Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1)#[CH:23]>>[CH3:11][C:10]1[C:5]2[N:6]([C:2]([C:23]#[C:22][C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=3)=[CH:3][N:4]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3ccc(N)nc3)cnc12

Procedure:
The title compound was prepared from 3-iodo-8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20 step 3) (804 mg, 2 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (307 mg, 2.6 mmol) according to general procedure II. Obtained as an off-white solid (160 mg, 20%). MS (ISP) 393.1 [(M+H)+]; mp 239-240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:20][C:13]3=[N:14][CH:15]=[C:16]([S:18][CH3:19])[CH:17]=[C:12]3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:20][C:13]3=[N:14][CH:15]=[C:16]([S:18]([CH3:19])=[O:26])[CH:17]=[C:12]3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cnc2c(c1)CCC(c1ccc(Cl)c(Cl)c1)O2
Solvent: ClCCl
Product: CS(=O)c1cnc2c(c1)CCC(c1ccc(Cl)c(Cl)c1)O2
Temperature: -5 °C

Procedure:
To a stirred solution of 1.0 g of 2-(3,4-dichlorophenyl)-3,4-dihydro-6-(methylthio)-2H-pyrano[2,3-b]pyridine in 25 ml of methylene chloride at -25° C. there was added dropwise a solution of 0.55 g of 80-85% m-chloroperoxybenzoic acid in 20 ml of methylene chloride over 5-10 minutes while keeping the temperature between -20° and -30° C. A precipitate formed. The mixture was then allowed to warm to -5° C. over 2 hours and then extracted with aqueous saturated sodium bicarbonate solution, aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to leave a pale yellow solid. This was recrystallized from a mixture of ethyl acetate and hexane to give 2-(3,4-dichlorophenyl)-3,4-dihydro-6-(methylsulfinyl)-2H-pyrano[2,3-b]pyridine as a cream-colored solid melting at about 159°-162° C.
Reaction SMILES: N#N.[C:3]([O:7][C:8]([NH:10][C@@H:11]([C:24](O)=[O:25])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH:22]=[O:23])[CH:14]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.[CH2:28]([O:35][C:36](=[O:46])[CH2:37][NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl.O>[CH2:39]([N:38]([CH2:37][C:36]([O:35][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:46])[C:24](=[O:25])[C@H:11]([NH:10][C:8]([O:7][C:3]([CH3:5])([CH3:6])[CH3:4])=[O:9])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH:22]=[O:23])[CH:14]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(CNCc1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N(CC(=O)OCc1ccccc1)Cc1ccccc1
Reaction time: 2 h
Yield: 101.6 %

Procedure:
To a mixture of N2 -(tert-butoxycarbonyl)-N1 -formyl-D-tryptophan (3.99 g) and N-benzyl glycin benzyl ester hydrochloride (3.50 g) in dichloromethane (70 ml) was added triethylamine (5.85 ml) under nitrogen atmosphere. To the mixture was added 2-chloro-1-methylpyridinium iodide (3.67 g) at room temperature, and the resulting mixture was stirred for 2 hours. After the reaction was completed, dichloromethane (30 ml) and water (30 ml) were added. The organic layer was separated, washed with 0.5N hydrochloric acid (10 ml), water (10 ml), aqueous sodium bicarbonate solution (10 ml) and brine (20 ml) successively and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified on a silica gel column (140 g) eluting with a mixture of toluene and ethyl acetate (4:1) to give (2R)-N-benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(N-formyl-1H-indol-3-yl)propanamide (6.41 g) as an oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH3:25])[C:20](=[O:26])[C:19]([CH2:27][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)=[N:18]3)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:39][C:40]([O:42][CH2:43]C)=[O:41]>O1CCCC1>[CH3:43][O:42][C:40]([CH2:39][N:14]([S:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)(=[O:12])=[O:13])[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[C:20](=[O:26])[C:19]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]#[N:33])=[CH:34][CH:35]=1)=[N:18]2)=[O:41]
Reactant: CCOC(=O)CBr
Reactant: Cn1c(=O)c(Cc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C#N)cc1)c(=O)n2C)S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g (4.15 mmol) of 4-{[6-(quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzonitrile are dissolved in 150 ml tetrahydrofuran and after the addition of 0.2 g (4.15 mmol) of sodium hydride (50% in oil) stirred for 2 hours at ambient temperature. After the addition of 0.47 ml (4.15 mmol) of ethyl bromoacetate the reaction mixture was stirred for 5 hours. The precipitate is suction filtered, the mother liquor is evaporated down and chromatographed on silica gel, eluting initially with petroleum ether and then with petroleum ether/ethyl acetate (55:45). The desired fractions are combined and evaporated down.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:32]=3[F:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2cc(F)ccc2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2,5-difluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.41 (m, 1 H), 7.23-7.17 (m, 1 H), 7.14 (t, J=3.4 Hz, 1 H), 7.06 (td, J=4.5, 9.3 Hz, 1 H), 7.01-6.92 (m, 3 H), 6.32 (dd, J=3.5, 11.3 Hz, 1 H), 5.64-5.53 (m, 3 H), 4.29 (t, J=4.6 Hz, 2 H), 2.96-2.80 (m, 2 H), 2.79 (s, 3 H), 2.09 (d, J=5.3 Hz, 2 H), 1.03-0.90 (s, 9H); LC/MS (m/z) ES+=521.36 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:3]([NH:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].[C:28]([NH:38][C@H:39]([C:43](O)=[O:44])[CH:40]([CH3:42])[CH3:41])([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[C:7]([O:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:43](=[O:44])[C@H:39]([CH:40]([CH3:41])[CH3:42])[NH:38][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)ONC(=O)[C@@H](N)CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NOC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-amino-N-tert-butoxy-3-(4-phenoxyphenylsulfonyl)-propionamide (1.9 g) in methylene chloride (30 ml) was added CBZ-(S)-valine (1.6 g), 1-hydroxybenzotriazole (0.9 g), triethylamine (1 ml), and N'-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (1.3 g). After stirring overnight at room temperature, the solution was partitioned between methylene chloride and water, and after the organic layer was dried over magnesium sulfate, solvent was removed under reduced pressure to give (R)-N-tert-butoxy-2-(CBZ-valinamido)-3-(4-phenoxyphenylsulfonyl)-propionamide, which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6]C(=N)N.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.N[C@H](C(O)=O)CCCNC(=N)N>[O-]S([O-])(=O)=O.[Mn+2].O>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH2:6]
Reactant: N=C(N)NCCCC(N)C(=O)O
Agent: [Mn+2]
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: O
Product: NCCC[C@H](N)C(=O)O
Reaction time: 22 h

Procedure:
100 ml of a 1.25 molar, racemic solution of DL-arginine are mixed with 5·10-4 mol/l MnSO4.H2O, 2.5·10-4 mol/1 ascorbic acid and 14.0 mg L-arginase (=10000 U/(l·mol L-Arg)). After 22 hours, the conversion was 50% of the original amount of arginine and a corresponding amount of ornithine had been produced.
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:6][C:5](=[CH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4]1.[CH3:18][O:19][C:20]1[CH:46]=[CH:45][C:23]([CH2:24][N:25]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=2[Cl:32])=[CH:22][CH:21]=1>O1CCOCC1.C1=CCCC=CCC1.[Rh]Cl>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[C:26]2[CH:27]=[C:28]([C:5]3([CH2:7][C:8]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:9])[CH2:4][O:3][CH2:6]3)[CH:29]=[CH:30][C:31]=2[Cl:32])=[CH:45][CH:46]=1
Reactant: O=C(C=C1COC1)OCc1ccccc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(B(O)O)ccc2Cl)cc1
Agent: Cl[Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: [K+]
Solvent: C1COCCO1
Solvent: C1=CCCC=CCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(C3(CC(=O)OCc4ccccc4)COC3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under argon and at room temperature, 1.6 ml (2.37 mmol) of a 1.5 M aqueous potassium hydroxide solution, 272 mg (1.82 mmol) of benzyl oxetan-3-ylideneacetate and 750 mg (1.82 mmol) of {3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}boronic acid were added successively to a solution of 45 mg (0.09 mmol) of (1Z,5Z)-cycloocta-1,5-diene/rhodium(I) chloride dimer in 25 ml of dioxane. The reaction solution was then stirred at room temperature for 4 h. After the reaction had gone to completion, the solution was concentrated to dryness and the residue was taken up in 25 ml of water and 25 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted three more times with ethyl acetate, and the combined organic phases were dried over magnesium sulphate and concentrated to dryness. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1→1:1). This gave 669 mg (1.17 mmol, 64% of theory) of the title compound.
Reaction SMILES: S(C)C.[CH2:4]([Mg]Br)[CH3:5].[B-](F)(F)(F)[O+](C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH:30]=[CH:29][C:28](=[O:31])[CH2:27][CH:26]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])(=[O:24])=[O:23])=[CH:18][CH:17]=1>C1COCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH:30]([CH2:4][CH3:5])[CH2:29][C:28](=[O:31])[CH2:27][CH:26]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])(=[O:23])=[O:24])=[CH:18][CH:17]=1
Reactant: CC[Mg]Br
Reactant: CCOC(=O)C1CC(=O)C=CN1S(=O)(=O)c1ccc(Cl)cc1
Agent: C[O+](C)[B-](F)(F)F
Solvent: CSC
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(=O)CC(CC)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 88.9 %

Procedure:
CuBr2.SMe2 (19.13 g, 93.1 mmol) was placed into a flame-dried flask along with THF (250 ml). The mixture was cooled to −78° C. and ethylmagnesium bromide (31 ml, 3.0 M in ether, 93.1 mmol) was added slowly. The reaction was stirred for 45 minutes under nitrogen. Boron trifluoride dimethyl etherate was added (11.7 ml, 93,1 mmol) and the mixture stirred for 5 minutes. Ethyl 1-(4-chlorophenylsulfonyl)-4-oxo-1,2,3,4-tetrahydropyridine-2-carboxylate (103; 8.0 g, 23.3 mmol) was added via syringe pump over a 2 hour period while maintaining −78° C. bath temperature. The reaction was stirred for 4 hours and quenched with a 1:1 solution of 2% NH4Cl/NH4OH. An equal amount of EtOAc and water was added and the mixture was filtered to remove solids. The layers were separated and the aqueous layer was extracted with two more portions of EtOAc. The organic layers were combined and dried over Na2SO4 and concentrated to yield a colorless oil (7.74 g). The material was purified by column chromatography using EtOAc/hexanes gradients to yield 5.84 g (67%) of a mixture of cis/trans (4:96) isomers.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH:25]([CH3:27])[CH3:26]>>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:10][C:8]([C:4]3[CH:3]=[C:2]([N:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][O:21][CH3:20])[N:7]=[CH:6][N:5]=3)=[O:9])=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Reactant: COCCNC(C)C
Product: COCCN(c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1)C(C)C

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1H-indazol-5-yl)-amide (Intermediate 16) and N-(2-methoxyethyl)isopropylamine (ABCR), the title compound was obtained as a yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23]1([CH2:29]Br)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[CH:23]1([CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=3[CH:16]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrCC1CCCCC1
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCC3CCCCC3)ccc2CCC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 78.7 %

Procedure:
To methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (400 mg, 1.83 mmol) dissolved in DMF (8 ml) were added potassium carbonate (507 mg, 3.67 mmol) and cyclohexylmethyl bromide (0.511 ml, 3.66 mmol), and the resulting mixture was stirred at room temperature for 23 hours and at 100° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue and the resulting mixture was extracted with ethyl acetate (×3). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 15 g, ethyl acetate/hexane=1/19). The objective fractions were concentrated under reduced pressure, hexane was added to the residue and an insoluble material was collected by filtration. The insoluble material was washed with hexane and was then dried under reduced pressure to obtain methyl 2-cyclohexylmethyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (452 mg, 1.44 mmol, 78%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:26])[CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:24][CH3:25])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:9].I[CH3:28]>CN(C=O)C.O>[CH3:26][N:4]([CH3:3])[CH2:5][CH2:6][CH2:7][C:8]([N:10]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:24][CH3:25])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:28])=[O:9]
Reactant: CI
Reactant: CCn1c2ccccc2c2cc(NC(=O)CCCN(C)C)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(N(C)C(=O)CCCN(C)C)ccc21
Reaction time: 5 h
Yield: 5.9 %

Procedure:
Sodium hydride (8 mg of a 60% suspension in mineral oil, 4 mg, 0.19 mmol, 1.2 equiv) was added to a solution of 4-dimethylamino-N-(9-ethyl-9H-carbazol-3-yl)-butyramide (50 mg, 0.15 mmol, 1 equiv) in DMF (0.3 mL). The resultant suspension was stirred at room temperature for 1 hour, and then iodomethane (0.012 mL, 27 mg, 0.19 mmol, 1.25 equiv) was added via syringe. After an additional 5 hours at room temperature, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water (1×10 mL) and brine (1×10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by rotary chromatography (CH2Cl2 grading to 2% ammonium hydroxide in 5% MeOH/CH2Cl2) to provide 4-dimethylamino-N-(9-ethyl-9H-carbazol-3-yl)-N-methyl-butyramide (3 mg, 5%) as a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][C@H:16]([OH:21])[CH2:17][C:18]#[C:19][CH3:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>COCCOC>[CH2:7]([O:14][CH2:15][C@H:16]([OH:21])[CH2:17]/[CH:18]=[CH:19]/[CH3:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC#CC[C@@H](O)COCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: C/C=C/C[C@@H](O)COCc1ccccc1
Temperature: 100 °C

Procedure:
Lithium aluminum hydride (93 g, 2.4 mol) was gradually added portion-wise to a 10-20° C. solution of C9 (167 g, 0.818 mol) in 1,2-dimethoxyethane (2.2 L), and the reaction was heated at 100° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, and was then quenched with ice followed by aqueous hydrochloric acid (2 M, 2 L) at 10-20° C. The resulting mixture was extracted with ethyl acetate (2 L), and the combined organic layers were dried over sodium sulfate and concentrated, affording the product as a pale brown oil. This material was used for the next step without further purification. Yield: 160 g, 0.78 mol, 95%. 1H NMR (400 MHz, CDCl3) δ 7.27-7.41 (m, 5H), 5.49-5.60 (m, 1H), 5.39-5.49 (m, 1H), 4.56 (s, 2H), 3.80-3.88 (m, 1H), 3.51 (dd, half of ABX pattern, J=9.5, 3.4 Hz, 1H), 3.39 (dd, half of ABX pattern, J=9.3, 1.9 Hz, 1H), 2.4 (br s, 1H), 2.16-2.24 (m, 2H), 1.66-1.70 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][NH2:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[OH:1][C:2]1[C:3]([C:12]([NH:14][N:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NNC(=O)c1cc2ccccc2cc1O
Reactant: O=Cc1ccccc1
Solvent: CO
Product: O=C(NN=Cc1ccccc1)c1cc2ccccc2cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A four neck flask (2 liters) equipped with a thermometer, a reflux condenser and a stirrer was charged with 101 g (0.5 mol) of 3-hydroxy-2-naphthohydrazide and 1.5 liter of methanol, and 63.7 g (0.6 mol) of benzaldehyde was dropwise added thereto in 30 minutes while stirring at room temperature. After heating under reflux for 5 hours, the reaction liquid was cooled down to 15° C. or lower, and crystal was filtered off. The crystal was washed with a small amount of methanol and then dried under reduced pressure, whereby the intended compound (slightly yellow crystal) was obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[NH2:17])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:2]=[CH2:3].[CH2:18](OC(OCC)OCC)C>FC(F)(F)C(O)=O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[NH:17][CH3:18])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc(N)c(OCC=C)c1
Reactant: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)c1ccc(NC)c(OCC=C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
Allyl 3-allyloxy-4-aminobenzoate (7 g, 30 mM) was dissolved in triethylorthoformate (70 ml), treated with trifluoroacetic acid (10 drops), and heated under reflux for 5 hours. Solvent was removed by evaporation, and the residual oil was dissolved in ethanol (70 ml), then treated with glacial acetic acid (8.59 ml, 150 mM) followed by sodium cyanoborohydride (9.43 g, 150 mM) in several portions. The mixture was then left to stir at ambient temperature under a blanket of argon for 18 hours. Solvent was removed, and the residue treated with water (50 ml) and extracted into diethyl ether. The combined extracts were washed with water and brine before being dried over MgSO4. After removal of the solvent, the residue was purified by chromatography over silica, eluting with a gradient of dichloromethane/ethyl acetate (100:0 to 95:5), to give allyl 3-allyloxy-4-methylaminobenzoate (3.08 g, 41%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([N:15]2[CH:19]=[N:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][C:23]3([CH3:29])[CH3:28])=[O:21])=[N:16]2)[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.[Cl:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](Cl)=[O:44]>CN(C=O)C>[Cl:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([N:25]1[CH2:26][CH2:27][N:22]([C:20]([C:17]2[N:18]=[CH:19][N:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=3)[N:16]=2)=[O:21])[C:23]([CH3:29])([CH3:28])[CH2:24]1)=[O:44]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC1(C)CNCCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CN(C(=O)c2cccc(Cl)c2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 43 mg (0.10 mmol) [1-(3-chloro-phenyl)-1H-[1,2,4]triazol-3-yl]-(2,2-dimethyl-piperazin-1-yl)-methanone trifluoroacetate and 43 μL (0.25 mmol) DIPEA in 1.0 mL DMF was added 13 μL (0.10 mmol) 3-chloro-benzoyl chloride. The reaction mixture was stirred at RT for 30 min and purified by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH3:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH2:31])[S:30][C:26]=2[CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:31][C:29]3[S:30][C:26]4[CH:25]=[C:24]([CH3:23])[CH:33]=[CH:32][C:27]=4[N:28]=3)=[O:19])=[CH:20][CH:21]=2)(=[O:11])=[O:12])=[CH:5][CH:4]=1
Reactant: Cc1ccc2nc(N)sc2c1
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3nc4ccc(C)cc4s3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with 6-methylbenzo[d]thiazol-2-amine (43 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamide as an off white solid. Yield: 57 mg (47%). 1H-NMR: 8.28 (d, J=8.5 Hz, 2H), 7.83 (s, 1H), 7.74-7.63 (m, 3H), 7.30 (dd, J=8.0, 1.5 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.90 (d, J=8.5 Hz, 2H), 3.75 (s, 3H), 3.16 (s, 3H), 2.44 (s, 3H).