Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:42])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:41]=[CH:40][C:23]([C:24]([NH:26][C@H:27]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:25])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>[Pd].FC(F)(F)C(O)=O.C(Cl)Cl>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:42])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[CH:41]=[CH:40][C:23]([C:24]([NH:26][C@H:27]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:25])=[CH:22][CH:21]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Reaction time: 24.5 h
Yield: 100.3 %

Procedure:
A mixture of 0.59 g of diethyl N-[4-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl)benzoyl]-L-glutamate and 1.5 g of 5% palladium on charcoal in 30 ml of trifluoroacetic acid is hydrogenated at 53 psi at room temperature for 24.5 hours. The reaction mixture is diluted with methylene chloride and filtered through Celite. The solvent is removed under reduced pressure. The residue is redissolved in methylene chloride and extracted with a saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue chromatographed on silica gel using a 4% methanol:methylene chloride mixture as the eluent. Evaporation of the eluate yields 0.60 g (100%) of diethyl N-(4-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate as a white solid: m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.22 (t, 3H, J=7.20 Hz), 1.29 (s, 9H), 1.30 (t, 3H, J=7.20 Hz), 1.61-3.35 (m, 13H), 4.11 (q, 2H, J=7.20 Hz), 4.23 (q, 2H, J=7.20 Hz), 4.77-4.84 (m, 1H), 5.15 (brs, 1H), 7.17 (d, 1H, J=7.50 Hz), 7.23 (d, 2H, J=8.10 Hz), 8.56 (brs, 1H); IR (KBr) 3400, 3280, 2980, 1735, 1630, 1570, 1460, 1390, 1350, 1310, 1200, 1155, 1025, 930, and 800 cm-1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])=[C:6]([CH:8]2[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=1.[Mn]([O-])(=O)(=O)=[O:24].[K+].O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:17]([S:15]([C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[CH:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])(=[O:24])=[O:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCS(=O)c1ccc(Cl)cc1C1NC(=O)NC1=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCS(=O)(=O)c1ccccc1C1NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 29.1 %

Procedure:
To a solution of 5-(5-chloro-2-hexylsulfinylphenyl)hydantoin (4.8 g, 0.014 mol) in glacial acetic acid (50 ml) was added potassium permanganate (2.2 g, 0.014 mol) and water (5 ml). The mixture was stirred at room temperature for 45 minutes then poured into 10% sodium bisulfite solution (50 ml). The resulting solution was extracted with ether, the ethereal extract then dried (MgSO4) and evaporated under reduced pressure. The brown oily residue was chromatographed on silica gel and the product eluted with ethyl acetate:hexane (40:60). Evaporation of the eluate under reduced pressure afforded 1.32 g of product as a white solid (26% yield). M.P. 188°-189° C.
Reaction SMILES: BrC[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][CH:13]=[N:12][C:11]=2[CH:15]=1.[Na+].[I-].[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH:26]1[CH2:31][CH2:30][N:29]([CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[S:14][CH:13]=[N:12][C:11]=3[CH:15]=2)[CH2:28][CH2:27]1
Reactant: Clc1cccc(C2CCNCC2)c1Cl
Reactant: BrCCCCOc1ccc2scnc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Clc1cccc(C2CCN(CCCOc3ccc4scnc4c3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
A mixture of intermediate 26 (218 mg, 0.8 mmol) and NaI (240 mg, 1.6 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 47 (320 mg, 1.2 mmol) and anhydrous K2CO3 (442 mg, 3.8 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 5-(3-(4-(2,3-dichlorophenyl)piperidin-1-yl)propoxy)benzo[d]thiazole (compound 22) (211 mg, 56%). 1H NMR (300 MHz, CDCl3): δ 8.98 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.62 (d, J=3.0 Hz, 1H), 7.34-7.31 (m, 1H), 7.24-7.18 (m, 3H), 7.15-7.09 (m, 1H), 4.15 (t, J=5.7 Hz, 2H), 3.18-3.12 (m, 3H), 2.70-2.66 (m, 2H), 2.27-2.19 (m, 2H), 2.17-2.10 (m, 2H), 1.92-1.81 (m, 4H). HPLC: 99%, RT 2.622 min. MS (ESI) m/z 421.1 [M+H]+. mp: 114-116° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([SH:13])([CH3:12])[CH3:11]>N1C=CC=CC=1.C(O)C>[C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([SH:13])([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(C)(S)[C@H](N)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)N[C@H](C(=O)O)C(C)(C)S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (96 mmol, 9.80 g) was added dropwise to a well stirred solution of D-(−) penicillamine (40 mmol, 5.97 g) in pyridine (50 mL) at 0° C. After 30 min, the flask was removed from ice and allowed to stir at room temperature for 15 h. The resultant orange solution was partitioned between chloroform and dilute HCl and washed 4× with dilute HCl. After drying over MgSO4, the organic phase was evaporated to yield an orange residue. The residue was first dissolved in absolute ethanol (20 mL), and then precipitated in pentane at −78° C. The light yellow crystalline product was isolated by filtration (2.07 g, 30%). 1H NMR (CDCl3) δ 1.65 (s, CH3), 1.86 (s, CH3), 2.05 (s, NHCOCH3), 5.68-5.70 (d, CH(CH3)2), 6.56 (NHCOCH3). 13C NMR (CDCl3) δ 22.52 (NHCOCH3), 26.20 (CH(CH3)2), 30.22 (CH(CH3)2), 51.23 (CH), 169.37 (NHCOCH3), 192.21 (SCO).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14][C@H:13]2[O:32][CH:33]([CH3:35])[CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].O.[OH-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14][C@H:13]2[O:32][CH:33]([CH3:34])[CH3:35])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OC(C)C)C3)sc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4cccc(C(=O)O)c4s3)C[C@H]2OC(C)C)nc1Cl
Yield: 97.5 %

Procedure:
Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-isopropoxypiperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (148b) (0.140 g, 0.269 mmol) was dissolved in tetrahydrofuran (5 mL). The solution was subjected to the same operation as in Example (1i) using lithium hydroxide monohydrate (0.135 g, 3.23 mmol) and water (5 mL), to obtain 0.129 g of the title compound as a white solid (98%).
Reaction SMILES: [H-].[Li+].[C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[CH:11]=[CH:12][C:13](=[O:16])[N:14]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:15]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)c[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(C(c2ccccc2)c2ccccc2)ccc1=O
Reaction time: 0.25 h

Procedure:
To a suspension of LiH (45.6 mg) in DMF (6.0 mL) was added portionwise 5-(diphenylmethyl)-2(1H)-pyridinone (500 mg) at ambient temperature and the mixture was stirred at the same temperature for 15 minutes. Ethyl bromoacetate (255 μL) was added dropwise to the mixture. The mixture was stirred at ambient temperature for 14 hours. The reaction was quenched with 1M HCl aqueous solution (10.0 mL) and the mixture was extracted with EtOAc (30 mL). The organic layer was washed successively with saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=3:2) to afford 5-(diphenylmethyl)-1-ethoxycarbonylmethyl-2(1H)-pyridinone (574 mg) as a colorless amorphous.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].Cl.[F:25][CH2:26][C@H:27]([NH2:29])[CH3:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:29][C@H:27]([CH3:28])[CH2:26][F:25])=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: C[C@@H](N)CF
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Agent: Cl
Product: C[C@H](CF)NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 38.9 %

Procedure:
In a similar manner to Example 146, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (100 mg) and (2R)-1-fluoro-2-propylamine hydrochloride (32.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-(4-[N-[(2R)-1-fluoro-2-propyl]amino]carbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (41.9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:17]([OH:19])=O)[CH:11]=[C:12]2[CH:16]=[CH:15][S:14][C:13]=12.[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:20]([N:22]([CH2:23][CH3:24])[C:17]([C:10]1[CH:11]=[C:12]2[CH:16]=[CH:15][S:14][C:13]2=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1)=[O:19])[CH3:21]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2ccsc2c(-c2ccccc2Cl)n1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc2ccsc2c(-c2ccccc2Cl)n1
Yield: 40.6 %

Procedure:
Operations are carried out as for Example 7, starting from 2.9 g of 7-(2-chloro phenyl) thieno[2,3-c]pyridine 5-carboxylic acid, 1.17 g of triethylamine, 1.25 g of ethyl chloroformate and 0.94 g of diethylamine in 100 ml of chloroform. 1.4 g of N,N-diethyl 7-(2-chloro phenyl) thieno[2,3-c]pyridine 5-carboxamide, melting at 86° C., is obtained.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: O[C@@H]1CCNC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CC[C@@H](O)C3)n2n1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 52 mg, 0.151 mmol) and (R)-pyrrolidin-3-ol (53 mg, 0.603 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (25-25% MeCN/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (21.1 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H), 1.91-2.12 (m, 2 H), 2.34 (s, 3 H), 3.82-4.13 (m, 5 H), 4.44 (br. s., 1 H), 6.16 (s, 1 H), 6.71 (s, 1 H), 7.63 (d, J=8.59 Hz, 2 H), 7.98 (d, J=8.34 Hz, 2 H), 10.95 (s, 1 H); ESI-MS: m/z 396.2 (M+H)+.
Reaction SMILES: C([Mg]Br)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=1.O1CCCCC1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>O1CCCC1>[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Reactant: BrCCCCCCCCOC1CCCCO1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: OCCCCCCCCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 30 ml of a 2M solution of ethylmagnesium bromide in tetrahydrofuran under nitrogen at 0°-5° is added dropwise over 30 minutes a solution of 10.0 g of 2-(3-pyridyl)indole in 60 ml of tetrahydrofuran. The mixture is stirred for 0.5 hour at 0°-5° followed by the dropwise addition of 17.6 g of 1-tetrahydropyranyloxy-8-bromooctane in 50 ml of tetrahydrofuran. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture is poured into ice-water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting mixture is kept at room temperature for 0.5 hour, washed with ether, basified with aqueous with 3N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness to give 3-(8-hydroxyoctyl)-2-(3-pyridyl)-indole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](Cl)(=O)C>CO>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([OH:11])[CH:10]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cc(O)cc(Br)c1
Solvent: CO
Product: COC(=O)c1cc(O)cc(Br)c1

Procedure:
To a solution of 3-bromo-5-hydroxybenzoic acid (3.41 g, 15 mmol) (J. Chem. Soc. 1955, 463) in anhydrous methanol (80 mL) was added acetyl chloride (2.56 mL, 36 mmol) at 0° C. The mixture was then heated under reflux overnight. The volatiles were removed in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Na].C[O-].[Na+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]C1CCCCO1)=[O:33]>O.CC(N(C)C)=O>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(CCCCCBr)OC1CCCCO1
Reactant: CCCCCCc1ccc(N=Nc2ccc(O)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCCCc1ccc(N=Nc2ccc(OCCCCCC(=O)O)cc2)cc1
Temperature: 100 °C
Yield: 68.3 %

Procedure:
One g. (3.73×10-3 mol) of 4'-hexyl-4-hydroxyazobenzene (1) converted into a sodium salt with sodium methylate and 1.03 g (3.69×10-3 mol) of 2-tetrahydropyranyl 6-bromohexanoate and 5 ml of dimethylacetamide added thereto were heated for reaction at 100° C. for 73 hours. After the reaction was completed, the reaction mixture was diluted with water and left to cool to room temperature. The yellow crystals which were consequently precipitated were separated by filtration. The crystals were extracted with ethyl acetate, dried with magnesium sulfate, and subjected to vacuum distillation for expulsion of the solvent. The residue of the vacuum distillation was recrystallized with a mixture of hexane with benzene. Consequently, 1 g of 6-[4-(4-hexylphenylazo)-phenoxy]-hexanoic acid was obtained. A mixture of 200 mg (5.05×10-4 mol) of this carboxylic acid with 5 ml of thionyl chloride was refluxed for 2 hours to expel excess thionyl chloride and then mixed with 3 ml of dry ether and 0.15 g (1.485×10-3 mol) of triethylamine. This mixture kept cooled with ice and a solution of 0.11 g (4.98×10-4 mol) of triethoxyaminopropylsilane in 3 ml of dry ether added dropwise thereto were stirred for two hours, then filtered to expel the formed salt in an atmosphere of nitrogen gas, and subjected to vacuum distillation at room temperature to expel the solvent. Consequently, 213 mg of yellow waxy N-(3-triethoxysilylpropyl)-6-[4-(4-hexylphenylazo)phenoxy]hexanoic acid amide was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[C:21]([CH2:22][N:23]3C(=O)C4=CC=CC=C4C3=O)=[N:20][N:19]=[C:18]2[CH2:34][N:35]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=O.O.NN>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]3[C:18]([CH2:34][NH2:35])=[N:19][N:20]=[C:21]3[CH2:22][N:23]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]=2[CH:16]=1
Reactant: O=C(c1ccccc1F)c1cc(Br)ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Example 22, 5-bromo-2'-fluoro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-bromo-1-(aminomethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=[S:3].Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[N:4]1([C:2]2[S:3][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)N1CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(N2CCOCC2)n1
Yield: 55.2 %

Procedure:
A mixture of 1.85 g (12.7 mmol) of 4-((amino)thiocarbonyl)morpholine, 1.59 ml (12.7 mmol) of ethyl bromopyruvate, and excess MgSO4 in 50 ml of acetone was heated at reflux for 2 h. The resulting mixture was allowed to cool, filtered, and concentrated in vacuo. The residue was taken up in chloroform, washed with aqueous NaHCO3, dried over Na2SO4, and concentrated. Silica gel chromatography using 1% methanol in chloroform provided 1.7 g (55%) of the desired compound, Rf 0.70 (ethyl acetate). Mass spectrum: (M+H)+ =243.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[S:11][C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[C:13](OCC)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[S:11][C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH2:13][OH:14]
Reactant: CCOC(=O)C(C)(Sc1cc2ccccc2n1C)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1c(SC(C)(CO)c2ccccc2)cc2ccccc21
Temperature: 0 °C
Yield: 70 %

Procedure:
A solution (20 ml) of ethyl 2-(1-methylindol-2-yl)thio-2-phenylpropionate (3 g) in anhydrous tetrahydrofuran was added dropwise to a suspension (75 ml) of lithium aluminum hydride (670 mg) in anhydrous tetrahydrofuran, and the mixture was heated and refluxed for 2 hours. The reaction solution was allowed to cool, and was poured into ice water. The mixture was acidified by adding 6N hydrochloric acid, and was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was recrystallized from ligroin to give 1.84 g (yield: 70 %) of the product compound as a pale yellow powder. The melting point was 118°-119° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[C:4]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])[C:5](=O)[NH:6][N:7]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:5]1[N:6]=[N:7][C:2]([CH3:1])=[C:3]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[C:4]=1[C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[F:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccc(C(F)(F)F)cc1
Product: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
2.43 g of 6-methyl-5-(4-trifluoromethylphenyl)-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.50 g of 3-chloro-6-methyl-5-(4-trifluoromethylphenyl)-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xxiv) of the present invention).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9].[OH-].[Na+]>>[C:1]([NH:5][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: C[Si](C)(C)CCl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)NC[Si](C)(C)C
Temperature: 200 °C

Procedure:
A mixture of tert-butylamine (18.0 mL, 171 mmol) and (chloromethyl)trimethylsilane (7.00 g, 57.1 mmol) was heated in a thick-walled glass tube at 200° C. overnight. After cooling to ambient temperature, the reaction mixture was poured into 1 N NaOH and extracted three times with diethyl ether. The combined organic extracts were washed with brine, dried (MgSO4), and the volatiles evaporated in vacuo. Distillation (atmospheric pressure; ˜135° C.) of the residual liquid gave the title compound 77 as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[C:4]([CH3:12])[C:3]=1[OH:13]>C(OCC)(=O)C>[NH2:9][C:6]1[CH:5]=[C:4]([CH3:12])[C:3]([OH:13])=[C:2]([Br:1])[C:7]=1[CH3:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Br)c1O
Solvent: CCOC(C)=O
Product: Cc1cc(N)c(C)c(Br)c1O
Reaction time: 1.5 h

Procedure:
Into a Parr bottle was charged 2-bromo-3,6-dimethyl-4-nitrophenol (13.6 grams, 55.3 mmol) prepared in Part A and ethyl acetate (50 milliliters). The reaction vessel was purged with nitrogen and 5% platinum on carbon (1.36 grams) was added immediately following the purge. Hydrogenation was carried out on a rocking Parr hydrogenator for 1.5 hours at 40-50 psi hydrogen and room temperature. The reaction mixture was filtered through celite and concentrated under reduced pressure to give 4-amino-2-bromo-3,6-dimethylphenol as a brown solid in quantitative yield. H'-NMR (CDCl3 -DMSO-d6), 6.40 (S, 1H), 2.17 (brS, 6H).