Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12]([NH:14][N:15]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]1[C:21]([O:23]C)=O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[C:39]([F:41])[CH:40]=1)[NH2:37]>>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:25][C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:12]([NH:14][N:15]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]1[C:21](=[O:23])[NH:37][C:36]1[CH:35]=[C:34]([F:33])[CH:40]=[C:39]([F:41])[CH:38]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Yield: 67.5 %

Procedure:
The title compound was prepared from (S)-methyl 1-(4-(benzyloxy)-2-(tert-butoxycarbonylamino)butanamido)-3-bromo-1H-pyrrole-2-carboxylate (4.0 g, 7.8 mmol) and 3,5-difluoroaniline (5.1 g, 39.0 mmol) following the experimental procedure described in Preparation 44a. 3.2 g (66% yield) of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=O.CO.[CH3:30][NH2:31].[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[ClH:1].[Cl:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH2:7][NH:31][CH3:30]
Reactant: CN
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c1Cl
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
2-Chloro-5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde (160 mg) was dissolved in methanol (20 mL), 40% methylamine methanol solution (150 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (44 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (10 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:4→0:1), and dissolved in ethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 98 mg, 55%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[Cl:12][C:13]1[C:28]([Cl:29])=[CH:27][C:16]2[N:17]([CH3:26])[C:18](=O)[C:19]3[C:20](=[CH:22][S:23][CH:24]=3)[NH:21][C:15]=2[CH:14]=1.[OH-].[Na+]>O>[Cl:12][C:13]1[C:28]([Cl:29])=[CH:27][C:16]2[N:17]([CH3:26])[CH2:18][C:19]3[C:20](=[CH:22][S:23][CH:24]=3)[NH:21][C:15]=2[CH:14]=1
Reactant: CN1C(=O)c2cscc2Nc2cc(Cl)c(Cl)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2cscc2Nc2cc(Cl)c(Cl)cc21
Reaction time: 8 h

Procedure:
To a suspension of 4 g. of lithium aluminum hydride in 150 ml. of tetrahydrofuran stirred under nitrogen, is added a solution of 10 g. of 6,7-dichloro-4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 350 ml. of tetrahydrofuran. The mixture is stirred under reflux for 31/2 hours and then allowed to stand overnight. The mixture is cooled in an ice bath and treated, under nitrogen with stirring, with 4 ml. of water, 4 ml. of 15% sodium hydroxide and 12 ml. of water. The complex is filtered and washed with ether. The combined filtrate and washing is dried over sodium sulfate, filtered and concentrated to a residue. This residue is dissolved in a mixture of 10 ml. of 30% methylene chloride in hexane and 10 ml. of methylene chloride and chromatographed on an alumina column as described in Example 20. Those fractions which contain the desired product as determined by thin layer chromatography are combined and concentrated to give a blue-green crystalline solid. The crystalline product is heated to the boil in 200 ml. of hexane, and filtered. The filtrate is cooled and an standing produces a solid which is collected, washed with hexane and dried giving the desired product, mp. 92°-93° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C@H:15]1[CH2:20][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:18]([N:29]=[N+]=[N-])[C@@H:17]([CH3:32])[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C@H:15]1[CH2:20][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:18]([NH2:29])[C@@H:17]([CH3:32])[CH2:16]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N
Reaction time: 4 h
Yield: 88 %

Procedure:
To a degassed a solution of (+/−)-tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-azido-3-methylcyclohexyl)carbamate (1.0 equiv.) in ethanol (0.10 M) was added Pd/C (0.2 equiv.). The mixture was stirred under H2 for 4 hrs. Filter the mixture over cetlite and wash the cake with MeOH. Concentrate the filtrate to yield (+/−)-tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-amino-3-methylcyclohexyl)carbamate in 88% yield. LC/MS (m/z)=421.3 (MH+), Rt=0.58 min.
Reaction SMILES: [Br-:1].O[C@@H:3]1[CH2:8][CH2:7][CH2:6][N+:5]([CH2:10][C:11](=[O:18])[NH:12][C:13]2[CH:17]=[CH:16][O:15][N:14]=2)([CH3:9])[CH2:4]1.CN1CCC([OH:26])CC1>>[Br-:1].[OH:26][CH:8]1[CH2:7][CH2:6][N+:5]([CH2:10][C:11](=[O:18])[NH:12][C:13]2[CH:17]=[CH:16][O:15][N:14]=2)([CH3:9])[CH2:4][CH2:3]1
Reactant: CN1CCC(O)CC1
Reactant: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H](O)C1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CCC(O)CC1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-Hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide (Intermediate C) by replacing (R)-1-methyl-piperidin-3-ol (step C3) with 1-methyl-piperidin-4-ol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:46])[CH:31]=[C:32]([O:44][CH3:45])[C:33]=1[O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1.[OH-].[Na+]>CC(O)=O>[NH:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[N:8]([C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:46][C:30]2[CH:29]=[C:28]([O:27][CH3:26])[C:33]([O:34][CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)=[C:32]([O:44][CH3:45])[CH:31]=2)[N:7]=1
Reactant: Cc1cccc(C)c1N(c1ccnc(Cl)n1)c1nc2ccccc2[nH]1
Reactant: COc1cc(N)cc(OC)c1OCCN1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(Nc2nccc(N(c3nc4ccccc4[nH]3)c3c(C)cccc3C)n2)cc(OC)c1OCCN1CCN(C)CC1
Temperature: 100 °C

Procedure:
A pressure tube was charged with a solution of 2-(N-(2-chloropyrimid-4-yl)-2,6-dimethylphenylamino)-1H-benzimidazole (50 mg, 0.14 mmol), 3,5-dimethoxy-4-[2-(4-methylpiperazin-1-yl)-ethoxy]phenylamine (42 mg, 0.14 mmol) in glacial AcOH (2 mL). The reaction, a dark brown solution, was heated to 100° C. for 18 h. The reaction was cooled to RT and then basified by careful addition of 5M NaOH (15 mL). The aqueous solution was extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography (silica; CH2Cl2:MeOH; 8:2) to afford the title compound as a light purple solid. MS m/z=609 (M+H). Calc'd for C34H40N8O3=608.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].O.[NH2:16][NH2:17]>>[NH:16]([C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8])[NH2:17]
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Reactant: NN
Solvent: O
Product: Cc1cc(-c2ccccc2)nnc1NN
Reaction time: 1 h

Procedure:
The mixture of 5 g of 3-chloro 4-methyl 6-phenyl pyridazine and 12 ml of hydrazine hydrate is taken to reflux. After one hour thirty minutes, the reaction medium is left to cool. A solid separates, which is drained and washed with a little water. The product is recrystallized in the mixture of isopropanol-isopropyl ether. Weight 4.5 g. m.p.: 162° C.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[CH:3]=[C:4]1[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]C=3)CC1=[N:6]2.N1C2C(=CC=CC=2)C=CC=1.[C:28]1(=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](=O)[CH2:29]1.P([O-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C1C(O)=CC=CC=1C>C(N(CC)CC)C.CO>[C:4]1([C:3]2[C:2]3[CH:1]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:30]3[C:31]4[C:36]([C:28](=[O:38])[C:29]=23)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:17]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc2c(c1)Cc1nc3ccccc3cc1-2
Reactant: O=C1CC(=O)c2ccccc21
Agent: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1cccc(O)c1
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: O=C1c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Temperature: 140 °C
Yield: 81.3 %

Procedure:
The 6H-indeno[2,1-b]quinoline derivative of the present invention can be synthesized at high percentage yield by performing non-metal catalytic Friedlämder reaction to obtain derivatives containing quinolin and ketone. The starting materials 1H-indene-1,3(2H)-dione (307 mg, 1.00 m), 2-amonobenzophenone (400 mg, 2.00 mmol), diphenyl phosphate (DPP, 751 mg, 3.00 mmol) and just-evaporated m-cresol are mixed in a round bottom flask and heated to 140° C. for two hours under nitrogen atmosphere. After reaction, 10% triethylamine/methanol is added into the crude product and then filtered to remove precipitates. Finally, 10-phenyl-11H-indeno[1,2-b]quinolin-11-one, appearing yellow, is separated from the mixture by using column chromatography with N-hexane:ethyl acetate =10:1. The percentage yield is 81.3%. 10-phenyl-11H-indeno[1,2-b]quinolin-11-one obtained here can be also used as starting materials to produce other 6H-indeno[2,1-b]quinoline derivatives.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(C1CCC(=[O:28])CC1)CC.C(C1CCC([Mg]Br)CC1)CC>C1CCCCC1>[CH2:16]([C@H:13]1[CH2:14][CH2:15][C@H:10]([C:7]2([OH:28])[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]2)[CH2:11][CH2:12]1)[CH2:17][CH3:18]
Reactant: CCCC1CC=C([C@H]2CC[C@H](CCC)CC2)CC1
Reactant: CCCC1CCC(=O)CC1
Agent: CCCC1CCC([Mg]Br)CC1
Solvent: C1CCCCC1
Product: CCCC1CCC(O)([C@H]2CC[C@H](CCC)CC2)CC1

Procedure:
A solution in 300 ml of cyclohexane of 24.8 g of 1-(trans-4-propylcyclohexyl)-4-propylcyclohexene [obtainable by reacting 4-propylcyclohexanone with 4-propylcyclohexylmagnesium bromide to give 1-(trans-4-propylcyclohexyl)-4-propylcyclohexanol and dehydrating the latter] is hydrogenated over 4 g of 10% PdC at 20° and 1 bar until absorption of H2 ceases. The mixture is filtered and worked up analogously to Example 3 via the thiourea adduct to give trans,trans-4,4'-dipropylbicyclohexyl, c.p. 41°.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH3:23])[C:14]([Br:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C(OC)=C(C(CSC2C=CC=CC=2)=CC=1)C(OC)=O>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([Br:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: COC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 61, starting from methyl 3-bromo-6-(phenylthiomethyl)-2-methoxybenzoate (Intermediate 80).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:20])=[C:10]([CH:19]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[Cl-].[NH4+].Cl>O1CCCC1.CCOCC>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:20])=[C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH:1]=[CH2:2])[OH:12])[CH:19]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: C=C[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(O)(c1ccccc1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
225 ml of a filtered solution of 2.5 M/liter of vinyl magnesium chloride in tetrahydrofuran were added dropwise with stirring at -10° C. to a mixture of 58 g of 5-chloro-2-hydroxy-benzophenone and 900 ml of anhydrous ether and the mixture was stirred at room temperature for 16 hours and was refluxed for 3 hours. The mixture was iced and 600 ml of aqueous 10% ammonium chloride solution and 50 ml of concentrated hydrochloric acid were added thereto dropwise. The decanted organic phase was washed twice with 100 ml of water, was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The oil residue was chromatographed over silica gel and was eluted with methylene chloride to obtain 34.4 g of 5-chloro-2-hydroxy-α-phenyl-α-ethenyl-benzene-methanol.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[C:22][C:23]2[C:28](=[O:29])[N:27](CC3C=CC(OC)=CC=3)[CH:26]=[C:25]([Cl:39])[N:24]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[O:29][C:28]3=[N:27][CH:26]=[C:25]([Cl:39])[N:24]=[C:23]3[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1ccc(Cn2cc(Cl)nc(C#CC3CCN(C(=O)OC(C)(C)C)CC3)c2=O)cc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nc(Cl)cnc3o2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Silver triflate (6 mg) and trifluoroacetic acid (0.36 mL) are added to a solution of 4-[6-chloro-4-(4-methoxy-benzyl)-3-oxo-3,4-dihydro-pyrazin-2-ylethynyl]-piperidine-1-carboxylic acid tert-butyl ester (430 mg) in dichloromethane (6 mL). The reaction mixture is stirred at room temperature for 20 min, diluted with dichloromethane and washed with aqueous NaHCO3 solution and brine. The organic phase is dried (MgSO4) and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 25:70) to give the title compound as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].CN1C(=O)CCC1.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[NH2:43][C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH:46]=[N:47][N:48]2[CH2:53][C:54]1[CH:55]=[C:56]([CH:59]=[CH:60][CH:61]=1)[C:57]#[N:58]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:57]([C:56]1[CH:55]=[C:54]([CH:61]=[CH:60][CH:59]=1)[CH2:53][N:48]1[C:49]2[C:45](=[C:44]([NH:43][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[O:21])[CH:52]=[CH:51][CH:50]=2)[CH:46]=[N:47]1)#[N:58]
Reactant: N#Cc1cccc(Cn2ncc3c(N)cccc32)c1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4cnn5Cc4cccc(C#N)c4)cnc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a vial was added lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.187 g, 0.544 mmol) and NMP (3.0 mL), and the mixture was warmed until homogeneous and then cooled to ambient temperature. 2,4,6-Trichlorobenzoyl chloride (0.0793 mL, 0.507 mmol) was added and the dark solution was stirred at ambient temperature for 0.5 hours. 3-((4-Amino-1H-indazol-1-yl)methyl)benzonitrile (0.090 g, 0.362 mmol) was added as a NMP solution (3.0 mL) and the mixture was heated to 75° C. with stirring for 3 hours. The reaction was equilibrated to ambient temperature and the mixture was diluted with EtOAc (30 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (15% MeOH/CH2Cl2 adding 1% 7N NH3/MeOH). The red/brown solid was slurried in Et2O and then filtered, and the isolated solid was washed with Et2O providing a pale red/brown solid that was dried under vacuum to provide 0.095 g (42%) of the desired product. MS (ES+APCI) m/z=535 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13]C(=O)OCC1C=CC=CC=1)[CH:7]=2>[Pd].CO>[NH2:13][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:3]([CH2:2][OH:1])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=C(Nc1ccc2cc(CO)cnc2c1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2cc(CO)cnc2c1
Reaction time: 1 h

Procedure:
A mixture of benzyl 3-(hydroxymethyl)quinolin-7-ylcarbamate (480 mg, 0.0016 mol), 10% Pd-C (50 mg), and MeOH (50 mL) was stirred under H2 (1 atm) for 1 h. The catalyst was filtered-off and the filtrate was concentrated to give the product as a yellow solid. LC-MS: 0.34 min, 175.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([N:13](C)[C:14](=O)C(F)(F)F)=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22].[O-]CC.[Na+].O>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc(-n2ccc(N(C)C(=O)C(F)(F)F)n2)ccc1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNc1ccn(-c2ccc(Br)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To an ice cold solution of N-(1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-yl)-2,2,2-trifluoro-N-methylacetamide (300 mg, 0.793 mmol) in EtOH (5 mL) was added a solution of 21% sodium ethoxide in EtOH (0.4 mL, 0.793 mmol). The mixture was stirred at room temperature overnight, then was poured into water. The mixture was extracted with EtOAc. The combined organic layers were washed with aqueous saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(4-bromo-3-methoxyphenyl)-N-methyl-1H-pyrazol-3-amine (200 mg, MS: 284.3 [M+H+]).
Reaction SMILES: I[CH3:2].[I:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:8][C:5]=1[CH:6]=[O:7].[NH4+].[Cl-]>CCOCC>[I:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:8][C:5]=1[CH:6]([OH:7])[CH3:2]
Reactant: CI
Reactant: COc1cc(I)c(C=O)cc1OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cc(I)c(C(C)O)cc1OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of Mg turnings (195 mg, 8.02 g·atom) in dry Et2O (3.0 mL) was stirred at 0° C. under a nitrogen atmosphere then treated, dropwise, with a solution of iodomethane (0.58 mL, 9.31 mmol) in dry Et2O (7.5 mL). After 0.5 h a solution of aldehyde 5 (1.00 g, 3.12 mmol) in dry Et2O (7.5 mL) was added, dropwise, and the ensuing mixture then allowed to warm to 18° C. Stirring was continued at this temperature for a further 1 h then the reaction mixture was treated with NH4Cl (5 mL of a 20% w/v aqueous solution) and Et2O (10 mL). The separated organic phase was washed with H2O (1×5 mL) then dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound 6 (1.05 g, quant.) as a pale-yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:10]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:11]([C:17](O)=[O:18])=[C:12]([CH3:16])[NH:13][C:14]=1[CH3:15])=[O:8]>ClCCl>[Cl:3][C:17]([C:11]1[C@H:10]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:9]([C:7]([O:6][CH3:5])=[O:8])=[C:14]([CH3:15])[NH:13][C:12]=1[CH3:16])=[O:18]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)Cl)[C@@H]1c1cccc([N+](=O)[O-])c1

Procedure:
Thionyl chloride (0.4 g, 3.4 mmol) was slowly added to a solution of 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1.0 g, 3 mmol) in dichloromethane dropwisely at −25° C. After the completion of the dropwise addition, the reaction was continued under cooling in an ice bath until the solution became clear. After the completion of reaction, the reaction solution was rotary evaporated to dryness. The product was directly used in the next step.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.Cl>ClC(Cl)C.O1CCOCC1>[CH3:1][N:2]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[CH:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CN(CCc1ccc(Oc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(Cl)Cl
Product: CN(CCc1ccc(Oc2ccccc2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1,1-dimethylethyl 4-(methyl(2-(4-phenoxyphenyl)ethyl)amino)-1-piperidinecarboxylate (290 mg, 0.71 mmol) in dichloroethane was added a solution of hydrogen chloride in dioxane (4N). The reaction was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated to dryness to give N-methyl-N-[2-(4-phenoxyphenyl)ethyl]-4-piperidinamine.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:35][CH3:36])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:18]>>[CH2:35]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]2=[O:16])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(-c4ccccc4)cc32)c1C
Yield: 38.6 %

Procedure:
5-Phenyl-1,3-dihydroindol-2-one (1.5 g, 7.16 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (2 g) to give 1.3 g (40%) of the title compound as a yellow-orange solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH2:37][O:38][CH3:39])[C:28]([NH:30][C:31]1[S:35][N:34]=[C:33]([CH3:36])[N:32]=1)=[O:29])(C(C)(C)C)(C)C>O1CCCC1.CCOC(C)=O>[OH:26][C@@H:27]([CH2:37][O:38][CH3:39])[C:28]([NH:30][C:31]1[S:35][N:34]=[C:33]([CH3:36])[N:32]=1)=[O:29]
Reactant: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1nc(C)ns1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@H](O)C(=O)Nc1nc(C)ns1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (2.353 mL, 2.35 mmol) was added in one portion to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (Intermediate E2) (390 mg, 1.18 mmol) in tetrahydrofuran (10 mL). The resulting solution was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with EtOAc (20 mL), and washed sequentially with water (10 mL) and saturated brine (10 mL). The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane to afford (S)-2-hydroxy-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (192 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 2.49 (3H, s), 3.37 (3H, s), 3.60 (1H, d), 3.72 (2H, d), 4.46 (1H, q), 10.20 (1H, s); m/z (ESI+) (M+H)+=218.30; HPLC tR=0.89 min.