Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH2:20][OH:21].C([O:25][B:26](OC(C)C)OC(C)C)(C)C.Cl>O1CCCC1>[O:13]([C:10]1[CH:11]=[CH:12][C:7]2[B:26]([OH:25])[O:21][CH2:20][C:8]=2[CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: OCc1cc(Oc2ccccc2)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB1OCc2cc(Oc3ccccc3)ccc21
Temperature: -78 °C
Yield: 73.4 %

Procedure:
A solution of n-butyl lithium in n-hexanes (2.24 M, 8.6 mL, 0.019 mol) was slowly added to a solution of (2-bromo-5-phenoxyphenyl)methanol (2.21 g, 0.0079 mol) in anhydrous tetrahydrofuran (50 mL) at −78° C. under an atmosphere of nitrogen. The reaction was stirred for thirty minutes at −78° C., then stirred for twenty minutes at −25° C. The reaction was cooled to −50° C. and triisopropylborate (4.075 g, 0.0216 mol) was slowly added. The reaction was warmed to room temperature and was stirred for one hour. An 1 N aqueous solution of hydrochloric acid (20 mL) was added to achieve pH 5, then the reaction was stirred at room temperature for one hour. The reaction mixture was extracted with ethyl ether (3×40 mL). The combined organic extracts were washed with water (60 mL) and brine (60 mL) and dried over sodium sulfate. The solvents were evaporated under the reduced pressure to give a residue, and the residue was purified by flash column chromatography on silica using ethyl acetate/n-heptane (1:5) followed by ethyl acetate/n-heptane (1:4) as mobile phase to yield 5-phenoxy-1,3-dihydro-2,1-benzoxaborol-1-ol (1.3 g, 0.0058 mol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.C(O)(C)(C)C.N.[Li]>C1COCC1.C(O)C>[NH2:11][C@H:9]([C:6]1[CH2:7][CH:8]=[C:3]([O:2][CH3:1])[CH2:4][CH:5]=1)[CH3:10]
Reactant: COc1ccc([C@H](C)N)cc1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(C)(C)O
Product: COC1=CCC([C@H](C)N)=CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mechanically stirred solution of the above amine (30) (24 g) in dry THF (200 mL) and t-butanol (12 g) was condensed via a cold finger ammonia (800 mL). Lithium wire (3.1 g) was next added piece-wise over 15 min and the now dark blue reaction stirred for 1 h. Ethanol was then dripped into the reaction very slowly over 1 h until the reaction turned blue. The reaction was then allowed to warm to room temperature, with external warming, to allow the ammonia to evaporate. The remaining mixture was taken up in ethyl ether, washed with H2O, dried over Na2SO4 and evaporated to yield the titled product (31): GC RT 5.63 min (HP 530 mμ×20 m methylsilicone colunm, He carrier flow rate 20 mL/min, 100° C. isothermal).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][CH:23]([OH:29])[CH:24](OC)[O:25]C)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)CC>[CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:29])[CH2:24][OH:25])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(O)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCCO
Product: O=C(CO)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 45 %

Procedure:
To a solution of N-benzyl-N-(3-hydroxy-4,4-dimethoxybutyl)-2-nitrobenzenesulfonamide (0.212 g, 0.5 mmol) in 1-Propanol (1.5 ml) was added 37% hydrochloric acid (0.104 ml, 1.250 mmol) and the mixture was stirred at 90° C. in a weaton vial. Cooled, evaporated to dryness under vacuum, applied on a column in petroleum ether-ethyl acetate mixture 1:1, eluted with the same system. Fractions collected to give N-benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide (0.085 g, 0.225 mmol, 44.9% yield), yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Br:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1I.C(=O)([O-])[O-].[Cs+].[Cs+]>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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[Br:23])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Reactant: Clc1ccc(I)c(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.2 %

Procedure:
A RBF was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (8.25 g, 26.3 mmol, made via Method 42, Steps 1-2), 2-bromo-4-chloro-1-iodobenzene (10.02 g, 31.6 mmol), Xantphos (0.762 g, 1.316 mmol), Pd2(dba)3 (0.603 g, 0.658 mmol), and cesium carbonate (21.44 g, 65.8 mmol) were added. A reflux condenser was attached and the flask was lowered into a 110° C. heating bath for 1 h. The mixture was cooled to room temperature then filtered through celite with the aid of toluene. The filtrate was concentrated. The residue was taken up in 2-PrOH and concentrated to give a yellow solid with some tan chunks. The mixture was taken up in 2-PrOH and the resulting slurry was heated to boiling for 5 min to give a brown solution (after breaking up some solid with a spatula). The resulting solution was allowed to cool to RT while being stirred. The mixture became a thick slurry that was diluted with 2-PrOH and filtered. The collected solid was washed with 2-PrOH (3×), then dried under a stream of N2 (g) to give (E)-ethyl 3-(5-(benzylthio)-2-((2-bromo-4-chlorophenyl)amino)phenyl)acrylate (10.473 g, 20.83 mmol, 79% yield) as a bright-yellow solid. 1 H NMR (400 MHz, DMSO-d6)□=7.76-7.61 (m, 4 H), 7.38-7.27 (m, 5 H), 7.27-7.20 (m, 2 H), 6.88 (d, J=8.4 Hz, 1 H), 6.62-6.52 (m, 2 H), 4.27 (s, 2 H), 4.14 (q, J=7.1 Hz, 2 H), 1.22 (t, J=7.1 Hz, 3 H). m/z (ESI) 502.0 (M+H)+.
Reaction SMILES: C(#N)C.[I-].[Na+].C[Si](Cl)(C)C.[O:11]1CCO[CH:12]1[C:16]1[CH:17]=[C:18]([CH:22]([C:24]2[S:25][C:26]([CH3:29])=[CH:27][CH:28]=2)O)[CH:19]=[CH:20][CH:21]=1>O>[CH3:29][C:26]1[S:25][C:24]([CH2:22][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[CH:12]=[O:11])=[CH:28][CH:27]=1
Reactant: Cc1ccc(C(O)c2cccc(C3OCCO3)c2)s1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(Cc2cccc(C=O)c2)s1
Temperature: -20 °C
Yield: 41.8 %

Procedure:
To a solution of acetonitrile (20 mL) and sodium iodide (2.9 g) was added trimethylsilyl chloride (2.1 g) at room temperature under stirring. The reaction solution thus obtained was cooled to −20° C., and (3-[1,3]dioxolan-2-yl-phenyl)-(5-methyl-thiophen-2-yl)-methanol (1.1 g) described in Manufacturing Example 52-1 and acetonitrile (5 mL) were added thereto under stirring. The reaction solution was returned to room temperature and stirred for 10 minutes. Water was added to the reaction solution, which was then extracted with ethyl acetate. The solvent was evaporated from the organic layer under a reduced pressure, and the residue was purified by silica gel chromatography (heptane:ethyl acetate=2:1) to obtain the titled compound (360 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:26][CH2:25]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-methylpiperazine (1.2 equiv) to give 159 (17.7 mg, M+1 396.0)
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]3[C:16]([N:17]=2)=[C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:14]=[C:13]([C:24]2[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=2)[N:12]=3)[CH2:3]1.[O:36]1CCC[CH2:37]1.CN(CCS(O)(=O)=O)C>C(Cl)Cl>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([N:4]4[CH2:3][C@@H:2]([CH3:1])[N:7]([CH:37]=[O:36])[C@@H:6]([CH3:8])[CH2:5]4)[N:10]3[CH2:31][C:32]([F:35])([F:34])[F:33])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)=[CH:25][N:26]=1
Reactant: C1CCOC1
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@H](C)N1
Agent: CN(C)CCS(=O)(=O)O
Solvent: ClCCl
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@H](C)N1C=O
Reaction time: 24 h
Yield: 91 %

Procedure:
5-[8-(cis-3,5-Dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (101.7 mg, 0.21 mmol) were added to a tetrahydrofuran solution (5.0 ml) of 1H-benzotriazole-1-carboxyaldehyde (33.8 mg, 0.21 mmol) at room temperature and the resulting mixture was stirred for 1 day. 1H-Benzotriazole-1-carboxyaldehyde (5.1 mg, 0.03 mmol) was added, the resulting mixture was further stirred for 1 day, and then the reaction mixture was poured into methylene chloride and washed with a 2 N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (98.0 mg, 91%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([Cl:17])[CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: O=C(O)c1ccc(-c2cc(Cl)cc(Cl)c2)o1

Procedure:
5-Bromo-2-furoic acid (1 g, 4.8 mmol) was coupled to 3,5-dichloro-phenylboronic acid (833 g, 4.4 mmol) acid using Method F to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][CH:10]([CH:17](C(O)=O)[C:18]([OH:20])=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1>CC(C)=O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:24])[CH2:9][CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:17][C:18]([OH:20])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(CC(c1ccccc1)C(C(=O)O)C(=O)O)c1ccc(Cl)cc1
Solvent: CC(C)=O
Solvent: CO
Product: O=C(O)CC(CC(=O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
Neat 2-[3-(4-chlorophenyl)-3-oxo-1-phenylpropyl]malonic acid (0.3 g) was heated to 160° C. with stirring for 1 h. After cooling to rt the crude was dissolved in acetone/methanol. Precipitation of product was effected by addition of dichloromethane. The precipitate was collected to afford 5-(4-chlorophenyl)-5-oxo-3-phenylpentanoic acid (0.19 g) as colourless crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][CH2:10]/[C:11](/[CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[O:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[O:50][NH2:51].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][CH2:10]/[C:11](/[CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:51][O:50][CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49][O:44]2)=[O:18])[CH2:3][CH2:2]1
Reactant: O=C(O)CCCC/C=C(/CNCCN1CCOCC1)COc1cccc2ccccc12
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Product: O=C(CCCC/C=C(/CNCCN1CCOCC1)COc1cccc2ccccc12)NOC1CCCCO1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
(Z)-8-(2-morpholinoethylamino)-7-((naphthalen-1-yloxy)methyl)oct-6-enoic acid (268 mg, 0.63 mmol) obtained in Example (3-1-2) was dissolved in N,N′-dimethylformal (3.2 ml) in a 25 ml vessel, and to the resulting mixture, N-hydroxy-6-trifluorobenzotriazole (FOBt; 140 mg, 0.69 mmol, 1.1 eq.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl; 157 mg, 0.82 mmol, 1.3 eq.), tetrahydro-2H-pyran-2-yloxyamine (THPONH2; 111 mg, 0.95 mmol, 1.5 eq.), and triethylamine (0.18 ml, 1.26 mmol, 1.5 eq.) were added at 0° C., while stirring. The resulting mixture was heated to room temperature and stirred for 12 hrs. After the completion of reaction, 10% aqueous potassium carbonate solution was added to the reaction mixture, and then the resultant was extracted with ethyl acetate. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 142 mg of the title compound as dark yellow foam (yield 43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]2=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO>O=[Pt]=O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CCC1CC2=Cc1ccc(Cl)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CCC1CC2Cc1ccc(Cl)c(Cl)c1
Yield: 88.4 %

Procedure:
5-(3,4-Dichloro-benzylidene)-2-aza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (0.45 g) was stirred under 1 atm of H2 in 20 ml of 1:1 of EtOH:EtOAc in the presence of PtO2 for 20 min. The reaction mixture was filtered through celite and concentrated to give 0.4 g of 5-(3,4-dichloro-benzyl)-2-aza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (M+: 369).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([C:22]#[N:23])=[C:18]([CH3:24])[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([C:22]#[N:23])=[C:18]([CH3:24])[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1C#N
Solvent: CN(C)C=O
Product: Cc1c(C#N)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[5-cyano-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[5-cyano-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 171°-173° C.,
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5].[N:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH2:25][C:26](O)=[O:27])[NH:24][CH:23]=[CH:22][S:21]2)=[CH:16][CH:15]=1>>[C:4]([C:3]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:2]=1[NH:1][C:26](=[O:27])[CH2:25][C:20]1([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[NH:24][CH:23]=[CH:22][S:21]1)#[N:5]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: O=C(O)CC1(c2ccncc2)NC=CS1
Product: COc1cc(C#N)c(NC(=O)CC2(c3ccncc3)NC=CS2)cc1OC

Procedure:
This compound was prepared according to the method described in Example 1c by employing 2-amino-4,5-dimethoxybenzonitrile (Aldrich) and 2-(4-pyridyl)-thiazole acetic acid (Example 1, Step b) . Mp: 165-167° C. MS m/z: 381.1 (M+1). Calc'd for C19H16N4O3S: 380.09.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1.[H][H]>C(O)C.[Ni]>[CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1N(c1ccccc1)C(=O)C2
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(N)cc1N(c1ccccc1)C(=O)C2

Procedure:
33.5 g of 1-methyl-8-nitro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 100 ml of ethanol containing 2.0 g of Raney nickel is hydrogenated at room temperature at an initial hydrogen pressure of 50 p.s.i. The reaction is stopped when 0.3 moles of hydrogen has been absorbed; the suspension is filtered and the filtrate evaporated to give the title compound.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.[C:28]1([N:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)N)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:25][CH:23]([CH3:24])[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:6]3[C:29]4[C:28](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:2]=3)[CH2:10][CH2:11]2)[CH:16]=1)=[O:26]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC3OCCO3)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCc3cn(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[3-(1,3-dioxolan-2-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 466.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:17]/[OH:18])/[C:8]([O:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:9])[N:6]=1.Br[CH:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:17]/[O:18][CH:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:28])/[C:8]([O:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:14])=[O:15])=[O:9])[N:6]=1
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)CCOC(=O)/C(=N\O)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(O/N=C(\C(=O)OCCS(C)(=O)=O)c1csc(N)n1)C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 75.4 %

Procedure:
In 100 ml of acetone was suspended 5 g (0.017 mole) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate and 5.33 g (0.0255 mole) of t-butyl 2-bromopropionate was added. After a serial addition of 0.3 ml of water and 9.4 g of anhydrous potassium carbonate, the mixture was stirred at 40° C. for about 2.5 hours. After completion of the reaction, the insoluble matter was filtered off. To the filtrate was added 100 ml of water and the mixture was extracted with 150 ml of ethyl acetate. The organic layer was washed with 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated to dryness under reduced pressure. The concentrate was crystallized from ethyl acetate-isopropyl ether (1:5, v/v). After cooling to 0° C. or below, the crystalline precipitate was collected by filtration and dried under reduced pressrue to give 5.4 g (yield, 75.4%) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxyimino)acetate as white crystals.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1>CC#N>[Br:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:2][CH3:1])=[CH:6][CH:5]=1
Reactant: CN
Reactant: BrCc1ccc(Br)nc1
Solvent: CC#N
Product: CNCc1ccc(Br)nc1

Procedure:
To a mixture of 12.3 g of 40% aqueous methylamine solution and 40 ml of CH3CN was added 8.0 g of crude (6-bromo-3-pyridyl)methyl bromide with stirring. The mixture was further stirred at room temperature for 30 minutes. The reaction mixture thus obtained was concentrated and the residue was diluted with toluene and subjected to azeotropic distillation to remove the water. Then, the soluble fraction was extracted with Et2O. The Et2O layer was dried over MgSO4 and concentrated to recover 4.4 g of the title compound as a yellow oil.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1.C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1.O>[N:4]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)=[C:1]=[S:3]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: S=C=S
Agent: Cl
Agent: II
Agent: O=S([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(N=C=S)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 2-(4-aminophenyl)acetic acid (0.23 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 24 hours. To the obtained reaction mixture, a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) was dropwise added over a period of 8 minutes at 0° C., followed by stirring at 0° C. for further 1.5 hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and mixed. Then, ethyl acetate (6 mL) was added, and the organic layer was separated, and the aqueous layer was extracted once with a solvent mixture of ethyl acetate (3 mL) and tetrahydrofuran (1 mL). The organic layers were combined and concentrated under reduced pressure to dryness. To the obtained residue, water (8.0 mL) and saturated sodium hydrogencarbonate aqueous solution (2.0 mL) were added and thoroughly mixed. The insoluble matter was filtered off, and to the filtrate, 1M hydrochloric acid (3.0 mL) was added. The precipitated solid was collected by filtration to obtain 2-(4-isothiocyanatophenyl)acetic acid as a colorless solid (0.22 g, yield: 75%, HPLC purity: 95%, HPLC retention time: 3.4 min). LC-MS ES-192 (retention time: 20.5 min, condition 3).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:10][C:11]([F:16])([F:15])[C:12](O)=O>>[F:10][C:11]([F:16])([F:15])[CH:12]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][NH:9]1
Reactant: NCCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Product: FC(F)(F)C1NCCc2ccccc21

Procedure:
In accordance with the same procedures as in Preparation 1-1, except that 25 ml of phenethylamine(0.2M) and 30 ml of anhydrous trifluoroacetic acid(0.21M) were used as starting materials, 5.4 g of the title compound was prepared.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:18]=[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])[C:14]([C:15]#[N:16])=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[S:23]=S.[NH4+]>CO>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:12]=[CH:13][C:14]([C:15](=[S:23])[NH2:16])=[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])[CH:18]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: S=S
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C#N
Agent: [NH4+]
Solvent: CO
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C(N)=S
Temperature: 60 °C

Procedure:
To a stirred solution of 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinonitrile (19) (30 mg, 0.09 mmol) in MeOH (2 mL), ammonium thiosulfide (5 mL) was added. The reaction mixture was heated at 60° C. in a pressure tube overnight. The reaction mixture was then evaporated to remove excess of solvent. The crude material was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent to afford 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridine-3-carbothioamide.