Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[NH:28][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(Nc2cc(-c3ccccn3)nc(-c3ccccn3)n2)c1
Yield: 60.5 %

Procedure:
A mixture 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol), m-anisidine (16 μl, 0.140 mmol) and 2N HCl (75 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was filtered, washed with water and aqueous ethanol to give a yellow solid (20 mg, 60%). 1H NMR (CDCl3): 8.87–8.85 (m, 1H), 8.69–8.61 (m, 3H), 7.95 (s, 1H), 7.92–7.84 (m, 2H), 7.44–7.36 (m, 2H), 7.33 (d, J=8.1 Hz, 1H), 7.30 (s, 1H), 7.05 (t, J=2.1 Hz, 1H), 6.98 (dd, J=2.1, 8.1 Hz, 1H), 6.79–6.75 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: [C:1]([S-:3])#[N:2].[K+].BrBr.[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>CO>[CH3:7][N:8]1[C:12]([S:3][C:1]#[N:2])=[CH:11][CH:10]=[CH:9]1
Reactant: Cn1cccc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CO
Product: Cn1cccc1SC#N
Temperature: -78 °C
Reaction time: 0.12 h
Yield: 93.2 %

Procedure:
Under nitrogen atmosphere, to a mixture of 25.08 g of KSCN (0.125 mole) in 60 ml dry methanol chilled to -78° C. was added dropwise 20 g of Br2 (in 40 ml methanol). The resulting yellow solution was stirred for 5-10 minutes and 10.1 g (0.125 mole) of the 1-methylpyrrole added in one portion. The mixture was allowed to warm to ambient temperature and stirred for one hour. The mixture was poured into 600 ml of ice-water, extracted 2 times with 300 ml CH2Cl2. The CH2Cl2 extract was dried and concentrated to 16.1 g (90% yield) of 1-methyl-5-cyanothiopyrrole.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=2)[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:21]([O-])([OH:23])=[O:22].O>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[C:16]=2[N+:21]([O-:23])=[O:22])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc2cc(O)ccc2c1)c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=C(Oc1ccc2c([N+](=O)[O-])c(O)ccc2c1)c1ccccc1

Procedure:
The thus obtained 6-hydroxy-2-naphthyl benzoate was dispersed in acetic acid, nitric acid was added dropwise to the dispersion while keeping it at 15° C., and water was further added thereto, followed by stirring. The thus obtained deposit was recrystallized from ethanol/acetic acid to obtain 6-hydroxy-5-nitro-2-naphthyl benzoate.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH2:25])[C:9]1=[O:26])=[O:6])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32]([NH:34][C@H:35]([C:43](O)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C.O.C(N(CC)CC)C>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH:25][C:43](=[O:44])[C@@H:35]([NH:34][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]1=[O:26])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)C(=O)CN1C(=O)C(N)CN(c2ccccc2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1CN(c2ccccc2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Reaction time: 0.08 h
Yield: 100 %

Procedure:
1-tert-Butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (3.62 g) was dissolved in anhydrous N,N-dimethyl formamide (30 ml) under argon atmosphere, N-tert-butoxycarbonyl-L-phenylalanine (3.00 g), 1-hydroxybenzotriazole (1.73 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.17 g) and triethylamine (2.08 g) were added at ice-cooling, thereto the mixture was stirred for 5 minutes under ice-cooling, and stirred at room temperature for one hour. Water and ethyl acetate were added to the reaction mixture, separated, the organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 6.17 g of the title compound.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[CH2:5][NH:4]1.C=O.[CH:18](O)=O.C([O-])=O.[Na+]>O>[ClH:1].[CH3:18][N:4]1[CH:3]([CH3:2])[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[CH2:5]1
Reactant: O=CO
Reactant: CC1Cc2ccc([N+](=O)[O-])cc2CN1
Agent: C=O
Agent: Cl
Agent: O=C[O-]
Solvent: O
Product: CC1Cc2ccc([N+](=O)[O-])cc2CN1C

Procedure:
To 3-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.0 g, 8.75 mmol) in 37% formaldehyde (7.0 ml, 87.5 mmol) was added 96% formic acid (3.5 ml, 87.5 mmol) and sodium formate (0.60 g, 8.75 mmol). The mixture was heated at reflux for 1 h, cooled, dumped into basic water and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to an oil. The oil was dissolved in ethanol and treated with isopropanol-HCl. The solids were collected by filtration (2.0 g, 95%), m.p. 242-244° C.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:25]=[C:24]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[CH:23]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+].Cl>C(O)C.O>[O:37]1[C:36]2[CH:40]=[CH:41][C:33]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)C(C)C)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.6 %

Procedure:
To a solution of 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-isobutyryl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (191 mg) in ethanol (2 mL) was added 10 M NaOH (566 μL) and the resulting mixture was stirred at room temperature for 5 h. Then the reaction mixture was diluted with water, acidified with 3 N HCl and extracted into ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified on a reverse-phase HPLC to yield 50 mg of the title compound (29% yield). HRMS calcd for C36H42O9 [M+Na]+ 641.2721, observed 641.2720.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[Cl:13][C:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: OB(O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2ccnc(Cl)c2)c2ccccc12
Temperature: 160 °C

Procedure:
A mixture of 4-chlorophthalazin-1(2H)-one (300 mg, 1.66 mmol), 2-chloropyridin-4-ylboronic acid (314 mg, 1.99 mmol), Cs2CO3 (1080 mg, 3.32 mmol) and PdCl2(dppf) (71.5 mg, 0.083 mmol) in dioxane (6 mL) was heated at 160° C. under microwave condition for 20 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated to afford the title compound: MS (APCI) M/Z 257 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5](CC2C=CC(OC)=CC=2)[C:4](=[O:22])[C:3]=1[C:23]#[N:24]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4](=[O:22])[C:3]=1[C:23]#[N:24]
Reactant: COc1ccc(Cn2c(=O)c(C#N)c(Cl)c3cc(F)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(Cl)c2cc(F)cnc2[nH]c1=O
Yield: 93 %

Procedure:
4-Chloro-6-fluoro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (94) (4.3 g, 12.50 mmol) in neat TFA was refluxed for 24 h. The solution was cooled and excess TFA was distilled off under reduced pressure. The residue was taken in water, basified by solid NaHCO3 and filtered. The solids were washed with excess water and dried to yield 2.6 g (96%) of 4-chloro-6-fluoro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (96) as white solids. MP: 272° C.; 1H-NMR (DMSO-d6): δ 8.26 (dd, J=2.8, 8.2 Hz, 1H), 8.81 (d, J=2.8 Hz, 1H), 13.03 (S, 1H); EIMS: 224 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[N+:13]([C:16]1[C:28]([OH:29])=[CH:27][C:26]2[C@@H:25]3[C@@H:20]([NH:21][CH2:22][CH2:23][CH2:24]3)[CH2:19][C:18]=2[CH:17]=1)([O-:15])=[O:14]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:21]3[CH2:22][CH2:23][CH2:24][C@@H:25]4[C:26]5[CH:27]=[C:28]([OH:29])[C:16]([N+:13]([O-:15])=[O:14])=[CH:17][C:18]=5[CH2:19][C@H:20]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cc2c(cc1O)[C@H]1CCCN[C@H]1C2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cc(O)c([N+](=O)[O-])cc3C[C@@H]21
Yield: 32 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-7-nitro-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-ol following a procedure analogous to that described in Example 1. Yield: 32% of theory; LC (method 1): tR=2.43 min; Mass spectrum (ESI+): m/z=379 [M+H]+.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:18][CH3:19])[C:16]=1[OH:17])[CH:12]=O.S([O-])([O-])(=O)=O.O[NH3+:26].O[NH3+].ClC1C2C(=CC=CC=2)C=CC=1>ClCCl>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:18][CH3:19])[C:16]=1[OH:17])[C:12]#[N:26]
Reactant: COc1cc(C=O)cc(Br)c1O
Reactant: [NH3+]O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Clc1cccc2ccccc12
Solvent: ClCCl
Product: COc1cc(C#N)cc(Br)c1O
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
With stirring (20 rpm), a turbine dryer is charged at room temperature with 1280 parts by weight of anhydrous sodium sulfate, 462 parts by weight of 3-bromo-4-hydroxy-5-methoxybenzaldehyde, 172 parts by weight of hydroxylammonium sulfate and 298 parts by weight of 1-chloronaphthalin. Following evacuation to 70 mbar, the mixture is heated to 130° C. and kept at this temperature for 31/2 hours. The reaction mixture is then cooled to 30° C. and nitrogen is introduced until atmospheric pressure is reached. After 2650 parts by weight of dichloromethane are added, the suspension is kept for 20 min at room temperature while further stirred and then filtered. The filter cake is extracted three times each with 2000 parts by weight of dichloromethane. The solvent extracts are combined with the first filtrate and evaporated to 1/3 of their volume. The solution of the raw product in dichloromethane is subjected to column chromatography using 1400 parts by weight of silica gel 60 [70-230 mesh (Merck)] and 26500 parts by weight of dichloromethane as eluent. After a portion corresponding to the dead volume of the column is first discarded, the next 17000 parts by weight are collected in one fraction and evaporated to dryness. The residue is freed from traces of adsorbed 1-chloronaphthalin at 80° C. in the vacuum. 334.5 parts by weight of 3-bromo-4-hydroxy-5-methoxybenzonitrile are obtained with a purity of over 98% (TLC) and a melting point of 144°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[OH:10].[CH3:11][O:12]C(Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:10][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH:11]=[O:12])=[C:6]([CH3:9])[CH:5]=1
Reactant: COc1ccc(C)cc1O
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C=O)c(C)cc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-methoxy-5-methylphenol (50.0 g, 362 mmol) in CH2Cl2 (1000 mL) at −5° C. were added titanium (IV) chloride (80.0 mL, 724 mmol) slowly via syringe (internal temperature was kept below 0° C. during addition) and dichloromethyl methyl ether (52.9 mL, 593 mmol). After being stirred at room temperature for 3 h, the mixture was poured into ice water. The resulting precipitate was collected by filtration and then washed with EtOAc and Et2O to afford 4-Hydroxy-5-methoxy-2-methylbenzaldehyde. 1H NMR (CDCl3) δ 10.22 (s, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.14 (s, 1H), 3.96 (s, 3H), 2.62 (s, 3H); LC/MS: (IE, m/z) (M+1)+=16.0; tR=2.06 min.
Reaction SMILES: [CH3:1][Si:2]([CH3:53])([CH3:52])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[CH:9]=1.[Br:54]N1C(=O)CCC1=O>CC#N.ClCCl>[CH3:51][Si:48]([CH3:50])([CH3:49])[CH2:47][CH2:46][O:45][CH2:44][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:52])[CH3:53])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH:31]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:34]([CH2:33][CH2:32]3)[CH2:35]2)[C:9]=1[Br:54]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a mixture of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g, 2.3 mmol) in CH3CN (10 mL) and dichloromethane (10 mL) was added N-bromosuccinimide (0.45 g, 2.5 mmol) portionwise and the resulting mixture was stirred at room temperature for 0.5 h, at which time LC/MS confirmed full conversion of starting material to product. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-50%) gave tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g, 93%).
Reaction SMILES: [NH:1]([C:5]1[C:6]([F:13])=[CH:7][C:8]([Cl:12])=[C:9]([SH:11])[CH:10]=1)C(C)=O.[OH-].[Na+].Cl>O>[NH2:1][C:5]1[C:6]([F:13])=[CH:7][C:8]([Cl:12])=[C:9]([SH:11])[CH:10]=1
Reactant: CC(=O)Nc1cc(S)c(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(S)c(Cl)cc1F
Yield: 97.2 %

Procedure:
Into a 100 ml reaction flask, 4.8 g (0.022 mol) of 5-acetamino-2-chloro-4-fluoro-thiophenol, 2.55 g (0.064 mol) of sodium hydroxide and 25.5 cc of water were added and stirred under reflux for 4 hours to obtain a uniform solution. The solution was cooled to room temperature and neutralized with 10% hydrochloric acid. The precipitated solid was extracted with 25 cc of ethyl acetate, followed by removal of water and distillation under reduced pressure to obtain 3.8 g of 5-amino-2-chloro-4-fluoro-thiophenol as slightly yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4](Cl)[N:3]=1.[Na].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18]>>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[CH:5]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: COCCOCCO
Agent: [Na]
Product: COCCOCCOc1cc(N)nc(N)n1
Temperature: 80 °C
Yield: 109 %

Procedure:
28.9 g (0.20 mol) of 2,4-diamino-6-chloropyrimidine was added to a solution of 4.6 g (0.20 mol) of sodium in 178 ml of 2-(2-methoxyethoxyl)ethanol and heated to 80° C. for 48 h while stirring was performed. After termination of the reaction, the precipitated NaCl was separated and the solution was concentrated to dryness. The residue was taken in ethanol multiple times and concentrated again in order to remove remaining 2-(2-methoxyethoxyl)ethanol. After drying, 6-[2-(2-methoxyethoxyl)ethoxy]pyrimidine-2,4-diamine (49.8 g, 109%) was obtained as brown oil, which still contained 2-(2-methoxyethoxyl)ethanol as a contaminant.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].C(#N)C.O.C1(C)C=CC=CC=1>CC(C)=O.CCCCCC>[CH:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(O)cc1
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: C#Cc1ccc(O)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 17.7 %

Procedure:
32.1 g of the p-vinylphenol-containing fraction as a polymerization raw material was poured into a 300-ml flask. Thereto was added 29.4 g of acetonitrile. The resulting mixture was stirred with cooling by water of room temperature. Thereto was dropwise added 1.0 ml of an acetonitrile solution of 2% of a boron trifluoride-diethyl ether complex. Then, a polymerization reaction was conducted for 30 minutes. During the period, the temperature of the reaction system was maintained at 25 to 35° C. The reaction mixture was poured into 300 ml of toluene, followed by stirring. The resulting precipitate was recovered. The precipitate was dissolved again in 50 ml of acetone. The resulting solution was poured into 300 ml of toluene to form a precipitate. This precipitate was dissolved in 50 ml of acetone. The resulting solution was poured into 300 ml of hexane for reprecipitation. The thus-purified polymer was dried under vacuum to obtain 5.6 g of a white poly(p-vinylphenol). The poly(p-vinylphenol) had a weight-average molecular weight (Mw) of 29,200, a number-average molecular weight (Mn) of 14,300, a far-ultraviolet light transmittance at a wavelength of 248 nm (sample concentration: 0.1 g per liter of ethanol solution, cell length: 1 cm) of 79.4% (the far-ultraviolet light transmittance is hereinafter abbreviated as light transmittance), a light transmittance at a wavelength of 450 nm (sample concentration. 1.0 g per liter of ethanol solution, cell length: 10 cm) of 96.1%, and a glass transition temperature of 182° C. Incidentally, the w/Mn as an indicator of molecular weight distribution was 2.04.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]#[N:13])[C:6]=1[Br:14])(=[O:3])[CH3:2].Cl[CH2:16][C:17](=[O:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:17]([C:18]1[O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:1]([CH3:2])=[O:3])=[C:6]([Br:14])[C:7]=2[C:12]=1[NH2:13])(=[O:19])[CH3:16]
Reactant: CC(=O)Oc1ccc(O)c(C#N)c1Br
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2oc(C(C)=O)c(N)c2c1Br
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a mixture of 12D (7 g, 0.027 mol) and 1-chloro-propan-2-one (3 mL) in DMF (30 mL) was added K2CO3 (4.1 g, 0.029 mol). The reaction mixture was stirred at 90° C. for 1 hour. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and added dropwise to ice-water. The precipitated solids were collected by filtration to give a crude product 12E (6.8 g, 79.6% yield).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:26][C:27]([F:44])([F:43])[C@H:28]([O:30][C:31](=O)[O:32]C1C=CC([N+]([O-])=O)=CC=1)[CH3:29]>>[F:26][C:27]([F:44])([F:43])[C@H:28]([O:30][C:31]([N:23]1[CH2:24][CH2:25][CH:20]([C@@H:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:32])[CH3:29]
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Product: C[C@@H](OC(=O)N1CCC([C@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (R)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=0.97 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:18]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)(=[O:20])=[O:19])=[N:6][CH:7]=1
Reactant: COc1cc(Br)cnc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: COc1cc(Br)cnc1NS(=O)(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
To a solution of 5-bromo-3-methoxypyridin-2-amine (100 mg, 0.493 mmol) in pyridine (1 mL) stirred in air at room temperature was added a solution of 4-fluorobenzene-1-sulfonyl chloride (115 mg, 0.591 mmol) in pyridine (1 mL). The reaction mixture was stirred at 20° C. for 16 hours then the solvent was evaporated in vacuo to give the crude product. The crude was passed through an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol followed by 2M ammonia/methanol, then a sulphonic acid (SCX) SPE cartridge eluting with methanol followed by 2M ammonia/methanol. The appropriate fractions were combined and evaporated under a stream of nitrogen to give the crude product. Final purification by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane+0-20% methanol gradient), gave the title product (133 mg) as an off-white solid. LCMS (2 min, formic) Rt 1.03 min, m/z (ES+) 361/363 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18]C)=[O:17])=[CH:8]2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O.[OH-].[K+].[ClH:29]>CO>[ClH:29].[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:18])=[O:17])=[CH:8]2)[CH:4]=[N:3]1
Reactant: COC(=O)c1cn(-c2cnn(C)c2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-n2cc(C(=O)O)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carboxylate, TFA (3.5 mg, 9.48 μmol) in MeOH (95 μl) was added a solution of aq. KOH (33.2 μl, 0.066 mmol, 2 M). The reaction mixture was stirred at RT overnight, then acidified with 1N HCl. The solvent was evaporated under reduced pressure and the residue was dried under vacuum overnight. The title compound was used without further purification.