Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Cl[C:20]1[N:25]=[N:24][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:20]1[N:25]=[N:24][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:33])([CH3:34])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:22][CH:21]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1ccc(O)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(O)cc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 100 °C
Yield: 82.8 %

Procedure:
To a microwave vial was added 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (400 mg, 1.60 mmol), 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 452 mg, 1.60 mmol), potassium phosphate (1.4 g, 6.40 mmol), Pd2(dba)3 (146 mg, 0.16 mmol), and SPhos (65.7 mg, 0.16 mmol), followed by addition of 1,4-dioxane (4 mL)/H2O (0.8 mL). The vial was purged with N2 for 5 minutes and the reaction mixture was heated at 100° C. in the microwave for 2 h. The reaction mixture was concentrated in vacuo. The crude material was adjusted to pH 3 using 12 M HCl aqueous solution and loaded onto an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford 4-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (491 mg) MS [M+H+]=371.2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1.[O:18]1[CH2:21][CH:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:17][N:14]1[C:15](=[O:16])[N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[N:25]2[CH2:26][CH2:27][N:22]([CH:20]3[CH2:21][O:18][CH2:19]3)[CH2:23][CH2:24]2)[N:12]=[N:13]1
Reactant: C1CN(C2COC2)CCN1
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])ccc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnn(-c2cc([N+](=O)[O-])ccc2N2CCN(C3COC3)CC2)c1=O
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 1-(2-fluoro-5-nitrophenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (1.1 g, 1.0 eq, 4.5 mmol) (see, e.g., WO 2011/068898), 1-(oxetan-3-yl)piperazine (0.64 g, 1.0 eq, 4.5 mmol) was dissolved in annhydrous DMF (100 mL) and stirred at room temperature. K2CO3 (1.9 g, 3.0 eq, 13.5 mmol) was added to the above solution and the heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL) and partitioned with H2O (50 mL). The layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to leave a crude solid. Purification of the crude solid by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 1:9 to 1:1) as eluent gave the product in 50% yield.
Reaction SMILES: CC(=CC)C.Cl([O-])=O.[Na+].[CH2:10]([O:17][C:18]1[C:25]([CH3:26])=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[CH3:27])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])(O)(O)=[O:29].[K+]>O.CC(O)(C)C>[CH2:10]([O:17][C:18]1[C:25]([CH3:26])=[CH:24][C:21]([C:22]([OH:29])=[O:23])=[CH:20][C:19]=1[CH3:27])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=P([O-])(O)O
Reactant: Cc1cc(C=O)cc(C)c1OCc1ccccc1
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Methyl-2-butene (3.31 mL, 31.2 mmol) and sodium chlorite (282 mg, 3.12 mmol) were sequentially added to a mixture of 4-(benzyloxy)-3,5-dimethyl-benzaldehyde (455 μl, 2.081 mmol) and potassium dihydrogen phosphate (425 mg, 3.12 mmol) in 1:1 water/t-BuOH (8.0 mL), and the resulting mixture was stirred at 25° C. for 4 h. Additional potassium dihydrogen phosphate (991 mg, 7.28 mmol) and sodium chlorite (659 mg, 7.28 mmol) were then sequentially added, and the resulting mixture was stirred at 25° C. for 15 h. The reaction mixture was subsequently partitioned between EtOAc (120 mL) and 0.02N aq. HCl (50 mL). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc/Hexanes) gave 4-(benzyloxy)-3,5-dimethylbenzoic acid as a white solid. MS (ESI) m/z: Calculated: 256.1; Observed: 257.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)CC)C.[CH3:17][CH:18]([CH3:22])[C:19](Cl)=[O:20]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:19](=[O:20])[CH:18]([CH3:22])[CH3:17])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Into a solution of 1.0 g (5.40 mmol) of 3-bromo-4-methylaniline and 0.91 mL (6.50 mmol) of triethylamine in 10 mL THF at 0° C. was slowly added 0.68 mL (6.50 mmol) of 2-methylpropanoyl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 1.37 g (5.35 mmol, 99%) of the desired product: ESMS m/e: 255.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16](=O)[C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3F)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[NH2:30][NH2:31].CN1CCCC1=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]3[C:17]4[C:18](=[CH:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=4)[NH:31][N:30]=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2cc(C(F)(F)F)ccc2F)[nH]1
Reactant: NN
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ccc(C(F)(F)F)cc23)[nH]1
Temperature: 120 °C

Procedure:
A mixture of 5-(2-fluoro-5-trifluoromethyl-benzoyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide, hydrazine hydrate, 1-methyl-pyrrolin-2-one and toluene was heated at 120° C. for 2 hours. The reaction was concentrated, mixed with water and filtered. The solid was washed to give the titled compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>ClCCl>[O:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][C:4]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:5][CH:6]=2)[N:8]=[CH:9]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(-c2cocn2)cc1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(-c2cocn2)cc1
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 23 %

Procedure:
4-Phenyl-oxazole (Intermediate 25, 550 mg, 3.79 mmol) was dissolved in a minimum of dichloromethane and was added slowly to chlorosulfonic acid (2.537 mL, 37.9 mmol) at 0° C. The reaction mixture was stirred for 20 min 0-5° C. then warmed to room temperature then to 45° C. and stirred for 2 h. The reaction mixture was cooled to room temperature and cautiously poured on ice water. The aqueous layer was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to crude 4-oxazol-4-yl-benzenesulfonyl chloride. The starting material and product have Rf values in 20% EtOAc/heptane of Rf=0.47 and Rf=0.23, respectively. The crude product was purifed by chromatography on a Biotage 25M column eluting ethyl acetate/heptane to yield 4-oxazol-4-yl-benzenesulfonyl chloride (212 mg, 0.870 mmol). MH+=244.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](F)=[C:10]3[O:14][C:13]([CH:15]4[CH2:17][CH2:16]4)=[N:12][C:11]3=[C:18]([C:21]#[N:22])[C:19]=2[CH3:20])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:38])[C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([N:35]3[CH2:36][CH2:37][C@H:33]([N:32]([CH3:38])[CH3:31])[CH2:34]3)=[C:10]3[O:14][C:13]([CH:15]4[CH2:17][CH2:16]4)=[N:12][C:11]3=[C:18]([C:21]#[N:22])[C:19]=2[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2cccc(N)c2)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccc(N)c2)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 90 °C
Reaction time: 19 h

Procedure:
6-(3-Aminophenyl)-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-178) (200 mg, 0.65 mmol) was dissolved in dimethyl sulfoxide (4 ml), then at room temperature, triethylamine (136 μl, 0.98 mmol) and (3S)-3-(dimethylamino)pyrrolidine (124 μl, 0.98 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 19 hours, then cooled to room temperature. This was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution.
Reaction SMILES: O.[OH-].[Li+].[OH:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:53][CH2:54][CH3:55])[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:10]=1[C:11]([O:13]CC)=[O:12]>O.O1CCOCC1>[OH:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:53][CH2:54][CH3:55])[N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=2)[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CCCc1nc(CO)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 0.66 g of lithium hydroxide monohydrate in 20 ml of water was added to a solution of 1.22 g of ethyl 4-hydroxymethyl-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 35(b)] in 5 ml of dioxane, and the resulting mixture was stirred at 80° C. for 5 hours. At the end of this time, the reaction mixture was freed from dioxane by distillation under reduced pressure, and the aqueous residue was mixed with ice and with ethyl acetate: 15.7 ml of 1N aqueous hydrochloric acid were then added. The title compound precipitated, and was collected by filtration and washed with water. The ethyl acetate layer was then separated from the filtrate and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was washed with diethyl ether, to give more of the title compound as a powder. The two portions of the title compound were combined and together weighed 0.98 g, and this was immediately used in the subsequent esterification reaction without further purification or characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:37][C:38]1([C:44]2[CH:45]=[C:46]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:47]=[CH:48][CH:49]=2)[CH:43]2[CH:39]1[CH2:40][NH:41][CH2:42]2.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:41]2[CH2:42][CH:43]3[CH:39]([C:38]3([C:44]3[CH:45]=[C:46]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:47]=[CH:48][CH:49]=3)[CH3:37])[CH2:40]2)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: O=C(O)CCc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3ccc(Cl)c(Cl)c3)CC21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.8 %

Procedure:
To a solution of 3(3,4-dichlorophenyl)propanoic acid (35 mg, 0.16 mmol) in N,N-dimethylfonnarnide (4 ml) was added 1-hydroxybenzotriazole monohydrate (26 mg, 0.17 mmol) and 1-(3dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol). After stirring at room temperature for 5 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl)methanesulfonamide (Peparation 53, 52 mg, 0.17 mmol) and triethylarnine (33 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 72 h before concentrating in vacuo. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml) and saturated brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The residue was purified by chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 amnionia (300:8:1) to afford the title compound as a white foam (38 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10](C)[CH2:11][CH2:12][C:6]=2[C:5]([C:14]#N)=[CH:4][CH:3]=1.[OH2:16].[OH2:17].O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C(O)C.O.CO.C(=O)=O>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[C:5]([C:14]([OH:17])=[O:16])=[CH:4][CH:3]=1
Reactant: O
Reactant: CN1CCc2c(Cl)ccc(C#N)c2CC1
Agent: O=C=O
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: O=C(O)c1ccc(Cl)c2c1CCNCC2

Procedure:
A solution of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carbonitrile, prepared as in Example 12, (1.5 g, 6.8 mmol) in ethanol (25 ml) was treated with barium hydroxide octahydrate (2.6 g, 8.1 mmol) and water (25 ml) and heated to reflux for 94 hours. The mixture was cooled, diluted with water, ethanol and methanol, saturated with carbon dioxide and filtered. The filtrate was treated with Dry Ice to pH 5-6 and filtered. The filtrate was concentrated and extracted with ethyl acetate-ethyl ether and ethyl ether. The aqueous phase was treated with toluene, concentrated and the residue triturated with ethyl ether to give 9-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine-6-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1([C:8]2([C:23]#[N:24])[C:18]3[CH:17]=[C:16]4[C:12]([CH2:13][CH2:14][N:15]4[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:11][C:10]=3[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>[Ni].CO>[NH2:24][CH2:23][C:8]1([C:2]2([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[C:18]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][N:15]3[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:11][C:10]=2[CH2:9]1
Reactant: CS(=O)(=O)N1CCc2cc3c(cc21)C(C#N)(C1(O)CCCCC1)C3
Agent: [Ni]
Solvent: CO
Product: CS(=O)(=O)N1CCc2cc3c(cc21)C(CN)(C1(O)CCCCC1)C3
Reaction time: 24 h

Procedure:
5.5 g of the product obtained in Step 2 are dissolved in 250 ml of a 3.6N solution of ammoniacal methanol containing 2 mg of Raney nickel. The reaction mixture is hydrogenated for 24 hours at 60° C. under a pressure of 30 bar. After filtration and removal of the solvent by evaporation, the residue is taken up in dichloromethane, washed with water until neutral, dried and concentrated to isolate the expected product.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br.Br[CH2:16][C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18]>C1COCC1.[Cl-].[Na+].O>[C:1]([CH:9]([CH2:16][C:17](=[O:18])[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(CC(=O)c1cccnc1)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To 3.0 g (21 mmol) of benzoyl acetonitrile in 50 mL of THF, cooled in a wet ice bath, was added 0.84 g (21 mmol) of sodium hydride (60% oil dispersion). After 1 h, added 2.8 g (10 mmol) of 3-bromoacetylpyridine hydrobromide. After 3 h, poured the reaction mixture into brine, extracted with ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure and purified by flash chromatography (gradient elution: 40-80% ethyl acetate/hexane) to give 2.6 g (93%) of 2-benzoyl-4-oxo-4-pyridin-3-yl-butyronitrile (MH+=265).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)[CH3:2].[C:21]([BH3-])#N.[Na+].C=O.C(O)(=O)C>CO>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=1)[CH3:21])[CH3:20]
Reactant: [BH3-]C#N
Reactant: CCOC(CCCNCc1ccc(C#N)cc1)OCC
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(CCCN(C)Cc1ccc(C#N)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
The compound (1.16 g) obtained in Example 44-1 was dissolved in methanol (34.8 ml) and added with sodium cyanoborohydride (1.21 g) and a 36% formaldehyde aqueous solution (0.648 ml). The solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.22 g) as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][CH2:17][S:16](=[O:21])(=[O:20])[CH2:15]1.[O:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:20]=[S:16]1(=[O:21])[CH2:17][CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:24]4[CH:25]=[CH:26][O:22][CH:23]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Reactant: OB(O)c1ccoc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccoc2)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 45.5 %

Procedure:
5-Bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-indole-7-carboxamide (0.050 g, 0.135 mmol) and 3-furanylboronic acid (0.020 g, 0.175 mmol, 1.3 eq) was dissolved in a 6:1 solution of 1,4 dioxane (3 mL)/water (0.5 mL) in a 20 mL microwave reaction vessel. Potassium carbonate (0.093 g, 0.673 mmol, 5 eq) was added and the solution was degassed with Nitrogen. PdCl2(dppf)2 (0.017 g, 0.023 mmol) was added and the reaction was heated in a microwave at 100° C. for 20 min. The solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/Water with 0.1% NH4OH. The desired fractions were concentrated, giving 0.022 g (45%) of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH2:10].[N:11]1([C:16](N2C=CN=C2)=[S:17])[CH:15]=[CH:14][N:13]=[CH:12]1>C(#N)C>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH:10][C:16]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[S:17]
Reactant: Nc1nc2c(s1)CCCC2
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: S=C(Nc1nc2c(s1)CCCC2)n1ccnc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
To 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (0.5 g, 3.24 mmol) in acetonitrile (20 mL) was added di(1H-imidazol-1-yl)methanethione (0.58 g, 3.24 mmol). The reaction was stirred at 50° C. for 4 hours. The reaction was cooled and concentrated to yield crude product. The crude material was purified via flash chromatography (50-100% ethyl acetate-hexane) to yield N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (0.60 g, 2.27 mmol, 70.0% yield) as a white powder.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl>[Br:18][CH2:19][C:20]([N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:21]
Reactant: c1ccc(NC2CC2)cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)N(c1ccccc1)C1CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
To a stirred solution of 908 mg (6.83 mmol) Cyclopropyl-phenyl-amine (Kang, Sung, Kim, J. Chem. Soc., Chem. Commun., 1987, 897-898) and 690 mg (6.83 mmol, 1 equiv) Et3N in 10 mL DCM is added 1.38 g (6.83 mmol, 1 equiv) Bromoacetyl bromide in 4 mL DCM dropwise over 15 minutes at 0° C. The reaction mixture is stirred 3 h at 0° C., diluted with 30 mL DCM, washed with 1N HCl (30 mL), dried (MgSO4), and concentrated in vacuo. The crude product is purified by flash chromatography on 30 g silica gel eluted successively with EtOAc/Hexanes (1:9, 100 mL), (3:17, 300 mL). Appropriate fractions were combined and concentrated in vacuo to give 948 mg (3.73 mmol) of 2-Bromo-N-cyclopropyl-N-phenyl-acetamide as an amber oil: 1H NMR (CDCl3, 300 MHz) δ7.39 (m, 3H), 7.15 (m, 2H), 3.62 (s, br, 2H), 3.24 (m, 1H), 0.83 (m, 2H), 0.52 (m, 2H); TLC Rf =0.18 (EtOAc/Hexanes, 3:17).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[C:17](Cl)(=O)[C:18](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:17][CH2:18][C:9](=[O:11])[CH2:8]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (3-bromophenyl)acetic acid (˜10 g, 50 mmol) in 200 mL of DCM was added DMF (183 mg, 2.5 mmol) and then oxalyl dichloride (6.3 g, 50 mmol) was added dropwise over 30 min. The resulting mixture was stirred at room temperature for 6 hr and then concentrated under reduced pressure. A mixture of prepared acid chloride in 200 mL of DCM was added AlCl3 (13.2 g, 100 mmol) portion-wise at 0° C. After the mixture was stirred at 0° C. for 30 min, the solution was bubbled with ethene gas for 2 h and the resulting mixture was warmed to room temperature and stirred overnight. Then 300 mL of water was added dropwise over 30 min with stirring. Then separated the organic layer and extracted the aqueous layer with 200 mL of DCM. The combined organic layers were washed with 1N HCl (200 mL), saturated NaHCO3 (200 mL) and brine (200 mL) and then dried over Na2SO4. Then the organic layer was concentrated under reduced pressure to remove the solvent. The crude product was purified via chromatography (EtOAc/petrol ether 1:20 to 1:5) to give the desired 7-bromo-3,4-dihydronaphthalen-2(1H)-one along with the isomeric side product 5-bromo-3,4-dihydronaphthalen-2(1/1)-one. 1H-NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 3.01 (t, J=6.8 Hz, 2H), 2.54 (t, J=6.8 Hz, 2H); MS m/e 225 (M+1)+.