Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=N)[O:17][CH3:18])[N:11]=2)[N:9]=1)[NH2:3].Cl.C(=O)([O-])[O-:22].[K+].[K+]>O1CCCC1>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:17][CH3:18])=[O:22])[N:11]=2)[N:9]=1)[NH2:3]
Reactant: O=C([O-])[O-]
Reactant: COC(=N)c1cccc(-c2csc(N=C(N)N)n2)n1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[6-[(imino)(methoxy)methyl]pyridin-2-yl]thiazole (0.9 g) in 50% aqueous tetrahydrofuran (60 ml) was adjusted to pH 1.0 with 6N-hydrochloric acid and stirred for 5 minutes at ambient temperature. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and the mixture was extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-(6-methoxycarbonylpyridin-2-yl)thiazole (0.54 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=2[CH2:6][N:7]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[CH:9][C:8]2=[O:19])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH:1]1([C:4]2[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=2[CH2:6][N:7]2[C:12]3[N:13]=[C:14]([S:17]([CH3:18])=[O:32])[N:15]=[CH:16][C:11]=3[CH:10]=[CH:9][C:8]2=[O:19])[CH2:3][CH2:2]1
Reactant: CSc1ncc2ccc(=O)n(Cc3ccccc3C3CC3)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(=O)n(Cc3ccccc3C3CC3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
To a solution of 8-(2-cyclopropylbenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (88 mg, 0.27 mmol) in dichloromethane (1 mL) was added 3-chloroperbenzoic acid (70%, 67 mg, 0.27 mmol) at 0-5° C. and the mixture was stirred at room temperature for 18 h. After completion, it was diluted with dichloromethane (10 mL) and washed with saturated sodium bicarbonate solution (1×5 mL) then with water (1×5 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give 8-(2-cyclopropylbenzyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one as a pale yellow solid (80 mg, 0.23 mmol, 85%). ESMS m/z 340 (M+H)+.
Reaction SMILES: O[CH:2]([CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(=O)C(O)=O>C1(C)C=CC=CC=1>[CH:2](=[C:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)C1CCCC1=O
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCCC=C1CCCC1=O
Yield: 87.4 %

Procedure:
In a 300 ml four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were placed 2-(1-hydroxyhexyl)cyclopentanone (85 g) synthesized in Reference Example 2, oxalic acid (1.0 g) and toluene (150 ml), and the whole was refluxed to allow dehydration to proceed. The formed water was removed and the reaction was continued until water was not formed any more (about 3 hours). The reaction mixture was washed with water and the layers were separated from each other. Further, the resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover toluene and unreacted cyclopentanone, whereby a crude product (78 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 67 g of 2-hexylidenecyclopentanone (boiling point: 92° C./533 Pa; GC purity: 98.5%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10]([CH:12]=[N:13][CH3:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.COC1C=C(C=CC=1OC)CN=CC1SC2N=CN=CC=2C=1.CC1C=CC(S([CH:47]([C:50]2[CH:55]=[CH:54][C:53]([Br:56])=[CH:52][CH:51]=2)[N+:48]#[C-:49])(=O)=O)=CC=1>>[Br:56][C:53]1[CH:52]=[CH:51][C:50]([C:47]2[N:48]=[CH:49][N:13]([CH3:14])[C:12]=2[C:10]2[S:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([S:2][CH3:1])[C:4]=3[CH:11]=2)=[CH:55][CH:54]=1
Reactant: [C-]#[N+]C(c1ccc(Br)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CN=Cc1cc2c(SC)ncnc2s1
Agent: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Product: CSc1ncnc2sc(-c3c(-c4ccc(Br)cc4)ncn3C)cc12

Procedure:
The title compound was prepared by a similar process to that described for Example 6 but using N-[4-(methylthio)thieno[2,3-d]pyrimidin-6-ylmethylidene]methanamine (Intermediate 16) in place of N-(3,4-Dimethoxybenzyl)-N-[thieno[2,3-d]pyrimidin-6-ylmethylidene]amine. (intermediate 14) and (4-bromophenyl)(isocyano)methyl 4-methylphenyl sulfone (Intermediate 66) in place of PhTosMIC. Pale yellow solid (1.7 g, 81%);
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][S:19][CH2:20][CH2:21][CH2:22][CH2:23][Cl:24])[CH:13]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][S:19]([CH2:18][C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCCCCSCc1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(CCCCCl)Cc1cccnc1
Reaction time: 17 h
Yield: 23 %

Procedure:
A solution of 85% pure m-chloroperbenzoic acid (107 g) in methylene chloride (900 cc) is added dropwise, in the course of 1 hour 30 minutes, at a temperature of about 20° C., to a solution of 4-chlorobutyl pyridin-3-yl-methyl sulphide (103 g) in methylene chloride (900 cc). After stirring for 17 hours at the same temperature, a 10% (by weight) aqueous solution of sodium bicarbonate (3 liters) is added slowly. The organic solution is decanted and then washed with a 10% solution of sodium bicarbonate (1 liter). The aqueous phases are combined and extracted with methylene chloride (500 cc). The organic extracts are combined and washed twice with distilled water (2 liters in total), dried over anhydrous sodium sulphate and concentrated to dryness under reduced pressure (25 mm Hg; 3.4 kPa) at 35° C. The product obtained (87 g) is chromatographed on neutral silica gel (400 g) contained in a column of diameter 4.7 cm. Elution is carried out with methylene chloride (10 liters), three 1 liter fractions, ten 100 cc fractions and twelve 500 cc fractions being collected successively. Fractions 11 to 25 are combined and concentrated to dryness under reduced pressure (25 mm Hg; 3.4 kPa) at 35° C. to give 3-(4-chlorobutyl)sulphinylmethylpyridine (25.4 g) in the form of an orange oil [Rf=0.22; chromatography on a thin layer of silica gel; solvent: ethyl acetate/methanol (80/20 by volume)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][O:64][CH2:65][C@@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH2:70][C@H:66]1[CH2:65][O:64][CH3:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: COC[C@@H]1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC[C@@H]1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-methoxymethyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([OH:23])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[BH4-].[Na+]>CO>[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:17]([OH:23])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(C=O)c(O)c1
Reactant: NCCc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)c(O)c1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
1.83 g (13 mmol) of 2-(4-fluoro-phenyl) ethyl amine were added to 2.32 g (13 mmol) of 4-tert-butyl-2-hydroxy benzaldehyde dissolved in 130 ml methanol. The reaction mixture was stirred at rt over night under nitrogen. 492 mg (13 mmol) of sodium borohydride were added in portions and the reaction mixture was stirred for 2 h at rt. The solvent was evaporated and the residue was dissolved in DCM. The organic layer was washed with water and with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (250 g silica gel; DCM, then DCM/methanol 19:1) to yield 3.26 g (83%) of 5-tert-butyl-2-{[2-(4-fluoro-phenyl)-ethylamino]-methyl}-phenol as a yellow viscous oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.24 (t, 2H), 7.09 (t, 2H), 6.95 (d, 1H), 6.71 (d, 1H), 6.68 (s, 1H), 3.76 (s, 2H), 1.23 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30]([OH:32])=O)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[C:22]([CH2:28][CH3:29])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:68][N:69]1[CH2:74][CH2:73][CH:72]([N:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)[CH2:71][CH2:70]1.C([O-])(O)=O.[Na+]>CN(C=O)C.C1COCC1>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[C:22]([CH2:28][CH3:29])[CH:21]=3)[C:30]([N:78]3[CH2:77][CH2:76][N:75]([CH:72]4[CH2:73][CH2:74][N:69]([CH3:68])[CH2:70][CH2:71]4)[CH2:80][CH2:79]3)=[O:32])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CCc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 150 mg (0.30 mmol) (R)-1-carboxy-2-(3,4-diethyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 98 mg (0.30 mmol) TBTU, 0.2 mL (1.1 mmol) ethyldiisopropylamine and 15 mL THF as well as 3 mL DMF was stirred for 1 h at RT, then combined with 56 mg (0.30 mmol) 1-(1-methyl-piperidin-4-yl)-piperazin and stirred for 2 h. The reaction mixture was combined with 30 mL of a semisaturated NaHCO3 solution and extracted with 30 mL EtOAc. The organic phase was dried, evaporated down under reduced pressure and the residue was purified by chromatography on silica gel. The product fractions were evaporated down under reduced pressure, the residue was triturated with diisopropylether, suction filtered and dried.
Reaction SMILES: C([Li])CCC.[C:6]([Si:10]([CH3:38])([CH3:37])[O:11][C@H:12]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C@@H:28]([CH2:29][CH2:30][CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH3:9])([CH3:8])[CH3:7].CN([CH:42]=[O:43])C>CCOCC>[C:6]([Si:10]([CH3:38])([CH3:37])[O:11][C@H:12]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C@@H:28]([CH2:29][CH2:30][CH2:31][C:32]3[S:33][C:34]([CH:42]=[O:43])=[CH:35][CH:36]=3)[CH2:27][CH2:26][CH:25]=2)=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH3:9])([CH3:7])[CH3:8]
Reactant: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(C2=CCC[C@@H]2CCCc2cccs2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C=O)s2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
n-Butyllithium (0.14 mL, 0.22 mmol, 1.6 M/hexanes) was added to an ice cold solution of 41 (53 mg, 0.11 mmol) in 0.5 mL ether. After 1 h, DMF (85 μL, 1.1 mmol) was added and the reaction was allowed to stir for 40 min. At this time, the reaction was quenched by addition of 10 mL saturated NH4Cl solution. The mixture was extracted with ethyl acetate (2×20 mL) and the combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography using a Combiflash unit by Teledyne Isco (12 g silica gel, 0%→15% ethyl acetate/hexanes) which gave the title compound (43 mg, 0.084 mmol, 77%).
Reaction SMILES: [CH:1]1([C@@H:4]2[O:13][CH2:12][C@:7]3([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=4[F:21])[NH:8][O:9][C@@H:10]([CH3:11])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.N[C@@]1(C2C=CC(F)=CC=2F)CO[C@@H](COCC2C=CC=CC=2)C[C@H]1CO>>[NH2:8][C@@:7]1([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:12][O:13][C@@H:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][C@H:6]1[C@@H:10]([OH:9])[CH3:11]
Reactant: C[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12
Agent: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Product: C[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(N)c1ccc(F)cc1F

Procedure:
(3S,3aR,5R,7aS)-5-Cyclopropyl-7a-(2,4-difluorophenyl)-3-methyl hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C28) was converted to the product using the method described for synthesis of [(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C6) in Preparation P1. The resulting oil was used in the next step without additional purification. Yield: 0.11 g, 0.37 mmol, 87%. LCMS m/z 298.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[O:11]=[C:12]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH2:13][C:14]([O:16][CH3:17])=[O:15].N1CCCCC1.C(O)(=O)C>C(O)(C)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:13]([C:12](=[O:11])[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CC(=O)CCc1ccncc1
Reactant: O=Cc1ccc(F)cc1Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1ccc(F)cc1Cl)C(=O)CCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.44 g (15.4 mmol) of 2-chloro-4-fluorobenzaldehyde and 3.19 g (15.4 mmol) of the compound from Example X in 20 ml of isopropanol are mixed with 0.1 ml of piperidine and 0.13 ml of glacial acetic acid. Stirring at room temperature overnight is followed by concentration, and the residue is chromatographed on silica gel with dichloromethane->dichloromethane/methanol (50:1) as mobile phase. The product is employed further as cis/trans mixture.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.Cl.N([O-])=O.[Na+].[K+].C(OC([S-])=[S:20])C.[OH-].[K+]>O.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([SH:20])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S)cc1Br
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A cooled (−15° C.) solution of 3-bromo-4-methylaniline (ABCR; 2.0 g) in a 6N solution of HCl in water (30 mL) was treated drop-wise with a solution of sodium nitrite (1.78 g) in water (10 mL). The reaction mixture was stirred for 30 mins. The resulting clear solution was added dropwise to a stirred solution of O-ethyl xanthic acid potassium salt (6.1 g) in water (25 mL). The mixture was then heated to 80° C. for 15 minutes. The mixture was then cooled and extracted with diethyl ether twice. The solvents were evaporated under reduced pressure to give a residue, which was treated with a solution of KOH (6.1 g) in 95% ethanol (55 mL) and heated to reflux for 10 h. The reaction mixture was diluted with water and acidified with conc. HCl to pH 3 and extracted with diethyl ether. The organic layer was washed with water, brine and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel), eluting with petroleum ether. This product obtained was triturated with hexane to give the title compound (1.5 g, 70%) as an off-white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([CH:8]=[N:9]O)=[CH:5][CH:4]=1>C(O)(=O)C.[Zn]>[CH3:1][S:2][C:3]1[O:7][C:6]([CH2:8][NH2:9])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=NO)o1
Agent: [Zn]
Solvent: CC(=O)O
Product: CSc1ccc(CN)o1
Temperature: 23 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a solution of 5-(methylthio)furan-2-carbaldehyde oxime (220 mg, 1.40 mmol) in glacial acetic acid (15 mL) was added zinc dust (2.10 g, 32.2 mmol) and the reaction mixture was stirred at 23° C. for 4 h. After filtration on celite, the acetic acid was concentrated in vacuo and the crude material purified on functionalized silica gel (6 g) containing sulfonic acid (0.8 mmol/g) to afford 138 mg (69%) of the title compound as an orange oil. 1H NMR (400 MHz, CDCl3): 6.36 (1H, d, J=3.2 Hz), 6.11 (1H, d, J=3.2 Hz), 3.80 (2H, s), 2.36 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Li]CCCC.CON(C)[C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1)=[O:18]>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1)=[O:18]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Clc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-bromo-3-chlorobenzene (15 g, 78.3 mmol) in anhydrous THF (150 mL) cooled to −78° C. was added dropwise a solution of 2.5 M n-BuLi in hexanes (31.3 mL, 78.34 mmol). The reaction mixture was stirred at −78° C. for 1 h and a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (17.8 g, 65.3 mmol) in anhydrous THF (50 mL) was added dropwise. After addition, the mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with satd aq NH4Cl (250 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether/EtOAc 5:95) to give (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (12.9 g, 51%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.54-1.73 (m, 2H), 1.75 (m, 1H), 2.00 (m, 1H), 2.71-2.78 (m, 1H), 2.93 (m, 2H), 3.30-3.35 (m, 1H), 4.22 (m, 1H), 7.39-7.42 (t, 1H), 7.52 (d, 1H), 7.89 (d, 1H), 7.90 (m, 1H). MS m/z 324 (M+H+).
Reaction SMILES: [C:1]1([C:14]([OH:16])=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])[C:22]=1[CH3:23].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:24]2[CH:25]=[C:26]([NH:27][C:14]([C:1]3[C:13]4[NH:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:16])[CH:28]=[CH:29][CH:30]=2)[C:22]=1[CH3:23]
Reactant: Cc1ncn(-c2cccc(N)c2)c1C
Reactant: O=C(O)c1cccc2c1[nH]c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncn(-c2cccc(NC(=O)c3cccc4c3[nH]c3ccccc34)c2)c1C
Reaction time: 20 h

Procedure:
To a suspension of 9H-carbazole-1-carboxylic acid (116 mg) and 3-(4,5dimethylimidazol-1-yl)aniline (103 mg) in dichloromethane (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (158 mg) and 4-dimethylaminopyridine (101 mg), and the mixture was stirred for 20 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. After trituration with methanol, the residue was collected by filtration and dried to give N-[3-(4,5-dimethylimidazol-1-yl)-phenyl]-9H-carbazole-1-carboxamide (86 mg, 41.1%.
Reaction SMILES: [CH3:1][C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1[C:24]1[CH:38]=[CH:37][C:27]([C:28]([N:30]2[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:25]=1.[BH4-].[Na+].O>CO>[OH:36][CH:33]1[CH2:34][CH2:35][N:30]([C:28]([C:27]2[CH:26]=[CH:25][C:24]([C:3]3[N:4]=[C:5]4[N:11]([CH2:10][CH2:9][C:8]5[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=5[CH:6]4[O:16][CH:17]4[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]4)[C:2]=3[CH3:1])=[CH:38][CH:37]=2)=[O:29])[CH2:31][CH2:32]1
Reactant: Cc1c(-c2ccc(C(=O)N3CCC(=O)CC3)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(-c2ccc(C(=O)N3CCC(O)CC3)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Reaction time: 2 h

Procedure:
To a solution of 1-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-benzoyl}-piperidin-4-one (example 218) (93.7 mg, 0.183 mmole) in MeOH (2 mL) is added portionwise NaBH4 (10.5 mg, 0.275 mmole). After 2 hours at room temperature, water is added and the aqueous phase is extracted with AcOEt. AcOEt phase is dried over MgSO4, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) (90:1) then (CH2Cl2:MeOH:NH4OH) (9:1:0.1). The residual solid is triturated three times with Et2O to give (4-hydroxypiperidin-1-yl)-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-methanone.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CO[C:10](OC)([N:12]([CH3:14])[CH3:13])[CH3:11]>>[CH2:1]([N:7]=[C:10]([N:12]([CH3:14])[CH3:13])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(C)(OC)N(C)C
Reactant: CCCCCCN
Product: CCCCCCN=C(C)N(C)C
Reaction time: 0.5 h

Procedure:
N′-hexyl-N,N-dimethylacetamidine (1e) was synthesized by heating n-hexylamine (2.03 mL) with dimethylacetamide dimethyl acetal (2.5 mL) for 20 min at 60° C. under N2 in a 2-neck round bottom flask without solvent. A yellow solution formed and was allowed to cool. Methanol, a byproduct, was removed by evaporation under high vacuum. Diethyl ether (15 mL) and distilled water (3 drops) were added and CO2 was bubbled through the mixture for 1 h to convert the crude 1e into the bicarbonate salt 2e. The mixture was then put in a freezer for 30 min because the white solid so formed degrades back to the liquid readily upon exposure to air. This frozen material was used as the crude surfactant for emulsion stability tests. A sample of 1e was prepared by applying strong vacuum to a portion of the frozen material at room temperature.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:21]=[CH:22][C:23]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:25]=2)=[CH:12][CH:11]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Temperature: 150 °C

Procedure:
To a 2 mL heavy-walled tube was added (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (127 mg, 0.471 mmol), 4-(4-chlorophenyl)-4-oxobutanoic acid (91 mg, 0.428 mmol), Na2CO3 (136 mg, 1.284 mmol), dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (3.03 mg, 4.28 μmol), dioxane (1 mL), and water (0.15 mL). The tube was sealed and heated to 150° C. for 10 min under microwave irradiation. The mixture was purified by preparative HPLC to give the title compound as a white solid. LCMS m/z=366.1 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (d, J=6.3 Hz, 0.4H), 1.37 (d, J=6.3 Hz, 2.6H), 1.54-1.65 (m, 1H), 1.90-2.05 (m, 2H), 2.18-2.26 (m, 1H), 2.62 (t, J=7.8 Hz, 2H), 2.95-3.10 (m, 2H), 3.16-3.30 (m, 3H), 3.38-3.68 (m, 4H), 7.46 (d, J=8.2 Hz, 2H), 7.74 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.2 Hz, 2H), 8.06 (d, J=8.2 Hz, 2H), 9.34 (bs, 1H).