Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1=CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2C=C(C(=O)O)CC2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of methyl 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]-oct-6-ene-7-carboxylate (0.350 g, 1.31 mmol) in THF-methanol (6.0 mL, 1:1) was added a solution of lithium hydroxide (0.100 g in 1 mL of water, 3.94 mmol), and the reaction was stirred at ambient temperature for 3 h. The solvent was evaporated, the residue was acidified to pH 4 with 1 M aqueous hydrochloric acid, and extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried (anhydrous sodium sulfate), and concentrated to obtain 0.31 g (92% yield) of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]-oct-6-ene-7-carboxylic acid, as a white solid (1H NMR (CDCl3, 300 MHz): δ 6.76 (bs, 1H), 3.76-3.62 (m, 1H), 3.58-3.42 (m, 2H), 3.11-2.94 (m, 2H), 2.84-2.67 (m, 1H), 2.46-2.23 (m, 1H), 1.42 (s, 9H). MS (m/z): 254 (M+1), 198 (M+1-56)).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:27])[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([C:26]([N:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:27])[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: O=C(c1cncc(Cl)n1)N1CCCCC1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: O=C(c1cncc(-c2cnc3[nH]ccc3c2)n1)N1CCCCC1
Temperature: 90 °C

Procedure:
A stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.205 mmol, 1 eq) and (6-chloropyrazin-2-yl)(piperidin-1-yl)methanone (75) (41 mg, 0.184 mmol, 0.9 eq) in DME (8 mL) was degassed and purged under argon atmosphere for min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.410 mmol, 2 eq) followed by addition of Pd(dpp)Cl2 (6 mg, 0.00819 mmol, 0.04 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 90° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound (6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)(piperidin-1-yl)methanone 138 in 10 mg quantity. The compound 138 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 9.61 (s, 1H), 9.12 (s, 1H), 9.02 (s, 1H), 8.80 (m, J=87.55 1H), 8.60 (d, J=1.82, 1H), 7.42 (m, J=3.17, 1H), 6.64 (m, J=1.58, 1H), 3.87 (s, 2H), 3.59 (m, J=88.29, 1H), 1.75 (s, 4H), 1.69 (m, J=24.99, 2H); MS m/z 307.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:27]3[CH2:28][CH2:29][NH:30][CH2:31][C:26]=3[S:25][C:10]=2[N:11]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12](=[O:16])[CH:13]([OH:15])[N:14]=1.C(N(CC)CC)C.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([N:47]=[C:48]=[S:49])=[C:43]([N+:50]([O-:52])=[O:51])[CH:42]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:27]3[CH2:28][CH2:29][N:30]([C:48](=[S:49])[NH:47][C:44]4[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][C:43]=4[N+:50]([O-:52])=[O:51])[CH2:31][C:26]=3[S:25][C:10]=2[N:11]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12](=[O:16])[CH:13]([OH:15])[N:14]=1
Reactant: O=C1C(O)N=C(c2ccccc2Cl)c2c(sc3c2CCNC3)N1CCc1ccccc1
Reactant: COc1ccc(N=C=S)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=S)N2CCc3c(sc4c3C(c3ccccc3Cl)=NC(O)C(=O)N4CCc3ccccc3)C2)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-3-hydroxy-1-(2-phenylethyl)-8H-pyrido[4′,3′:4,5]thieno[2,3-e]-1,4-diazepine-2-one (0.167 g, 0.29 mmol) is dissolved in dichloromethane (2 ml). Triethylamine (0.06 ml, 0.44 mmol) then 4-methoxy 2-nitrophenylisothiocyanate (0.062 g, 0.29 mmol) are added. After agitation at 23° C. for 2 hours, the solvent is evaporated off. After purification by chromatography on a silica column (eluent: dichloromehane-methanol: 98-2), the fractions contining only the product are evaporated. The solid is taken up in ether and a drop of dichloromethame and a drop of acetone are added. After filtration on flit and washing the solid with ether, the desired product is obtained in the form of a yellow powder (0.08 g, 41%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:24]1([C:30]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1COCC1>[C:24]1([C:30]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:34][CH2:35]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.4 g (16.0 mmol) 3-(3-pyridyl)-acrylic acid and 2.9 g (17.6 mmol) CDI are heated under reflux in 150 ml absolute THF under moisture exclusion. After an hour, this is cooled to RT and 6.0 g (19.2 mmol) 4-(4,4-diphenyl-piperidin-1-yl)-butylamine, dissolved in 25 ml absolute THF, are added dropwise. After addition, this is stirred for a further three hours at RT and left to stand overnight. The mixture is poured into 200 ml water and extracted three times each with 100 ml acetic acid ethyl ester by shaking. The combined organic phases are washed with saturated NaCl-solution, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically pre-purified over silica gel with CHCl3/CH3OH (95/5). After removal of the solvent, crystallization occurs from 130 ml isopropanol: Colorless crystals with MP. 207-208° C.: Yield 2.0 g (28%).
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[NH2:15][C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[CH:17]=1>O>[CH3:21][N:20]1[C:16]2=[N:15][C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][C:4]([OH:14])=[C:17]2[C:18]([CH3:22])=[N:19]1
Reactant: Cc1cc(N)n(C)n1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: O
Product: Cc1nn(C)c2nc(-c3ccccc3)cc(O)c12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
96 gms. of benzoylacetic acid ethyl ester (0.5 mol.) are added dropwise to a stirred mixture of 55.5 gms. of 5-amino-1,3-dimethylpyrazole (0.5 mol) and 250 gms. of polyphosphorus acid heated to 120° C. After the reaction has occurred, which can be recognized by the changing of the color, the whole is heated for an additional hour at 120° C. After the mixture has cooled to room temperature, 600 ml. of water are added and stirring is continued until the compound becomes crystalline. The mixture is allowed to stand overnight and is then filtered off. The collected 1,3-dimethyl-4-hydroxy-6-phenyl-1H-pyrazolo[3,4-b]pyridine is washed with dilute ammonia, dried and treated with ethyl acetate yielding 73.6 gms. (61.6%), m.p. 262°-264°.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[C:5]#[C:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8])[CH3:2]>ClCCl.O=[Mn]=O>[CH2:16]([O:15][CH:4]([O:3][CH2:1][CH3:2])[C:5]#[C:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH3:17]
Reactant: CCOC(C#CC(O)c1ccccc1)OCC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOC(C#CC(=O)c1ccccc1)OCC
Yield: 83.7 %

Procedure:
4,4-Diethoxy-1-phenyl-but-2-yn-1-ol (9.46 g, 40.38 mmol) was dissolved in dichloromethane (200 ml) and treated with activated MnO2 (100 g) at rt for 15 h. The reaction mixture was filtered through a plug of celite and Na2SO4. The filtrated was concentrated under reduced pressure to afford the desired ketone (7.85 g, 84% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=2)O1>>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:40][N:41]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1
Yield: 88.6 %

Procedure:
Tert-butyl 4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (2.4 gm) was reacted with 1.64 gm 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to yield 2.4 g tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate. 150 mg of this crude intermediate was subjected to procedure D and subsequently reacted with 84 mg D-lactic Acid via General Procedure B to give 102.5 mg of 400 after reverse phase HPLC purification. MS (Q1) 485.2 (M)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][C:35](=[N:37]O)[NH2:36]>>[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][C:35]1[N:36]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:37]=1
Reactant: NC(Cc1ccc(F)cc1Cl)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(Cc4ccc(F)cc4Cl)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 45 mg (0.22 mmol, 1.1 eq.) of 2-(2-chloro-4-fluorophenyl)-N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 59 mg (57% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH:20]C(OC(C)(C)C)=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].[ClH:29].O1CCOCC1>>[ClH:29].[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH2:20])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To (R)-ethyl-4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (230.1 mg, 0.600 mmol) is added a solution of HCl in 1,4-dioxane (3.00 mL, 12.00 mmol) at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to give (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride. A solution of (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride, succinic anhydride (72.1 mg, 0.720 mmol) and DIPEA (0.126 mL, 0.720 mmol) in dichloromethane (4 mL) is allowed to stir for 1 hour. The reaction is quenched with 10% aqueous citric acid and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on CN-modified silica gel (eluent: heptane/EtOAc=100:0 to 0:100) and by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) to give (R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (148.2 mg). HPLC retention time=1.64 minutes (condition A); MS (m+1)=384.1; 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.21 (t, J=7.07 Hz, 3H) 2.31-2.39 (m, 2H) 2.40-2.56 (m, 4H) 2.77-2.92 (m, 2H) 4.08 (q, J=7.24 Hz, 2H) 4.33-4.48 (m, 1H) 6.62 (d, J=8.34 Hz, 1H) 7.30 (d, J=8.08 Hz, 2H) 7.32-7.39 (m, 1H) 7.41-7.49 (m, 2H) 7.54-7.60 (m, 2H) 7.60-7.67 (m, 2H) 10.02 (br. s., 1H).
Reaction SMILES: Cl.Cl.[N:3]1[NH:4][N:5]=[N:6][C:7]=1[C:8]1[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=1.[N:16]#[C:17]Br.[OH-].[Na+]>O>[N:6]1[NH:5][N:4]=[N:3][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:17]([NH2:16])=[N:15][C:10]=2[CH:9]=1
Reactant: Nc1ccc(-c2nn[nH]n2)cc1N
Reactant: N#CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc(-c3nn[nH]n3)ccc2[nH]1
Temperature: 4 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To 4-(2H-tetrazol-5-yl)-benzene-1,2-diamine dihydrochloride (8.56 g, 34 mmol) in water (45 ml) was adjusted to pH 6.0. Cyanogen bromide (3.91 g, 37 mmol) was added and the mixture stirred for 4 hours. The reaction mixture was analyzed by HPLC. The pH of the reaction mixture was adjusted to pH 4.0 with 40% (v/v) sodium hydroxide. The mixture was cooled to 4° C. and the brown solid filtered and washed with water. The material was dried to yield a brown solid 5-(2H-tetrazol-5-yl)-1H-benzimidazol-2y-amine (4.10 g) with a purity of 88%, Rt=7.3 mins. To a suspension of crude 5-(2H-tetrazol-5-yl)-1H-benzimidazol-2-ylamine (4.10 g) in water (40 ml), the pH was adjusted to 1.2 with 50% (v/v) hydrochloric acid. Activated carbon was then added (0.2 g) and the mixture stirred for 18 hours. The mixture was filtered and the pH of the filtrate adjusted to pH 3.7 to yield a tan colored solid. The material was dried (3.01 g) and had a purity of >97% by HPLC. 1H NMR (d6-DMSO, 400 MHz) 13.04 ppm (0.3H, s), 12.99 ppm (0.3H, s), 8.85 ppm (1H, s), 8.074 ppm (1H, s), 7.96 ppm (dd, 8.4 Hz, 1.2 Hz), 7.55 ppm (d, 8.4 Hz). MS: (Electrospray+) 201.8 m/z (M+), 223.7 m/z (M+Na).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[O: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.Cl>C(O)C.[Fe]>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2OCc2ccccc2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(Oc2ccccc2OCc2ccccc2)cc1
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 95.2 %

Procedure:
4-(2-Benzyloxyphenoxy)nitrobenzene (2.57 g, 8 mmol) was dissolved in reagent grade ethanol (20 mL) and treated with concentrated aqueous hydrochloric acid (2.5 mL). The solution was heated to 55° C. under nitrogen, then cautiously treated with iron powder (3.1 g, 55 mmol) in portions with cooling needed after initial exotherm to 75° C. After addition was complete, stirring was continued at 50-60° C. for 45 minutes, then the mixture was cooled to room temperature and filtered through celite® (rinse filter cake with dichloromethane). The filtrate was concentrated in vacuo, the residue dissolved in dichloromethane and the solution washed with saturated aqueous sodium carbonate. The organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic solution was dried (sodium sulfate), concentrated in vacuo, and chromatographed on silica gel (eluted with dichloromethane, then 10% ethyl acetate/dichloromethane, then 20% ethyl acetate/dichloromethane) to afford the title compound (2.22 g, 95%) as a tan solid; mp 111-112.5° C. 1H NMR: 7.30 (m,4H), 7.20-7.30 (m,1H), 6.97 (m,2H), 6.80-6.90 (m,4H), 6.60-6.65 (m,2H), 5.12 (s,2H), 3.50 (br s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:12]([S:13](C3C=CC(C)=CC=3)(=O)=O)=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([SH:13])=[N:11][N:10]=[N:9]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(Cn2nnnc2S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na]
Product: COc1ccc(Cn2nnnc2S)cc1

Procedure:
Treatment of the product of Example 4 as in the previous example gives the sodium salt of the title compound. This is recrystallized from ethyl acetate-hexane, m.p. 246°-250° C. (decomp).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:22][C:17]([CH2:32]OS(C5C=CC(C)=CC=5)(=O)=O)([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48].CCCC[N+](CCCC)(CCCC)CCCC.[F-:66].C1COCC1>>[F:66][CH2:32][C:17]12[CH2:22][CH2:21][C:20]([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])([C:14]3[N:15]([C:44](=[O:47])[C:45]([OH:46])=[C:12]([C:10]([NH:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:48])[CH:4]=4)=[O:11])[N:13]=3)[CH2:16]1)[CH2:19][CH2:18]2
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(N(C)C(=O)C(=O)N(C)C)(CC2)c2nc(C(=O)NCc4ccc(F)c(C)c4)c(O)c(=O)n2C3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC2(CF)CCC3(N(C)C(=O)C(=O)N(C)C)CC2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
A mixture of N-[2-[[[(4-fluoro-3-methylphenyl)methyl]amino]carbonyl]-6,7,8,9-tetrahydro-3-hydroxy-7-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-4-oxo-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl]-N,N′,N′-trimethyl-ethanediamide, Intermediate 28, (50 mg, 0.073 mmol) was treated with TBAF, 1M in THF (1.5 mL, 1.500 mmol) and 4 Å molecular sieves. The mixture was then stirred for 30 min at room temp and heated at 80° C. for 18 h. After cooling the reaction mixture was concentrated and purified by preparative HPLC to afford the title compound (14 mg, 0.025 mmol, 34.2% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 12.18 (1H, br. s.), 9.60 (1H, br. s.), 7.17-7.26 (2H, m), 6.94 (1H, t, J=8.85 Hz), 4.75 (1H, d, J=14.95 Hz), 4.56-4.65 (1H, m), 4.39-4.50 (1H, m), 4.28 (1H, d, J=2.75 Hz), 4.19 (1H, d, J=2.75 Hz), 3.42-3.57 (2H, m), 3.05 (3H, s), 3.03 (3H, s), 3.01 (3H, s), 2.27 (3H, s), 2.07-2.18 (3H, m), 1.80-1.88 (1H, m), 1.70-1.78 (2H, m), 1.42-1.52 (1H, m). LCMS (M+H)=532.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][Cl:21])=[O:18]>CCOCC>[C:17](=[O:18])([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)[O:19][CH2:20][Cl:21]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: O=C(Cl)OCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC1(C)OC[C@@H](COC(=O)OCCl)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
(R)-Glycerol acetonide (10 g) was dissolved in anhydrous ether (200 ml) and, after adding pyridine (6.6 g) at −10° C., a solution of chloromethyl chloroformate (10.7 g) in anhydrous ether (20 ml) was added dropwise over the period of 10 minutes. After the reaction mixture was stirred at room temperature for 20 hours, the deposited pyridine hydrochloride was removed by filtration. The filtrate was washed with a saturated sodium chloride aqueous solution (200 ml×2), and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by subjecting to silica gel chromatography (eluent: hexane→ethyl acetate/hexane=1/5→ethyl acetate/hexane=3/5) to obtain chloromethyl [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl carbonate (17 g) as a colorless oily product.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=O)[CH:9]=2)[CH2:4][CH2:3]1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1.N>>[OH:32][C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:21][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[N:20][C:12]=2[O:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][CH2:3][C:2]3=[O:1])=[CH:24][CH:25]=1)([CH3:31])[CH3:30]
Reactant: O=C1CCc2ccc(Oc3ncccc3C(=O)O)cc21
Reactant: CC(C)(O)c1ccc(CN)cc1
Agent: N
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)C(=O)CC3)cc1

Procedure:
Prepared from 2-(3-Oxo-indan-5-yloxy)-nicotinic acid and 2-(4-aminomethyl-phenyl)-propan-2-ol. MS (m/e): 435 (M++NH3), 417 (M++1), 400 (100). NMR (CDCl3): 8.62 (dd, J=2,8 Hz, 1H), 8.15 (dd, J=2,5 Hz, 1H), 8.07 (m, 1H), 7.32 (m, 8H), 4.67 (d, J=6 Hz, 2H), 313 (t, J=6 Hz, 2H), 2.72 (dt, J=2,4 Hz, 2H), 1.53 (s, 6H).
Reaction SMILES: CC(C)C(C1C=CC=CC=1)C([NH:6][C@@H:7]1[C@H:14]2[C@H:10]([CH2:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:13]2)[CH2:9][CH2:8]1)=O.C(N(CC)CC)C.[F:40][C:41]([F:53])([F:52])[C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>ClCCl>[F:40][C:41]([F:53])([F:52])[C:42]1[CH:43]=[C:44]([S:48]([NH:6][C@@H:7]2[C@H:14]3[C@H:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=4)[CH2:13]3)[CH2:9][CH2:8]2)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3aS*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E (200 mg, 0.703 mmol) in dichloromethane (2 mL) was added triethylamine (0.147 mL, 1.055 mmol) followed by 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.124 mL, 0.774 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organics were reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-24). The title compounds were eluted with a gradient of 0% to 10% methanol (2 N ammonia)/dichloromethane over 20 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH:12]1[NH:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4].Cl.Cl[C:20]([O:22][CH2:23][Cl:24])=[O:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:4])[CH:5]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:20]([O:22][CH2:23][Cl:24])=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCCl
Reactant: COC(=O)C(c1ccccc1)C1CCCCN1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(c1ccccc1)C1CCCCN1C(=O)OCCl
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
Methylphenidate hydrochloride (1) (2.70 g, 10 mmol) was suspended in DCM (75 mL) and cooled in an ice bath. 4-Dimethylaminopyridine (DMAP) (4.887 g, 40 mmol) was added and the resulting mixture was stirred for 10 min. Chloromethyl chloroformate (3.224 g, 25 mmol) in DCM (10 mL) was added slowly. The ice bath was removed and the reaction was stirred for 5 h at room temperature. Ethyl acetate (250 mL) was added, followed by water (20 mL) to quench the reaction. The ethyl acetate layer was separated and washed with 1N HCl (40 mL) and brine (2×40 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexanes:EtOAc, 3:1) to give 37 as a colorless oil (2.60 g) (yield, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:16][C:15]1[CH:14]=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]([O:11][CH3:10])=[CH:18][C:17]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: COc1ccc(N)cc1-c1ccccc1
Reactant: O=Cc1ccccc1Cl
Product: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1-c1ccccc1

Procedure:
(2-amino-5-methoxy-4-phenylphenyl)-(2-chlorophenyl)-methanone (Xff) was prepared by reacting 2-chlorobenzaldehyde with 0.0226 moles of 4-methoxy-3-phenyl aniline in a manner analogous to the Example 1. MH+/Z=338.