Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]([C:13](=O)[CH2:14][CH3:15])=[C:11](O)[C:10](=[O:18])[N:9]2[C:19]2[CH:20]=[C:21]([CH3:27])[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[CH:4][CH:3]=1.O.[NH2:29][NH2:30].C(O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3[C:13]([CH2:14][CH3:15])=[N:30][NH:29][C:11]=3[C:10](=[O:18])[N:9]2[C:19]2[CH:20]=[C:21]([CH3:27])[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: CCC(=O)C1=C(O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Reaction time: 18 h
Yield: 64.7 %

Procedure:
A mixture of 5-(2-(4-chlorophenyl)-4-hydroxy-5-oxo-3-propionyl-2,5-dihydro-1H-pyrrol-1-yl)-1,3-dimethylpyridin-2(1H)-one (Step 147.1) (1.5 g, 3.88 mmol), hydrazine monohydrate (0.942 mL, 19.39 mmol), ethanol (8 mL) and toluene (8 mL) was stirred for 18 h at reflux. The reaction mixture was concentrated, diluted with acetic acid (50 mL), stirred for 1 h at reflux, diluted with CH2Cl2/saturated aqueous solution of NaHCO3, and extracted twice with CH2Cl2. The combine organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH 7.5%) and subsequent trituration of the resulting product in diethyl ether to afford 961 mg of the title compound as a yellow solid. tR: 0.82 min (LC-MS 2); ESI-MS: 383.1 [M+H]+ (LC-MS 2); Rf=0.19 (NH3 1%/CH2Cl2/MeOH 5%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.64 Hz, 3H) 1.94 (s, 3H) 2.35-2.47 (m, 2H) 3.38 (s, 3H) 6.15 (s, 1H) 7.25 (d, J=8.44 Hz, 2H) 7.31-7.51 (m, 3H) 7.73 (d, J=2.69 Hz, 1H) 13.41 (br. s., 1H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1C=O.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[CH:27](OC)([O:30][CH3:31])[O:28][CH3:29]>ClCCl>[CH3:29][O:28][CH:27]([O:30][CH3:31])[C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1]
Reactant: COC(OC)OC
Reactant: O=Cc1sccc1Br
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: COC(OC)c1sccc1Br
Yield: 97 %

Procedure:
After dissolving 5.97 g of 3-bromothiophene-2-carboxaldehyde in 90 ml of dichloromethane, a mixture of 8.0 g of montmorillonite K-10 and 120 ml of trimethyl orthoformate was added while stirring and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and then the solvent was distilled off under reduced pressure to obtain the title compound (7.21 g, 97% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=4)[CH:20]=3)[CH2:14][CH2:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[C:41]([C:45]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH3:54])=[C:47]([O:55][CH3:56])[CH:46]=2)[CH:40]=1>>[ClH:37].[ClH:37].[ClH:37].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=4)[CH:20]=3)[CH2:16][CH2:17]2)[CH2:38][C:39]2[CH:44]=[CH:43][N:42]=[C:41]([C:45]3[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH3:54])=[C:47]([O:55][CH3:56])[CH:46]=3)[CH:40]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc(OC)c1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(OC)cc(N(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)c1
Product: Cl

Procedure:
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:41][C:42]#[C:43][C:44]([CH2:55][CH3:56])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH2:45][CH3:46].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:41][C:42]#[C:43][C:44]([CH2:55][CH3:56])([O:47][Si:48]([CH2:53][CH3:54])([CH2:49][CH3:50])[CH2:51][CH3:52])[CH2:45][CH3:46])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(C#CCBr)(CC)O[Si](CC)(CC)CC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#CCOC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 37.7 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (100 mg, 0.17 mmol), 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (150 mg, 0.47 mmol), sodium hydride (60% in oil, 41 mg, 1.02 mmol), 15-crown-5 (37 mg, 0.17 mmol) and tetrahydrofuran (3 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (at room temperature for 17 hours), worked up and purified by preparative thin layer chromatography (3 sheets (each 1.0 mm thickness), hexane:toluene=1:1) to give the titled compound (52 mg, 37.7%) as a yellow oil.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:39][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][CH:36]=1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1cccc(F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cccc(F)c1

Procedure:
Compound 66 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound. LC/MS [341 (M+H)].
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH2:27][CH2:28][C:29]([NH:31][NH2:32])=[O:30])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14].Cl>C(OCC)(OCC)OCC.C(OCC)(=O)C>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([CH2:27][CH2:28][C:29]2[O:30][CH:1]=[N:32][N:31]=2)[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]=1[OH:22])([CH3:12])[CH3:14]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CCc2nnco2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 774.4 %

Procedure:
A catalytic amount of p-toluenesulfonic acid (25 mg) is added to a stirring solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid hydrazide (0.50 g, 1.71 mmol) in triethyl orthoformate (10 mL). After 30 minutes, 10 mL of 1N hydrochloric acid is added, and stirring is continued for 30 minutes. The reaction mixture is diluted with ethyl acetate and washed twice with a saturated solution of sodium bicarbonate, twice with water, and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a crude product which is chromatographed on a column of silica with ethyl acetate/hexane (1/9 then 1/4) to afford 0.34 g (67%) of 2,6-bis(1,1-dimethylethyl)-4-[2-(1,3,4-oxadiazol-2-yl)ethyl]phenol, mp 100.0°-101.0° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1C)#[CH:2].BrC1C2C(=CC=CC=2)C=CC=1C.Br[C:27]1C2C(=CC=CC=2)C=C[C:28]=1[N:37](CC)[CH2:38][CH3:39]>>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[N:37]([CH2:38][CH3:39])[CH2:28][CH3:27])#[CH:2]
Reactant: CCN(CC)c1ccc2ccccc2c1Br
Reactant: C#Cc1c(C)ccc2ccccc12
Agent: Cc1ccc2ccccc2c1Br
Product: C#Cc1c(N(CC)CC)ccc2ccccc12

Procedure:
1-Ethynyl-2-diethylaminonaphthalene was prepared in a similar manner to 1-ethynyl-2-methylnaphthalene, except that 1-bromo-2-methylnaphthalene was replaced by 1-bromo-2-diethylaminonaphthalene.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:22][CH3:23])[C:9]=3[CH:8]2[S:24][CH2:25][CH2:26][C:27](O)=[O:28])=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>C(Cl)Cl>[CH2:36]([N:38]([CH2:39][CH3:40])[C:27](=[O:28])[CH2:26][CH2:25][S:24][CH:8]1[C:9]2[C:10]([O:22][CH3:23])=[C:11]3[C:16](=[C:17]([OH:21])[C:18]=2[C:19](=[O:20])[N:7]1[CH2:6][C:5]1[CH:30]=[CH:31][C:2]([F:1])=[CH:3][CH:4]=1)[N:15]=[CH:14][CH:13]=[CH:12]3)[CH3:37]
Reactant: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2SCCC(=O)O
Reactant: CCNCC
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CC)C(=O)CCSC1c2c(c(O)c3ncccc3c2OC)C(=O)N1Cc1ccc(F)cc1

Procedure:
A solution of 24 (10.7 mg, 0.024 mmol) in CH2Cl2 (0.24 mL) was stirred with EDC (14 mg, 0.73 mmol) and diethyl amine (10 μL, 0.097 mmol) for 1 day at ambient temperature. The product 25 was purified by reverse phase HPLC using 5-95% A. Buffer A contained CH3CN—1% HOAc and B contained H2O—1% HOAc. 1H NMR (300 MHz, CDCl3) δ 0.984 (t, 3H, J=6 Hz), 1.05 (t, 3H, J=7 Hz), 2.23-2.45 (m, 4H) 3.04 (q, 2H, J=7 Hz), 3.29 (q, 2H, J=8 Hz), 4.06 (s, 3H), 4.47 (d, 1H, J=14 Hz), 5.31 (d, 1H, J=15 Hz), 5.50 (s, 1H), 7.05 (t, 2H, J=9 Hz), 7.36-7.44 (m, 2H), 7.55-7.62 (m, 1H), J=9 Hz), 8.95-9.00 (m, 1H); EI MS (m/z) 520.2 [MH+], 1016.9 [2M+Na].
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH2:9]O)[C:3]=1[CH3:11].CN(C=O)C.S(Cl)([Cl:19])=O.C(O)C>C1(C)C=CC=CC=1>[Cl-:1].[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][NH+:5]=[C:4]([CH2:9][Cl:19])[C:3]=1[CH3:11]
Reactant: Cc1cnc(CO)c(C)c1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1c[nH+]c(CCl)c(C)c1Cl
Product: [Cl-]
Temperature: 25 °C

Procedure:
To a solution of 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine (60.7 g, 354 mmol) and DMF (0.25 mL, 3.54 mmol) in toluene (200 mL) was added thionyl chloride (26.9 mL, 371 mmol) over 2 h at 15-30° C. After stirring for 2 more h at ambient temperature, ethanol (6 mL) was added to the thick slurry. The solids were filtered off at about 10° C., washed with toluene (80 mL) and dried at 40° C. in vacuo to give 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride as an off-white solid (m. p. 195-196° C.); yield 66.5 g (84%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=2)=[C:10]([CH3:22])[CH:9]=1.[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:23][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)[CH:15]=2)=[C:10]([CH3:22])[CH:9]=1
Reactant: Cc1cc(Cl)ccc1-c1cccc(CCl)c1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1-c1cccc(COc2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium carbonate was added to a DMF solution of 4-chloro-3′-(chloromethyl)-2-methylbiphenyl and 4-hydroxybenzaldehyde, followed by stirring at room temperature for 20 hours to obtain 4-[(4′-chloro-2′-methylbiphenyl-3-yl)methoxy]benzaldehyde.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 3 h

Procedure:
12.8 g (29.2 mmol) 2-[3-(1-diphenylmethylpiperidine-4-yl)-propyl]-isoindol-1,3-dione are suspended in 110 ml ethanol and added to 2.2 ml (58.4 mmol) hydrazine hydrate and heated to boiling for three hours. After cooling, the mixture is concentrated under vacuum. The residue is dispersed between 300 ml dichloromethane and 50 ml 10% sodium hydroxide solution. The aqueous phase is extracted twice, each with 200 ml dichloromethane. The combined organic phases are washed twice, each with 20 ml water, and dried over sodium sulfate. The solvent is removed under vacuum and the residue is processed fruther without additional purification. Yield 7.3 g (81%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27]>>[CH2:26]([S:28]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:30])=[O:29])[CH3:27]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CCS(=O)(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 7.6 μL (0.11 mmol) ethanesulfonyl chloride. MMR was consistent with the proposed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]2[C:26]3[O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:25]=3[CH:24]=[CH:23][CH:22]=2)[CH:18]=[C:17]([Cl:34])[C:3]=1[O:4][C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7].CO.[OH-].[Na+].Cl>C1COCC1.O>[Cl:34][C:17]1[CH:18]=[C:19]([C:21]2[C:26]3[O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:25]=3[CH:24]=[CH:23][CH:22]=2)[CH:20]=[C:2]([Cl:1])[C:3]=1[O:4][C@H:5]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Cl)cc(-c2cccc3c2oc2ccccc23)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Cl)cc(-c2cccc3c2oc2ccccc23)cc1Cl
Reaction time: 3 h

Procedure:
A solution of Example 1B (1.03 g, 2.10 mmol) in a mixture of THF (4 mL), methanol (6 mL), and water (3 mL) at room temperature was treated with NaOH (0.42 g, 10.5 mmol), stirred for 3 hours, adjusted to pH <7 with 1N HCl, and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated to provide a quantitative yield of the desired product.
Reaction SMILES: NC1C=CC=CC=1C(O)=O.C(N)=O.[N+]([O-])(O)=O.S(=O)(=O)(O)O.O[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.S(Cl)([Cl:39])=O>>[Cl:39][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(O)c2c1
Reactant: O=S(Cl)Cl
Agent: Nc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: NC=O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1

Procedure:
In brief, 2-aminobezoic acid substituted by a reactive group (G in Scheme 3), is reacted with formamide, at 160° C., for 3 hours. The resulting 4-hydroxyquinazolinesubstituted by the reactive group is then reacted with a mixture of nitric acid and sulfuric acid, to thereby obtain 4-hydroxy-6-nitroquinazoline substituted by the reactive group. The reactive 4-hydroxy-6-nitroquinazoline is thereafter reacted with thionyl chloride, so as to obtain 4-chloro-6-nitroquinazoline substituted by a reactive group. In these compounds, the nitro group serves as a first reactive group and G is a second reactive group.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11]Br)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[NH2:14][C:15]([NH2:17])=[S:16].C([O-])(O)=O.[Na+]>CCO.O>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:15]([NH2:17])[S:16][CH:11]=2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: NC(N)=S
Reactant: [N-]=[N+]=Nc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=Nc1ccc(-c2csc(N)n2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-azidophenyl)-2-bromoethanone (1.37 g, 5.71 mmol) in EtOH (15 mL) at room temperature was added thiourea (0.476 g, 6.25 mmol). The reaction mixture was heated to 70° C. for 3 d, poured into a solution of NaHCO3 (602 mg) in water (50 mL) and stirred for 30 min. The precipitate that formed was collected by filtration, washed with water, and dried under high vacuum to give 4-(4-azidophenyl)thiazol-2-amine.
Reaction SMILES: [Li]OC(C)=O.O.O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][C:15](C(O)=O)=[CH:14][C:13]=2[CH:21]=1.C1C(=O)N([Br:29])C(=O)C1>CC#N.O>[Br:29][C:15]1[CH2:16][O:17][C:12]2[C:13]([CH:14]=1)=[CH:21][C:9]([Cl:8])=[CH:10][CH:11]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2OC1
Agent: [Li]OC(C)=O
Solvent: O
Solvent: CC#N
Product: Clc1ccc2c(c1)C=C(Br)CO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.6 %

Procedure:
To a solution of LiOAc.2H2O (0.16 g, 1.62 mmol) in 97:3 CH3CN/H2O (30 mL) was added 6-chloro-2H-1-benzopyran-3-carboxylic acid (1.43 g, 8.12 mmol), followed by NBS (1.52 g, 8.53 mmol) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was then concentrated to dryness under reduced pressure. Purification by flash column chromatography (gradient, hexanes, then 98:2 to 90:10 hexanes/Et2O) gave 3-bromo-6-chloro-2H-chromene (0.47 g, 27%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.14-7.10 (m, 1H), 6.94-6.88 (m, 2H), 6.79 (d, J=8.1 Hz, 1H), 6.75 (s, 1H), 4.88 (d, J=1.5 Hz, 2H).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].NC1C=CC(C(O)C)=C([Cl:46])C=1>>[Cl:46][C:19]1[CH:18]=[C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[O:24])[CH:16]=[CH:15][C:14]=1[N:13]1[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:1][CH3:2]
Reactant: CC(O)c1ccc(N)cc1Cl
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4,6-Dimethyl-3-nitro-2-pyridine (0.66 g, 3.8 mmol, step 2 of Example 1) and 4-amino-2-chloro-phenylethanol (0.72 g, 3.8 mmol, Eur. J. Med. Chem., 1996, 31, 133.).
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14](Cl)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1.O.O1CCCC1.[Cl-].[NH4+]>C(O)C.[Zn]>[Cl:1][C:2]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1
Reactant: Fc1ccc2nn3c(Cl)c(-c4ccccc4)c(Cl)nc3c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2nn3cc(-c4ccccc4)c(Cl)nc3c2c1
Temperature: 25 °C

Procedure:
7.2 g (21.7 mmol) 2,4-Dichloro-9-fluoro-3-phenylpyrimido[1,2-b]indazole were suspended in a mixture of 551 mL ethanol, 392 mL water and 211 mL tetrahydrofuran. After addition of 5.5 g (102.7 mmol) ammonium chloride and 9.1 g (138.7 mmol) zinc the mixture was stirred over night at room temperature. The mixture was filtered via a glass fibre filter, and the organic solvents were removed. The product which precipitated was filtered off (3.4 g=51.9%). 3.4 g (42.2%) of the starting material wereregained by stirring the zinc slurry with 1 L ethyl acetate, filtration of the zinc via a glass fibre filter and evaporation of the organic solvent. The product was contaminated with 9-fluoro-3-phenylpyrimido[1,2-b]indazole (25%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][OH:25])[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16]([O:17][S:34]([CH3:33])(=[O:36])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccccc1C(O)c1cc(F)ccc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCc1ccccc1C(OS(C)(=O)=O)c1cc(F)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of (±)-(2-benzyloxy-5-fluoro-phenyl)-(2-hydroxymethyl-phenyl)-methanol (500 mg, 1.48 mmol, 1.00 eq.) and DMAP (9 mg, 0.07 mmol, 0.05 eq.) in DCM (30 mL), NEt3 (0.82 mL, 5.91 mmol, 4.00 eq.) and methanesulfonyl chloride (0.24 mL, 3.10 mmol, 2.10 eq.) were added dropwise. The mixture was stirred at 0° C. for 1 hour and further at r.t. for 2 hours. The reaction mixture was diluted with H2O (50 mL) and DCM (50 mL). The layers were separated. The aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were washed with water (1×150 mL), sat. aq. NaCl soln. (1×50 mL), dried over MgSO4, and concentrated in vacuo to give (±)-methanesulfonic acid 2-[(2-benzyloxy-5-fluoro-phenyl)-methanesulfonyloxy-methyl]-benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[N:26]1([CH2:32][CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:33][CH2:32][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCN2CCCCC2)cc1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCN4CCCCC4)cc32)nc1-c1cccc(Cl)c1
Yield: 56 %

Procedure:
To a mixture of 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.060 g (0.2 mmole) of toluene-4-sulfonic acid 2-piperidin-1-yl-ethyl ester and 1 mL of dimethylformamide was added 0.160 g (0.5 mmole) of cesium carbonate. The reaction mixture was heated at 100 degrees for 3 hours. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 30:70-100:0) to give 0.027 g of 4-(3-chloro-phenyl)-2-[6-(2-piperidin-1-yl-ethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.27) as a white powder. MH+/Z=482