Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Br:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28]O)[CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Br:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)[CH:24]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1csc(Br)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Br)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 30.7 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (98 mg), (5-bromo-3-thienyl)methanol (135 mg) and tributylphosphine (211 mg) in THF (3 ml) was added 1,1′-(azodicarbonyl)dipiperidine (264 mg), and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (48.8 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:44])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:52]C(=O)C(N)[C@@H](C(OCCCC)=O)C(N[C@@H](CC1C=CC=CC=1)CO)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(=O)C[C@@H](N)C(N[C@@H](CC1C=CC=CC=1)CO)=O)C1C=CC=CC=1.CO.C(Cl)Cl>ClCCCl>[CH2:1]([O:8][C:9](=[O:44])[CH2:10][CH:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:37]=[CH:38][C:39]([C:42](=[O:52])[NH2:43])=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)=[CH:26]1)[C:12]([NH:14][CH:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2ccc(-c3ccn([C@H](CC(=O)OCc4ccccc4)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Reactant: CCCCOC(=O)[C@@H](C(=O)N[C@H](CO)Cc1ccccc1)C(N)C(=O)OCc1ccccc1
Agent: N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: NC(=O)c1ccc(-c2ccc(-c3ccn(C(CC(=O)OCc4ccccc4)C(=O)NC(CO)Cc4ccccc4)c3)cc2)cc1
Yield: 31 %

Procedure:
As described in Example 4(a) for the preparation of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4′-cyano-biphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester, N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-butoxycarbonyl-amino-succinamic acid benzyl ester (0.320 mmol) was deprotected. A solution of the resultant crude N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-amino-succinamic acid benzyl ester trifluoroacetate salt and crude 3-(4′-carboxamidobiphenyl-4-yl)-2,5-dimethoxytetrahydrofuran (110 mg, 0.330 mmol) in 1,2-dichloroethane condensed in 18 hours to give a brown solid, which was punfied via flash column chromatography with 5% MeOH/CH2Cl2 as eluant to provide 60 mg (31%) of N-(1-benzyl-2-hydroxyethyl)-3-[3-(4′-carbamoylbiphenyl4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester as a pale yellow solid, mp 192-4° C. 1H NMR (DMSO-d6): δ 8.18 (d, 1H, J=8.5 Hz), 8.00 (s, 1H), 7.94 (d, 2H, J=8.1 Hz), 7.76 (d, 2H, J=8.5 Hz), 7.68 (d, 2H, J=8.5 Hz), 7.58 (d, 2H, J=8.5 Hz), 7.36-7.14 (bm, 7H), 6.84 (t, 1H, J=2.2 Hz), 6.47 (s, 1H), 5.10-4.95 (m, 3H), 4.81 (t, 1H, J=5.1 Hz), 3.88-3.75 (m, 1H), 3.00 (d, 2H, J=7.4 Hz), 2.80 (dd, 1H, J=5.5, 13.2 Hz), 2.67-2.60 (m, 1H). IR (KBr): 3330, 2962, 1729, 1655, 1606, 1560, 1498, 1261, 1092 cm−1. FABMS: 602 (M+H+). Anal. Calculated for C37H35N3O5•0.4 CH2Cl2: C, 70.67; H, 5.68; N, 6.61. Found: C, 70.78; H, 5.86; N, 6.98.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([O:11][C:12](=[O:19])[CH2:13][C:14](OCC)=N)[CH3:10]>C(O)(=O)C>[CH2:9]([O:11][C:12](=[O:19])[CH2:13][C:14]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CCOC(=N)CC(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc2ccccc2[nH]1
Yield: 81.3 %

Procedure:
54 g o-phenylenediamine (0.5 mol), 300 mL glacial acetic acid and 98 g 3-ethoxy-3-imino propionic acid ethyl ester (0.5 mol) were stirred at refluxing for 2 hours. After concentration under reduced pressure, the residual solution was poured into ice water and a solid was isolated. After sucking filtration, washing with water and a little amount of ethanol, and drying, 83 g off-white solid was obtained. Yield: 82%, MS: 205 (M+1).
Reaction SMILES: N[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:8]=2[F:12])[N:3]=1.[I:17]CI.N(OCCC(C)C)=O>C1COCC1.CCOC(C)=O.[Cu]I>[F:12][C:8]1[CH:7]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:4]2[C:9]=1[CH:10]=[N:11][C:2]([I:17])=[N:3]2
Reactant: ICI
Reactant: COC(=O)c1cc(F)c2cnc(N)nc2c1
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c2cnc(I)nc2c1
Temperature: 60 °C
Yield: 55.2 %

Procedure:
A suspension of methyl 2-amino-5-fluoro-quinazoline-7-carboxylate (4.28 g, 19.3 mmol, 1.00 equiv), CuI (1.81 g, 9.5 mmol, 0.49 equiv) and diiodomethane (7.80 mL, 96.8 mmol, 5.0 equiv) in THF (80 ml) was treated with isoamyl nitrite (7.80 mL, 58.1 mmol, 3.00 equiv) at ambient temperature, and the mixture heated to 60 ° C. After 18 h the reaction was cooled. The mixture was diluted with EtOAc (100 mL), filtered through a Celite® pad, and the dark green filtrate concentrated in vacuo to an oily residue (23.0 g) which was absorbed onto SiO2 and purified by flash chromatography eluting with an EtOAc/heptane gradient (0 to 30% EtOAc) to afford 3.54 g (55%) of methyl 5-fluoro-2-iodoquinazoline-7-carboxylate as a cream-white solid: 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.49 (s, 1H), 7.90 (d, J=9.5 Hz, 1H), 4.02 (s, 3H); LCMS: MH+333.0
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]=O)[CH3:5].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2C=CN[CH:16]=2)[CH:14]=1.CI>O>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:6][N:4]([CH3:5])[CH:3]=2)[CH:14]=1
Reactant: CN(C)C=O
Reactant: Brc1cncc(-c2cc[nH]c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1ccc(-c2cncc(Br)c2)c1

Procedure:
Sodium hydride (60% in oil) (6 mg) was added to a DMF (1 ml) solution containing 3-bromo-5-(1H-pyrrol-3-yl)pyridine (28 mg), followed by stirring. Methyl iodide (9 μl) was added, followed by stirring at room temperature for 3 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=30:1 to 3:1), and a white solid of 3-bromo-5-(1-methyl-1H-pyrrol-3-yl)pyridine (18 mg) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[C:9](I)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:9]([CH3:15])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: N#Cc1cc(I)c(N)cc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C#N)c(C(F)(F)F)cc1N
Temperature: 100 °C

Procedure:
To a solution of 4-amino-5-iodo-2-(trifluoromethyl)benzonitrile (commercially available, for example from Key Organics Ltd., Camelford, UK, 640 mg, 2.05 mmol) and potassium carbonate (567 mg, 4.10 mmol) in 1,4-Dioxane (10 ml) was added tetrakis(triphenylphosphine)palladium(0) (237 mg, 0.205 mmol) and trimethylboroxin (1.43 ml, 10.3 mmol) under argon atmosphere. The reaction mixture was heated to 100° C. overnight. The reaction mixture was diluted in EtOAc (100 ml) and water (50 ml). The aqueous was extracted with EtOAc (100 ml). The organics were combined, passed through a phase separator and concentrated to afford 1 g of a yellow oil which was purified by flash chromatography using a Biotage SP4 (eluting a gradient from 30% to 70% EtOAc in hexane). Relevant fractions were combined and concentrated to afford 300 mg of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[C:5]=1[OH:15])[CH:2]=[CH2:3].CC([O-])(C)C.[K+].C1COCC1.Cl>CS(C)=O>[OH:15][C:5]1[C:6]([CH3:14])=[C:7]([CH:12]=[CH:13][C:4]=1[CH:1]=[CH:2][CH3:3])[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=CCc1ccc(C(=O)OC)c(C)c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC=Cc1ccc(C(=O)OC)c(C)c1O
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
In a round bottom flask fitted with a dropping funnel was added methyl 4-allyl-3-hydroxy-2-methylbenzoate (4.12 g, 20 mmol) in anhydrous DMSO (20 ml) at room temperature under argon. t-BuOK in 1.0 M THF (5.61 g, 50 mmol) was added drop wise to the stirred solution. After the addition, the reaction mixture was heated at 55° C. overnight. The reaction was monitored using LCMS. After the reaction was complete, it is cooled, acidified with 1N HCl and stirred for 30 min. Aqueous work up and extraction with ethyl acetate gave the crude mixture which was purified using an ISCO system (40 g silica gel column, hexane/EtOAc solvent gradient) to give 4.12 g (77%) of the product. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 6.61 (dd, J=15.9, 1.7 Hz, 1H), 6.37-6.13 (m, 1H), 3.90 (s, 3H), 2.50 (s, 3H), 1.96 (dd, J=6.6, 1.7 Hz, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=3)[N:31]=2)=[CH:23][CH:22]=1.[CH3:39][N:40]([CH3:44])[CH2:41][C:42]#[CH:43]>C(NCC)C.C(#N)C.Cl[Pd]Cl.[Cu]I>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([CH2:43][C:42]#[C:41][N:40]([CH3:44])[CH3:39])=[CH:34][CH:33]=3)[N:31]=2)=[CH:23][CH:22]=1
Reactant: C#CCN(C)C
Reactant: Fc1ccc(-c2nc(-c3ccc(Br)cc3)cs2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CC#N
Product: CN(C)C#CCc1ccc(-c2csc(-c3ccc(F)cc3)n2)cc1
Reaction time: 0.25 h

Procedure:
In a 100 ml flask is placed triphenylphosphine (80 mg, 10%), PdCl2 (40 mg, 5%) and 2-(4'-fluorophenyl)-4-(4'-bromophenyl)thiazole (0.98 g, 2.9 mmol) in 20 ml of diethylamine. After stirring for 15 min under N2 atmosphere, CuI (30 mg, 5%) and 1-dimethylamino-2-propyne (0.27 g, 3.18 mmol) in 20 ml of acetonitrile are added to the mixture. After 18 h of heating, the solvent is evaporated under reduced pressure and the residue is filtered through silica gel pad (50 g) using CHCl3 (400 mL) and 2% MeOH in CHCl3 (400 mL). A large portion of unreacted 2-(4'-fluorophenyl)-4-(4'-bromophenyl)thiazole is recovered after removal of chloroform filtrate (0.55 g, 56%). The second part of the filtrate (2% MeCH in CHCl3) is concentrated and the residual solid is then purified over silca gel column eluting with 2% MeOH in CHCl3. 2-(4'-fluorophenyl)-4-[4'-(3-dimethylamino-2-propyn-1-yl)phenyl]thiazole is obtained after concentration and trituration with hexane (0.25 g, 27% yield), mp. 98-9° C.
Reaction SMILES: C(OC1C([N+]([O-])=O)=C(N)C2C(=CC=CC=2)[N:10]=1)C1C=CC=CC=1.C(OC1C([N+]([O-])=O)=C(Cl)C2C(=CC=CC=2)N=1)C1C=CC=CC=1.[O:45]1[CH2:50][CH2:49][CH:48]([C:51]([O:53]C)=O)[CH2:47][CH2:46]1.[OH-].[NH4+]>C(N(CC)CC)C.CO.ClCCl>[O:45]1[CH2:50][CH2:49][CH:48]([C:51]([NH2:10])=[O:53])[CH2:47][CH2:46]1
Reactant: COC(=O)C1CCOCC1
Reactant: Nc1c([N+](=O)[O-])c(OCc2ccccc2)nc2ccccc12
Agent: O=[N+]([O-])c1c(OCc2ccccc2)nc2ccccc2c1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: NC(=O)C1CCOCC1

Procedure:
In step (5) of Reaction Scheme I, a benzyloxy-4-chloro-3-nitroquinoline of Formula XIX is treated with an amine of Formula R1—NH2 to provide a benzyloxy-3-nitroquinolin-4-amine of Formula XX. The reaction is conveniently carried out by adding the amine of Formula R1—NH2 to a solution of the benzyloxy-4-chloro-3-nitroquinoline of Formula XIX in a suitable solvent such as dichloromethane or methanol in the presence of a tertiary amine such as triethylamine. The reaction can be carried out at ambient temperature or at an elevated temperature such as, for example, the reflux temperature of the solvent. The reaction product can be isolated using conventional methods. Several amines of Formula R1—NH2 are commercially available; others can be prepared by known synthetic methods. For example, methyl tetrahydro-2H-pyran-4-carboxylate treated with ammonium hydroxide to form tetrahydro-2H-pyran-4-carboxamide, which can then be reduced with lithium aluminum hydride to provide tetrahydro-2H-pyran-4-ylmethylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[C:6]([NH2:21])=[N:7][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[N:9][C:10]=1[NH2:11].CS(O[CH2:28][CH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[C:10]([NH2:11])=[N:9][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:28][CH:29]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[N:13]=2)=[N:7][C:6]=1[NH2:21]
Reactant: CS(=O)(=O)OCC1CCCCCC1
Reactant: COC(=O)Nc1c(N)nc(-c2n[nH]c3ncccc23)nc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Nc1c(N)nc(-c2nn(CC3CCCCCC3)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg (1.0 mmol) of the compound of Example 1A and 224 mg (1.1 mmol) of cycloheptylmethyl methansulfonate (preparation: see J. Med. Chem. 2000, 43(26), 5017-5029) were initially charged in 5 ml of dimethylformamide, 354 mg (1.1 mmol) of cesium carbonate were added and the resulting mixture was stirred at RT overnight. 0.5 ml of 1N hydrochloric acid was added, and the entire solution was separated by HPLC (Method 5). The appropriate fractions were concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 2.8 mg (0.7% of theory) of the target compound.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:5]([CH2:7][C:8]1[S:9][C:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:12]=1)[CH3:6].[OH-].[Li+:26]>CO.O1CCCC1>[Li+:26].[C:16]([O:15][C:13]([C:10]1[S:9][C:8]([CH2:7][N:5]([CH3:6])[C@H:4]([C:3]([O-:24])=[O:2])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:12][CH:11]=1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@H](CC(C)C)N(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)[O-])N(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Reaction time: 8 h

Procedure:
The compound (0.87 g, 2.4 mmol) obtained in step 1 was dissolved in methanol (2.7 mL) and tetrahydrofuran (5.4 mL), 1N aqueous lithium hydroxide solution (2.7 mL) was added, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was lyophilized to give the title compound (0.83 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[N+:13]([O-])=O.OC1C=C2C(C=NNC2=O)=CC=1.[H][H]>[OH-].[Na+].[Pd]>[NH2:13][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[OH:1])[C:9](=[O:12])[NH:8][N:7]=[CH:6]2
Reactant: O=c1[nH]ncc2cc([N+](=O)[O-])c(O)cc12
Reactant: [H][H]
Agent: [Pd]
Agent: O=c1[nH]ncc2ccc(O)cc12
Agent: [Na+]
Product: Nc1cc2cn[nH]c(=O)c2cc1O

Procedure:
7-Hydroxy-6-nitro-1(2H)-phthalazinone (which may be prepared by the nitration of 7-hydroxy-1(2H)-phthalazinone) is dissolved in aqueous sodium hydroxide, reduced with hydrogen and 10% palladium on charcoal catalyst and the solution filtered and neutralised to give 6-amino-7-hydroxy-1(2H)-phthalazinone.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([N:15]2[CH2:20][CH2:19][O:18][C:17]([OH:30])([C:21]3N=C(C(F)(F)F)S[CH:25]=3)[CH2:16]2)[CH3:14])=[CH:8][CH:7]=1)([OH:3])=[O:2].C(CO[C:37]1[CH:42]=[CH:41]C(CC(N2CCOC(O)(C3N=C(C(F)(F)F)SC=3)C2)C)=[CH:39][CH:38]=1)(OC)=O>>[C:1]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]([N:15]2[CH2:20][CH2:19][O:18][C:17]([OH:30])([C:21]3[CH:39]=[CH:38][CH:37]=[C:42]([CH3:41])[CH:25]=3)[CH2:16]2)[CH3:14])=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(O)(c3csc(C(F)(F)F)n3)C2)cc1
Reactant: CC(Cc1ccc(OCC(=O)O)cc1)N1CCOC(O)(c2csc(C(F)(F)F)n2)C1
Product: Cc1cccc(C2(O)CN(C(C)Cc3ccc(OCC(=O)O)cc3)CCO2)c1

Procedure:
N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine from N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][N:9]([CH3:23])[CH2:10][C:11]3[N:12]([C:13](=O)[NH:14][C:15]=3[C:16]#[C:17][Si](C)(C)C)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-:24].[K+]>CO>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[CH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CN1Cc2c(Cl)cccc2-n2c(c(C#C[Si](C)(C)C)[nH]c2=O)C1
Agent: [K+]
Solvent: CO
Product: C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
12.7 g (37 mmol) of 7-chloro-4,5-dihydro-5-methyl-3-[(trimethylsilyl)ethynyl]-6H-imidazo[1,5-a][1,4]benzodiazepine--one was dissolved in 40 ml of methanol and treated with 40 ml of 1N potassium hydroxide solution. After stirring for 1 hour the methanol was distilled off and the aqueous suspension was cooled and suction filtered. After drying there was obtained 7-chloro-3-ethynyl-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 194°-195°.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][CH2:15][CH2:16][CH:17]([OH:19])[CH3:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:19][CH:17]([CH3:18])[CH2:16][CH2:15][NH:14][C:11]([C:1]12[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2)=[O:13]
Reactant: CC(O)CCN
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)CCNC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 8 h
Yield: 30.2 %

Procedure:
Adamantane-1-carboxylic acid (404 mg, 2.24 mmol), 4-amino-butan-2-ol (200 mg, 2.24 mmol), EDCI (885 mg, 4.48 mmol) and HOBt (605 mg, 4.48 mmol) were dissolved in anhydrous CH2Cl2. DIEA (1.444 g, 11.2 mmol) was added to the above mixture at 0° C. under nitrogen. The mixture was stirred overnight and concentrated to give a residue, which was purified by preparative TLC to provide N-(3-hydroxybutyl)adamantane-1-carboxamide (170 mg, 30%). 1H NMR (MeOD, 400 MHz): δ=1.20 (d, 3H), 1.66˜2.04 (m, 17H), 2.87 (m, 2H), 3.79(m, 1H).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].S(=O)(=O)(O)O.O.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)(=[O:20])[CH3:19]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reaction time: 8 h

Procedure:
Tranexamic acid (10 g, 63.6 mmol) was suspended in acetic anhydride (50 mL), this suspension was added with concentrated sulfuric acid (0.01 mL) at room temperature, and the mixture was stirred overnight at the same temperature. Under ice cooling, the reaction mixture was added with water (100 mL), and the mixture was stirred at room temperature for 1 hour to decompose excess acetic anhydride. The reaction solution was concentrated under reduced pressure, and the residue was further azeotroped with toluene. The resulting precipitates were collected by filtration, washed with ether, and dried under reduced pressure to obtain trans-{4-[(acetylamino) methyl]cyclohexyl}carboxylic acid as white solid (12.46 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][N:27]=[C:26]3[CH3:30])=[CH:21][CH:20]=2)[CH:5]=[C:6]([C:8]2([C:14](O)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl.[CH3:32][NH:33][CH3:34].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C1COCC1.O>[CH3:32][N:33]([CH3:34])[C:14]([C:8]1([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[CH3:30])=[CH:23][CH:24]=3)[CH:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:15]
Reactant: CNC
Reactant: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(=O)O)CCOCC3)c2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(=O)N(C)C)CCOCC3)c2)cc1
Reaction time: 0.17 h
Yield: 48.6 %

Procedure:
To a stirred suspension of 4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylic acid (100 mg, 0.24 mmol), dimethylamine hydrochloride (98 mg, 1.2 mmol) and triethylamine (253 mg, 2.5 mmol) in THF (50 ml) at 0° C. was added diethyl cyanophosphonate (44 mg, 0.27 mmol). After 10 min, the reaction was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water (50 ml) and brine (50 ml), dried over magnesium sulfate and concentrated. Purification of the residue was performed by column chromatography (silica-gel, 50 g; gradient polarity of eluant from dichloromethane to 5% methanol in dichloromethane) to give 117 mg of crude product as a colorless foam. Recrystallization from a mixture of isopropyl ether-ethyl acetate (1:1) to give the titled compound (51 mg, 50%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](Cl)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:13]=[CH2:12]
Reactant: C=CCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(C(=O)OC)cc1
Yield: 100.3 %

Procedure:
A solution of methyl 4-hydroxybenzoate (15.21 g, 0.10 mol), allyl chloride (11.48 g, 0.15 mol) and potassium carbonate (20.73 g, 0.15 mol) in N,N-dimethylformamide (40 mL) was stirred at 50° C. overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 19.27 g of the title compound (yield: 100%) as a pale yellow oil.