Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH:56]1([O:60][CH:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:59][CH2:58][CH2:57]1>CN(C)C=O>[CH:56]1([O:60][CH:61]2[CH2:66][CH2:65][N:64]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[F:1])[CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)=[O:5])[CH2:63][CH2:62]2)[CH2:59][CH2:58][CH2:57]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: C1CC(OC2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OC2CCC2)CC1
Reaction time: 2 h
Yield: 5.8 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1b) (0.20 g, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (0.381 g, 1.01 mmol) were added to N,N-dimethylformamide (30 mL), and to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 4-cyclobutoxypiperidine (14) (0.104 g, 0.67 mmol). The reaction was stirred for 2 hours before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white solid (0.017 g, 5.82%); 1H NMR (400.132 MHz, CDCl3) δ 1.56-1.44 (2H, m), 1.72-1.64 (2H, m), 2.00-1.84 (4H, m), 2.23-2.14 (2H, m), 3.14-3.04 (1H, m), 3.48-3.41 (2H, m), 3.58-3.52 (1H, m), 4.00 (1H, quintet), 4.10-4.03 (1H, m), 4.26 (2H, s), 7.01 (1H, t), 7.31-7.24 (2H, m), 7.77-7.70 (3H, m), 8.47-8.44 (1H, m), 9.90 (1H, s); m/z (LC-MS, ESI+), RT=2.15 (M+H 436).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][N:3]=1.Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[S:7][CH:12]=[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:8]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(N)=S)cn1
Reactant: COC(=O)CC(=O)CCl
Product: COC(=O)Cc1csc(-c2ccc(C)nc2)n1

Procedure:
This material was prepared by the procedure described for Example 24(a) using 6-methyl-thionicotinamide (Maybridge) (1.52 g, 10.0 mmol) and methyl 4-chloroacetoacetate (Fluka) (1.42 g, 10.0 mmol). Chromatography (gradient elution: 10-50% EtOAc in hexanes) of the crude material afforded the title compound as an off-white solid. MS m/z: 249 (M+1). Calc'd for C12H12N2O2S: 248.06.
Reaction SMILES: CN(/[CH:4]=[C:5]1\[C:6](=[O:24])[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[N:8]=[C:9]\1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1F)C.[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29](=[O:39])[CH2:28]1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CS(C)=O>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:7]1[C:6](=[O:24])[C:5]2=[CH:4][N:25]([CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29](=[O:39])[CH2:28]3)[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[N:8]1
Reactant: CN(C)/C=C1\C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Reactant: NCC1CCN(c2ccccc2)C(=O)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CC(Cn2cc3c(=O)n(-c4ccccc4F)nc-3c3ccccc32)CCN1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(4Z)-4-[(Dimethylamino)methylidene]-2,5-bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one (0.12 g, 0.37 mmol), 4-(aminomethyl)-1-phenylpiperidin-2-one (76 mg, 0.37 mmol, 1 equiv) and potassium carbonate (0.15 g, 1.1 mmol, 3 equiv) were combined in degassed dimethylsulfoxide (5 mL) and placed into a preheated oil bath at 100° C. open to the air for 1 hour. Additional 4-(aminomethyl)-1-phenylpiperidin-2-one (0.15 g, 0.74 mmol, 2 equiv) and potassium carbonate (0.15 g, 1.1 mmol, 3 equiv) were added and the mixture was heated at 100° C. for an additional 2 hours. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (40 mL, aqueous saturated) and extracted with ethyl acetate (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100 hexanes:ethyl acetate containing 5% methanol; then eluted with chloroform containing 15% methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 8.93 (1H, s), 8.23 (1H, dd, 7.8, 1.4 Hz), 8.06 (1H, d, J=8.7 Hz), 7.79-7.75 (1H, m), 7.63-7.57 (2H, m), 7.47-7.30 (5H, m), 7.27-7.21 (3H, m), 4.49 (2H, d, J=7.1 Hz), 3.66-3.53 (2H, m), 2.68-2.58 (1H, m), 2.47-2.30 (2H, m), 1.89 (1H, br d, J=12.5 Hz), 1.85-1.73 (1H, m) ppm; low resolution mass spectrometry (ES+) m/z 466.97 [(M+H)+; calculated for C28H24FN4O2: 467.18].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Br[CH2:26][C:27]#[N:28].O>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:26][C:27]#[N:28])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (0.50 g, 1.84 mmol) in dimethyl formamide (50 ml) under nitrogen at room temperature, was added sodium hydrogen carbonate (1.50 g) followed by bromoacetonitrile (1.9 ml). The reaction mixture was stirred at room temperature for 16 h, then poured into water and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×50 ml), dried (MgSO4), filtered and the solvent was removed in vacuo to leave an oily residue. Trituration with diethyl ether, followed by recrystallisation from an ethyl acetate, petrol (60-80) mixture, gave the title compound as a white solid (0.15 g). Mp 209°-211° C. Found: C, 65.60; H, 3.74; N, 8.75; C17H11N2O2Cl requires C, 65.71; H, 3.57; N, 9.02%. δ (360 MHz, DMSO-d6) 4.59 (2H, s, OCH2CN), 7.31 (1H, dd, J=8.63 Hz, J=2.10 Hz, 6-H), 7.40-7.49 (6H, m, Ph+8-H), 7.83 (1H, d, J=88.63 Hz, 5-H), 12.10 (1H, bs, NH). m/z (CI+), 311, (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH:17]1[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[N:17]1([C:7]([CH:4]2[S:3][C:2]([Cl:1])=[N:6][CH2:5]2)=[O:9])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1cnc(Cl)s1
Reactant: C1CNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(C1CN=C(Cl)S1)N1CCC1
Reaction time: 16 h

Procedure:
To a solution of 2-chlorothiazol-5-carboxylic acid (815 mg, 5 mmol) in dichloromethane (10 mL) was slowly added oxalyl chloride (0.53 mL, 6 mmol) and then N,N dimethylformamide (1 drop) with stirring. The mixture was stirred for 16 hours, following which the organics were removed in vacuo, and the residues azeotroped with toluene (100 ml). The crude material was dissolved in dichloromethane (10 mL) and slowly added to a stirred suspension of azetidine hydrochloride (560 mg, 6 mmol) and triethylamine (2.5 mL, 18 mmol) in dichloromethane (25 mL). The mixture was stirred at ambient temperature for 2 hours before the organics were removed in vacuo. The residue was dissolved in ethyl acetate (50 mL) and water (25 mL), the organic layer washed with brine (25 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica with 40% ethyl acetate in iso-hexane as eluant to give 5-(azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazoline. 1H NMR δ (CDCl3): 2.4 (m, 2H), 4.1-4.4 (m, 4H), 4.55 (m, 1H), 7.2 (s, 1H) and 7.75 (s, 1H); m/z 203 (M+H)+.
Reaction SMILES: [C:1](/[CH:3]=[CH:4]\[C@:5]1([CH3:31])[S:11](=[O:13])(=[O:12])[C@H:10]2[N:7]([C:8](=[O:14])[CH2:9]2)[C@H:6]1[C:15]([O:17]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16])#[N:2].CC(CC(C)C)=O.C(C(CCCC)C([O-])=O)C.[Na+:49]>C1C(O)=CC=CC=1C>[C:1](/[CH:3]=[CH:4]\[C@:5]1([CH3:31])[S:11](=[O:13])(=[O:12])[C@H:10]2[N:7]([C:8](=[O:14])[CH2:9]2)[C@H:6]1[C:15]([O-:17])=[O:16])#[N:2].[Na+:49]
Reactant: C[C@]1(/C=C\C#N)[C@H](C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2S1(=O)=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: Cc1cccc(O)c1
Product: C[C@]1(/C=C\C#N)[C@H](C(=O)[O-])N2C(=O)C[C@H]2S1(=O)=O
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
95 mg (0.2 mmol) of benzhydryl (Z)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 3 ml of m-cresol and stirred at 50° C. for 45 minutes. The reaction mixture was treated with 10 ml of isobutyl methyl ketone and 120 μl Of sodium 2-ethylcaproate (2N in ethyl acetate, 1.1 eq.). The mixture was extracted twice with 3 ml Of water each time, the combined aqueous phases are washed with 10 ml of isobutyl methyl ketone and lyophilized. The yellow lyophilizate was dissolved in 1.3 ml of water and chromatographed over polymeric hydrophobic gel.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH2:6])[CH3:5].Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:10][C:8](=[O:9])[NH:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH3:12]
Reactant: COC[C@H](C)N
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@@H](C)COC

Procedure:
A solution of (S)-1-methoxy-2-propylamine in tetrahydrofuran was allowed to undergo the reaction with ethyl chloroformate in the presence of triethylamine to obtain [(1S)-2-methoxy-1-methylethyl]carbamic acid ethyl ester.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([C:7]([O:9]C(C2C=CC(C)=CC=2)=O)=[O:8])=[CH:3][CH:2]=1.CS(O)(=O)=O>[N+](C)([O-])=O>[C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)OC(=O)c2ccc(C)cc2)cc1
Agent: CS(=O)(=O)O
Solvent: C[N+](=O)[O-]
Product: Cc1ccc(C(=O)O)cc1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
25.4 g (0.1 mole) of para-toluic anhydride was dissolved in 100 ml of warm nitromethane and then 9.6 g (0.1 mole) of methane sulfonic acid was added. The reaction mixture was stirred for 20 minutes and then filtered, giving 13.72 g (0.1 mole) of para-toluic acid precipitant. The reaction was quantitative, resulting in the para-toluic methane sulfonic anhydride dissolved in nitromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([NH2:11])=[O:10].O.[C:22]12([CH2:32][S:33]([OH:36])(=[O:35])=[O:34])[C:29]([CH3:31])([CH3:30])[CH:26]([CH2:27][CH2:28]1)[CH2:25][C:23]2=[O:24]>CC(C)=O>[C:22]12([CH2:32][S:33]([OH:36])(=[O:34])=[O:35])[C:29]([CH3:31])([CH3:30])[CH:26]([CH2:27][CH2:28]1)[CH2:25][C:23]2=[O:24].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Yield: 37.8 %

Procedure:
A solution of 5 g (16.31 mmol) of (±)-(2-chloro-phenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide (prepared as given in Examples 10-15) and 4.15 g (16.2 mmol) (1S) (+)-camphor-10-sulphonic acid monohydrate in 100 mL acetone was stirred at room temperature for 20 h. Subsequently it was kept for 1 week in a freezer. Few crystals appeared concentration of volume by evaporating solvent under reduced pressure and repeated recrystallization in freezer for few days gave 3.3 g (75% yield) of (S)-2-(2-chloro-phenyl)-(4,5,6,7-tetrahydrothieno[3,2-c]pyrid-5-yl)acetamide (+)-camphor sulfonic acid salt. The salt was further purified by recrystallization in acetone, until constant specific optical rotation was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]2[CH:13]=1)[CH2:2][CH2:3][CH3:4].[Br:14]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:14][C:13]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn2ccccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2ccccn2c1Br
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A mixture of 3.5 g of the product of Stage C and 50 ml of chloroform was cooled to 10° C. and 4.55 g of N-bromo succinimide were added. The mixture was stirred at this temperature for 30 minutes and was then poured into a saturated solution of sodium carbonate and extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried, filtered and evaporated to dryness to obtain after chromatography on silica (methylene chloride: 95/methanol: 5), 3.8 g of the expected product in the form of a black oil.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[C:35](=[O:36])[CH2:34][CH2:33][CH2:32][C:31]=2OCC)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:11][CH:10]=1)#[N:8]>C(#N)C>[O:18]=[C:17]1[NH:16][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=2)[C:30]2[C:35](=[O:36])[CH2:34][CH2:33][CH2:32][C:31]=2[N:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=1
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reaction time: 1 h

Procedure:
Sodium tert-butoxide (2.55 g, 26.5 mmol) is added to a mixture of 1-((4-cyanophenyl)-(2-ethoxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 5, 10.1 g, 22.1 mmol) and acetonitrile (100 mL). After 20 min the mixture is filtered and the precipitate is washed with acetonitrile and methyl tert-butyl ether. The precipitate is mixed with water (300 mL) and the suspension is stirred for 1 h. The precipitate is filtered again and dried under reduced pressure. Yield: 5.24 g; ESI mass spectrum [M+H]+=412; Retention time HPLC: 0.88 min (Z018_S04).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][CH:7]=[CH:8][C:9]=1[C:10]([O:12]C)=O)=O.CCO.O.[NH2:18][NH2:19]>O>[O:6]1[C:5]2[C:3](=[O:2])[NH:18][NH:19][C:10](=[O:12])[C:9]=2[CH:8]=[CH:7]1
Reactant: NN
Reactant: COC(=O)c1ccoc1C(=O)OC
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c(=O)c2occc12

Procedure:
Furan-2,3-dicarboxylic acid dimethyl ester (1.6 g, 8.69 mmol) is added to EtOH (10 mL) and hydrazine hydrate (1.46 mL, 55% in water). Heat the reaction to reflux for 5-6 h. Cool and concentrate in vacuo to form a slurry. Dilute the material with additional H2O and filter the precipitate. Wash with additional H2O. Transfer material from filter to a round bottom flask and add HCl (7.2 mL, 2N in H2O). Heat reaction mixture to reflux for 4 h. Cool and filter the precipitate washing with H2O, to yield the title compound without further purification (930 mg, 70%)
Reaction SMILES: C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](O[C@H]2O[C@H](COC(=O)C)[C@H](OC(=O)C)[C@H](OC(=O)C)[C@H]2OC(=O)C)[C@@H](COC(=O)C)O[C@H]1OCCBr)(=O)C.[C@@H:48]1([O:59][C@H:60]2[C@@H:76]([CH2:77][OH:78])[O:75][C@@H:63]([O:64][CH2:65][CH2:66][S:67][C:68]3[CH:73]=[CH:72][C:71]([NH2:74])=[CH:70][CH:69]=3)[C@H:62]([OH:79])[C@H:61]2[OH:80])[O:56][C@H:55]([CH2:57][OH:58])[C@H:53]([OH:54])[C@H:51]([OH:52])[C@H:49]1[OH:50]>>[C@H:48]1([O:59][C@H:60]2[C@@H:76]([CH2:77][OH:78])[O:75][C@@H:63]([O:64][CH2:65][CH2:66][S:67][C:68]3[CH:69]=[CH:70][C:71]([NH2:74])=[CH:72][CH:73]=3)[C@H:62]([OH:79])[C@H:61]2[OH:80])[O:56][C@H:55]([CH2:57][OH:58])[C@H:53]([OH:54])[C@H:51]([OH:52])[C@H:49]1[OH:50]
Reactant: Nc1ccc(SCCO[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Agent: CC(=O)OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Product: Nc1ccc(SCCO[C@@H]2O[C@H](CO)[C@H](O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1

Procedure:
2-Bromoethyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-αD-galactopyranosyl)-β-D-galactopyranoside (15) (170 mg; 0.23 mmol) was treated as above (compound 26). The crude product, that was obtained after the deacetylation reaction, was filtered through a column (SiO2, ethyl acetate/methanol 2:3) which gave the title compound (27) as an amorphous solid. Yield: 110 mg (97%). Chromatography (SiO2, chloroform/methanol/water 65:35:10; lower phase) gave an analytical sample: [α]D23 +70.6° (c 0.58; H2O); 1H-NMR (DMSO-D6 plus D2O, 50°) δ 7.13, 6.56 (d, 2H each, J=8.4 Hz, aromatic H), 4.83 (d, 1H, J=3.3 Hz, H1'), 4.14 (d, 1H, J=7.6 Hz, H1), 2.89 (t, 2H, J=7.5 Hz, CH2 --S) ppm. 13C-NMR (DMSO-D6 plus D2O) δ 149.1, 136.5, 124.8, 119.7 (aromatic C), 105.7, (Cl), 102.9 (Cl'), 79.8, 77.7, 75.1, 73.6, 73.5, 71.9, 71.7, 71.4, 70.8 (C2-C5, C2'-C5', CH2O), 63.3, 62.8 (C6, C6'), 37.6 (CH2Br) ppm.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35][CH3:36])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[C:17]4[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37]C(O)=O.C=O.[BH3-]C#N.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35][CH3:36])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][CH2:19][CH:18]([N:21]([CH3:37])[CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[C:17]4[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(NCCN1CCCC1)c1ccccc1-3
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(N(C)CCN1CCCC1)c1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 13-cyclohexyl-5-[(2-pyrrolidin-1-ylethyl)amino]-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (prepared as in Example 3) was dissolved in DCM and the pH adjusted to 6 with AcOH; 37% aq HCHO and, after 30 min NaCNBH3 (3 eq), were added and the mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and washed with IN NaOH and brine, dried and evaporated affording methyl 13-cyclohexyl-5-[methyl(2-pyrrolidin-1-ylethyl)amino]-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate. Hydrolysis of the foregoing methyl ester was done with IM aqueous KOH (6 eq) in dioxane (0.1M) at 60 ° C.; the reaction was complete in 2 h, and the title compound was obtained in 29% yield after RP-HPLC purification and lyophilisation (Conditions: Column: Waters X-TERRA MS C18, 10 micron, 19×150 mm; Gradient: A: H2O+0.1% TFA; B: MeCN+0.1% TFA; 75% A isocratic for 3 min, linear to 20% A in 12 min).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([NH2:15])=[CH:13][NH:12][N:11]=1.[C:16]([N:20]=[C:21]=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:14]([NH:15][C:21]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[CH:13][NH:12][N:11]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: CC(C)(C)N=C=O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Yield: 34.9 %

Procedure:
A mixture or 3-(1H-Benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.50 mmol), tert-butyl isocyanate (60 ul, 0.60 mmol) in DMF (5 ml) was stirred at ambient temperature for 4 h. The mixture was reduced in vacuo. The residue was purified by preparative LC/MS, and following evaporation, gave 52 mg of the title compound as a white solid (35%). (LC/MS: Rt 2.61, [M+H]+ 299.15).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH2:12].[S:13](N)([NH2:16])(=[O:15])=[O:14]>O1CCOCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: NCC1CCc2ccccc2O1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)NCC1CCc2ccccc2O1

Procedure:
The oily amine (1.63 g, 10 mmol) and sulfamide (1.92 g, 20 mmol) were combined in dioxane (50 mL) and brought to reflux for 2 h. The solution was cooled and evaporated in vacuo to yield an oil, which was purified via column chromatography (DCM:Methanol 10:1) to yield a white solid. The solid was recrystallized from ethyl acetate/hexane to yield chroman-2-ylmethylsulfamide as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([CH:43]([CH3:45])[CH3:44])[CH2:39][CH2:38]1.[Cl:46][C:47]1[N:56]=[CH:55][C:54]2[C:49](=[C:50](O)[CH:51]=[CH:52][CH:53]=2)[N:48]=1>C1COCC1>[Cl:46][C:47]1[N:56]=[CH:55][C:54]2[C:49](=[C:50]([O:36][CH:37]3[CH2:42][CH2:41][N:40]([CH:43]([CH3:45])[CH3:44])[CH2:39][CH2:38]3)[CH:51]=[CH:52][CH:53]=2)[N:48]=1
Reactant: Oc1cccc2cnc(Cl)nc12
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2cccc3cnc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a 0.30M solution of triphenylphosphine (1.5 eq) in THF was added di-tert-butylazodicarboxylate (1.5 eq). The mixture was stirred 15 min at ambient temperature. 4-Hydroxy-1-isopropylpiperidine (4.0 eq) was added. The mixture was stirred 15 min at ambient temperature. 2-Chloroquinazolin-8-ol (1.0 eq) was added. The mixture was stirred an additional 2 h. The crude mixture was concentrated, purified by flash chromatography (EtOAc then 90:10:1 DCM:MeOH:NH4OH), and concentrated to give the desired product in 88% yield. ES/MS m/z 306 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[H][H]>FC(F)(F)C(O)=O.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: [H][H]
Reactant: COc1cc2ccccc2nc1C
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(nc1C)CCCC2
Yield: 99.6 %

Procedure:
A mixture of 3-methoxy-2-methylquinoline (0.081 mol) in trifluoro-acetic acid (150 ml) was hydrogenated at room temperature under a 34 bar pressure for 48 hours with palladium on activated carbon (2 g) as a catalyst. After uptake of hydrogen (2 equiv.), the catalyst was filtered through celite and washed with H2O. The filtrate was basified with a concentrated NH4 OH solution and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 14.3 g (quant.) of 5,6,7,8-tetrahydro-3-methoxy-2-methylquinoline (interm. 13).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[S:11][CH:12]=[C:13]([C:15]([O:17]C)=[O:16])[N:14]=1.O[C@@H:20]1[CH2:24][CH2:23][O:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:9][C:4]1[CH:5]=[C:6]([O:8][C@@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)[CH:7]=[C:2]([F:1])[C:3]=1[C:10]1[S:11][CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=1
Reactant: O[C@@H]1CCOC1
Reactant: COC(=O)c1csc(-c2c(F)cc(O)cc2F)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O)c1csc(-c2c(F)cc(O[C@@H]3CCOC3)cc2F)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 2-(2,6-difluoro-4-hydroxy-phenyl)thiazole-4-carboxylate (207 mg, 0.763 mmol) and (R)-3-hydroxytetrahydrofuran (3 equiv., 206 mg) in tetrahydrofuran (5 mL) was added triphenylphosphine (3 equiv., 600 mg) and diisopropyl azodicarboxylate (3 equiv., 0.45 mL) The mixture was stirred at RT for 2 days. The mixture was concentrated and partitioned between EtOAc and water. The organic layer was washed with sat. NaHCO3, brine, dried over Na2SO4 and concentrated. This residue was diluted with THF (3 mL) and water (1 mL) and LiOH (36 mg) was added. After stirring at rt for 2.5 hours, the reaction was neutralized with 1 N HCl(aq), diluted with EtOAc and washed with brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound, contaminated with triphenylphosphine oxide, and other by-products, which was used without further purification.