (0.89 ml) and then subjected to thermal reflux for 3 hours. After completion of the reaction, the resultant was filtrated through Celite and the solvent was then distilled off. The residue was dissolved in chloroform and washed with water. The solution was dried with anhydrous magnesium sulfate. The solvent was distilled off, thereby obtaining the subject compound (1.15 g) as a yellow viscous liquid.