Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([N:12]([CH3:14])[CH3:13])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]([N:12]([CH3:13])[CH3:14])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH3:11])=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CCC(C(=O)c1ccc(F)cc1)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(F)cc1)N(C)C

Procedure:
100 g (0.48 mol) of 1-(4-fluorophenyl)-2-dimethylamino-butan-1-one (crude product from A) are dissolved in 330 ml of acetonitrile. 98.1 g (0.57 mol) of benzyl bromide are slowly added dropwise, with stirring. After the mixture has been stirred at room temperature for 12 hours, the solvent is distilled off in vacuo. The residue is dissolved in 500 ml of water and the solution is heated to 55°-60°. 113 g of a 34% NaOH solution (0.96 mol) are added dropwise at this temperature and the mixture is subsequently stirred for 30 minutes.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.CCN(CC)CC.Br[CH2:44][C:45]([NH2:47])=[O:46]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:45]([CH2:44][N:23]1[CH2:22][CH2:21][CH:20]([C:18]2[CH:17]=[CH:16][C:15]([NH:26][C:27]([C:29]3[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=3)=[O:28])=[C:14]([C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=3)[CH:19]=2)[CH2:25][CH2:24]1)(=[O:46])[NH2:47]
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: NC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(CC(N)=O)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.8 %

Procedure:
A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (50 mg, 0.10 mmol) (as prepared in Example 14, step (b)), NEt3 (32 μL, 0.23 mmol), 2-bromoacetamide (16 mg, 0.12 mmol), and 0.5 mL of DCM and stirred for 4 h at 25° C. The reaction was concentrated and the title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA/H2O over 12 min to give 42 mg (75%) of a white solid. 1H-NMR (400 MHz, DMSO-d6): δ 14.28 (br s, 1H), 9.78 (s, 1H), 9.50 (br s, 1H), 8.34 (s, 1H), 8.00 (s, 1H), 7.88 (d, 1H), 7.72 (s, 1H), 7.18 (dd, 1H), 7.10 (d, 1H), 5.76 (m, 1H), 3.94 (s, 2H), 3.58 (m, 2H), 3.12 (m, 2H), 2.80 (m, 1H), 2.20 (m, 4H), 1.98 (m, 4H), 1.80 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C24H28N6O2, 433.2 (M+H), found 433.2.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([N+:15]([O-])=O)[CH:14]=1)[N:11]([CH3:18])[CH2:10][CH:9]=[CH:8]2>>[NH2:15][C:13]1[CH:14]=[C:5]([O:4][CH3:3])[CH:6]=[C:7]2[C:12]=1[N:11]([CH3:18])[CH2:10][CH2:9][CH2:8]2
Reactant: COc1cc2c(c([N+](=O)[O-])c1)N(C)CC=C2
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(N)c2c(c1)CCCN2C
Yield: 97 %

Procedure:
Reduction of the methiodide in aqueous solution was done with sodium borohydride. A 97% yield of dark red crystals of 6-methoxy-1-methyl-8-nitro-1,2-dihydroquinoline resulted. Recrystallization from a mixture of ether and hexane gave the pure compound which melted 56°-61° , resolidified and melted again at 174°-180°.
Reaction SMILES: [F:1][CH:2]([F:48])[C:3]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[C:29]([NH:31][C:32]5[CH:37]=[CH:36][C:35]([C:38]([N:40]6[CH2:45][CH2:44][O:43][CH2:42][CH2:41]6)=[O:39])=[CH:34][N:33]=5)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=4)[C:18]=2[CH:19]=[O:20])[CH2:10][CH2:9]3)[CH2:5][CH2:4]1.[BH4-].[Na+]>C1COCC1>[F:48][CH:2]([F:1])[C:3]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[C:29]([NH:31][C:32]5[CH:37]=[CH:36][C:35]([C:38]([N:40]6[CH2:41][CH2:42][O:43][CH2:44][CH2:45]6)=[O:39])=[CH:34][N:33]=5)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=4)[C:18]=2[CH2:19][OH:20])[CH2:10][CH2:9]3)[CH2:4][CH2:5]1
Reactant: Cn1cc(-c2cccc(N3CCc4cc(C5(C(F)F)CC5)ccc4C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(-c2cccc(N3CCc4cc(C5(C(F)F)CC5)ccc4C3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
2-[6-(1-Difluoromethyl-cyclopropyl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde (0.025 g, 0.038 mmole) was dissolved into THF (2 ml). To this solution was added NaBH4 (0.006 g, 0.015 mmole) and the mixture stirred at room temperature 0.5 hour after which it was quenched with ice water (4 ml) and extracted with ethylacetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC to afford 6-(1-Difluoromethyl-cyclopropyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one (XI), 0.020 g (80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:20]=1[NH2:21]>>[NH2:26][C:23]1[CH:24]=[CH:25][C:19]([O:18][CH3:17])=[C:20]([NH:21][C:14]2[CH:15]=[C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[N:11]=[CH:12][N:13]=2)[CH:22]=1
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: Fc1ccc(Nc2cc(Cl)ncn2)cc1Cl
Product: COc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1

Procedure:
In a manner substantially similar to that described above 4-(3-chloro-4-fluorophenylamino)-6-chloropyrimidine and 2-methoxy-5-nitroaniline gave N-(5-amino-2-methoxyphenyl)-N′-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine. (Int-G) MS (m/z): 360/362 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:17]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]([CH:23]=O)=[CH:19][CH:20]=[CH:21][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:17]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:14]1[CH2:13][CH2:12][N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:16][CH2:15]1
Reactant: COc1ccc(N2CCNCC2)cc1OC
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)cc1OC

Procedure:
167.9 mg of the target compound (0.43 mmol, 78.6%) was obtained using 1-(3,4-dimethoxyphenyl)piperazine (245 mg, 1.10 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[S:16][N:15]=[C:14]([S:17][CH3:18])[N:13]=1.[Cl-].[Na+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:12]1[S:16][N:15]=[C:14]([S:17][CH3:18])[N:13]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OCc1ccccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccccn2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 6.3 %

Procedure:
Into 2 ml of N,N-dimethylformamide was dissolved 218 mg of 2-pyridylmethanol, 84 mg of sodium hydride (60% in oil) was added thereto under ice-cooling. After stirring for 15 minutes, a solution of 334 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole in 2 ml of N,N-dimethylformamide was added dropwise into the mixture and the reaction mixture was stirred for 0.5 hour under ice-cooling and for 2 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 30 mg of 5-(2-pyridylmethyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (19)).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([NH:10][CH2:11]/[CH:12]=[CH:13]\[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([N:24]([C:33]1[C:42]([C:43]([O:45][CH3:46])=[O:44])=[C:41]2[C:36]([C:37]3[CH:49]=[CH:48][O:47][C:38]=3[CH2:39][O:40]2)=[CH:35][CH:34]=1)COCC[Si](C)(C)C)(=[O:23])=[O:22])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:8]([NH:10][CH2:11]/[CH:12]=[CH:13]\[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([NH:24][C:33]1[C:42]([C:43]([O:45][CH3:46])=[O:44])=[C:41]2[C:36]([C:37]3[CH:49]=[CH:48][O:47][C:38]=3[CH2:39][O:40]2)=[CH:35][CH:34]=1)(=[O:23])=[O:22])[CH3:9]
Reactant: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)N(COCC[Si](C)(C)C)c1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
TFA (1 mL) was added to a solution of methyl 7-{N-[2-((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(2-trimethylsilanylethoxymethyl)-amino}-furo[2,3-c]chromene-6-carboxylate (Intermediate 47, 0.410 g) in DCM (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. Aqueous potassium carbonate was added and the layers were separated. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with DMAW 350, followed by DMAW 240 to give methyl 7-[2-((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (0.096 g) as a yellow gum.
Reaction SMILES: [Na].[H][H].CC(C)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=1>C(O)C.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C.B#[Ni]>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: CC(=O)/C=C/c1ccc(-c2ccccc2F)cc1
Agent: B#[Ni]
Agent: [Ni+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: CC(=O)CCc1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
15 Gm (0.06 mol) of nickel(II)acetate tetrahydrate, dissolved in 600 ml of 95% ethanol, were reduced to black, colloidal nickel boride (P-2-catalyst) in a hydrogenation vessel with 60 ml of 1 M sodium borohyride solution in an atmosphere of hydrogen. In order to remove any unreacted borohydride which may be present, 14 gm (0.24 mol) of acetone were first added and the mixture was shaken for one hour at room temperature. Thereafter, 30.0 gm (0.123 mol) of (E)-4-(2'-fluoro-4-biphenylyl)-3-buten-2-one were added, and the mixture was hydrogenated at room temperature and 5 atmospheres until the absorption of hydrogen terminated. Subsequently, the catalyst was filtered off, the filtrate was evaporated in vacuo, and the residue was shaken with a mixture of water and ethyl acetate. The organic phase was dried over sodium sulfate and then evaporated, and the residue was distilled in a high vacuum, yielding 18.5 gm (62% of theory) of 4-(2'-fluoro-4-biphenylyl)-2-butanone in the form of a colorless, viscous oil having a boiling point of 153°-155°C at 0.4 mm Hg which solidified after prolonged standing and then had a melting point of 30°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:7]=1[Cl:20])[CH3:2].[CH3:22]CCCCC.CCOC(C)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[N:19]=[CH:22]2)=[CH:8][C:7]=1[Cl:20])[CH3:2]
Reactant: CCCCCC
Reactant: CCOC(=O)Cc1ccc(Nc2ncccc2N)cc1Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(-n2cnc3cccnc32)cc1Cl

Procedure:
is obtained analogously to the method as described in Step 1.2 but using [4-(3-amino-pyridin-2-ylamino)-2-chloro-phenyl]-acetic acid ethyl ester instead of [4-(3-amino-pyridin-2-ylamino)-phenyl]-acetic acid methyl ester as a starting material. ES-MS: 316.1 [M+H]+; single peak at tR=4.24 min (System 1); Rf=0.16 (Hexane/EtOAc, 1:1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]3[CH:23]=[CH:24][C:19]([CH3:30])=[CH:20][CH:21]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1ccc(/C=C/C(=O)O)cc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(C)cc3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-p-tolyl-acrylic acid.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH:26]([NH:30][C:31]([O:33]C(C)(C)C)=O)[C:27]([OH:29])=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(=O)O[C:41](=[O:42])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12>ClCCl.Cl.C1(C)C=CC=CC=1>[CH2:14]([O:21][C:22]([NH:24][CH2:25][C@H:26]([N:30]1[C:31](=[O:33])[C:39]2=[CH:47][CH:46]=[CH:45][CH:44]=[C:40]2[C:41]1=[O:42])[C:27]([OH:29])=[O:28])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(NC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of (2S) 3-benzyloxycarbonylamino-2-tert-butoxycarbonylaminopropionic acid dicyclohexylamine salt (3 g, 5.8 mmol) in dichloromethane (200 ml) was washed four times with 1M HCl solution, dried (MgSO4) and concentrated. The resulting oil was dissolved in dry dichloromethane (35 ml), cooled to 0° C. and treated with trifluoroacetic acid (35 ml). This solution was stirred at 0° C. for 1.5 h then evaporated to dryness. Dichloromethane (50 ml) was added to the residue then removed under vacuum. This process repeated six times to afford a white solid. The white solid was suspended in toluene (50 ml), treated with powdered phthalic anhydride (940 mg, 6.35 mmol) and refluxed for 18 h. The resulting solution was concentrated to afford an oil which was purified by flash chromatography (2-10% methanol/dichloromethane) to afford 266, 2.01 g (94%) as a white powder: IR (KBr) 3600-2500br, 1776, 1714, 1530, 1469, 1455, 1392, 1263, 1131, 722; 1H NMR (CDCl3) δ 7.83 (2H, m), 7.72 (2H, m), 7.29 (5H, m), 5.41 (1H, m), 5.03 (2H, s), 3.90 (2H, m); MS (ES-), 367 (M-1).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:11](O)[CH:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:20]#[N:21])[CH:8]=2)[O:3]1.[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1([CH3:22])[CH:11]=[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:20]#[N:21])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C(Sc2ccccn2)C1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)C=C(Sc2ccccn2)c2cc(C#N)ccc2O1

Procedure:
A mixture of 10 g of 2,2-dimethyl-4-(2-pyridylthio)-6-cyano-3-chromanol, 3 g of sodium hydroxide a 350 ml of dioxane is boiled for 20-minutes. The mixture is cooled and filtered, the filtrate is evaporated and 2,2-dimethyl-4-(2-pyridylthio)-6-cyano-3-chromene, m.p. 110°-112°, is obtained.
Reaction SMILES: C(OC1C=CC(C2CC(C(O)=O)C(=O)NN=2)=CC=1)C1C=CC=CC=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[C:33]([C:38]([O:40]CC)=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=1.[OH-].[Na+].Cl>>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH2:32][CH:33]([C:38]([OH:40])=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=1
Reactant: CCOC(=O)c1cc(-c2cccnc2)n[nH]c1=O
Agent: Cl
Agent: O=C(O)C1CC(c2ccc(OCc3ccccc3)cc2)=NNC1=O
Agent: [Na+]
Product: O=C(O)C1CC(c2cccnc2)=NNC1=O
Yield: 92.3 %

Procedure:
Working as in example 19 for the preparation of 6-[4-(benzyloxy)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid, but starting with 2 g of ethyl 6-pyridin-3-yl-3-oxo-2,3-dihydropyridazine-4-carboxylate, 24.5 cm3 of one molar sodium hydroxide solution and 25 cm3 of one molar hydrochloric acid solution, 1.65 g of 6-pyridin-3-yl-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid were obtained in the form of a cream-colored solid melting at a temperature above 260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([CH3:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([CH3:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (2.06 g, 3.9 mmol) in methanol (100 mL) and sodium hydroxide (0.31 g, 7.8 mmol) in water (2 mL) was stirred at room temperature overnight and then the solvents were evaporated. The residue was partitioned between water and ethyl acetate and the ethyl acetate layer was discarded. The aqueous layer was poured into 2 M HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, concentrated, and dried under high vacuum to give N-[2-chloro-4-[[[(3-hydroxyphenyl) methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (1.50 g, 75%) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH2:12][NH2:13]
Reactant: CC(C)(C)OC(=O)NCCNc1nc2ccccc2s1
Solvent: C1COCCO1
Product: NCCNc1nc2ccccc2s1
Reaction time: 3 h

Procedure:
tert-Butyl 2-(benzo[d]thiazol-2-ylamino)ethylcarbamate (597.7 mgs, 2.04 mmol) was dissolved in 1,4-dioxane (6 mL) then treated with 4N HCL in 1,4-dioxane (6 mL) and stirred for 3 h. A white separated solid was collected by filtration, washed with diethyl ether and dried in vacuum oven overnight at room temperature to yield the hydrochloride salt of N1-(benzo[d]thiazol-2-yl)ethane-1,2-diamine as an off-white amorphous solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][O:3]1.[CH3:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>>[CH3:17][C:18]1[C:19]([N:25]2[CH2:26][CH2:27][N:28]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:7]4[CH2:6][CH2:5][CH2:4][O:3][C:2]4=[O:1])=[CH:16][CH:15]=3)=[O:14])[CH2:29][CH2:30]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(N2CCCOC2=O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCOC4=O)cc3)CC2)c(C)c1
Yield: 86.4 %

Procedure:
Using 4-(2-oxo[1,3]oxazinan-3-yl)benzoic acid (111 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (96 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (171 mg) was obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]3[C:20]4[CH:33]=[CH:32][S:31][C:21]=4[C:22](=[O:30])[NH:23][C:24]=3[CH:25]=[CH:26][C:27]=2[O:28]C)=[CH:14][CH:13]=1)(=[O:11])=[O:10])(=O)=O.[Cl-:34].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:34][CH2:6][CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]3[C:20]4[CH:33]=[CH:32][S:31][C:21]=4[C:22](=[O:30])[NH:23][C:24]=3[CH:25]=[CH:26][C:27]=2[OH:28])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCOS(C)(=O)=O)cc1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: CC(Cl)Cl
Product: O=c1[nH]c2ccc(O)c(-c3ccc(S(=O)(=O)NCCCl)cc3)c2c2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
To a solution of 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenylsulfonamido)ethyl methanesulfonate (250 mg, 0.49 mmol) in anhydrous dichloroethane was added aluminum chloride (330 mg, 2.5 mmol) and the reaction mixture was heated at reflux for 20 h. The reaction was cooled to room temperature, concentrated and quenched with methanol (10 mL). The resulting mixture was allowed to stand at room temperature for 1 h and the resulting precipitate was filtered and dried to afford the desired product (88 mg, 41%) as an off-white solid: 1H NMR (500 MHz, DMSO-d) δ 11.83 (s, 1H), 9.42 (s, 1H), 8.13 (t, J=7.2 Hz, 1H), 7.94 (d, J=5.1 Hz, 2H), 7.74 (d, J=3.3 Hz, 1H), 7.51 (d, J=5.1 Hz, 2H), 7.41 (d, J=5.4 Hz, 1H), 7.18 (d, J=5.4 Hz, 1H), 5.82 (d, J=3.3 Hz, 1H), 3.65 (t, J=3.9 Hz, 2H), 3.22 (q, J=3.6 Hz, 2H); ESI MS m/z 435 [C19H15ClN2O4S2+H]+; HPLC 97.2% (AUC), tR=14.98 min,
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C(#N)C>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: COc1ccccc1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1CNCCOc1cccc(-c2noc3ccsc23)c1
Temperature: 75 °C
Yield: 89.9 %

Procedure:
Mix 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole (0.324 g, 1 mmol), potassium carbonate (0.28 g, 2 mmol), 2-methoxybenzylamine (0.686 g, 5 mmol) and acetonitrile (anhydrous, 4 mL) and heat at 75° C. for 16.5 hours. Cool the reaction mixture and filter through a Waters Sep-Pak silica gel cartridge (1 g) using ethyl acetate. Combine the appropriate fractions and concentrate to give a residue. Purify the residue by column (10 g silica) chromatography using a step gradient of 60% ethyl acetate in heptane to 100% ethyl acetate to give the title compound (342 mg, 90% Yield). Purity by LC/MS (APCI)=99%, [M+H]+=381.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[O:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:34][CH2:35][CH2:36][O:32]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: C1CNOC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCCO2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-isoxazolidin-2-yl-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and isoxazolidine following General Procedure B.