Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[Cl:9][CH2:10][CH2:11][N:12]1[CH:20]=[N:19][C:18]2[C:13]1=[N:14][C:15]([NH2:22])=[N:16][C:17]=2[NH2:21]>>[NH2:21][C:17]1[N:16]=[C:15]([NH:22][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:14]=[C:13]2[C:18]=1[N:19]=[CH:20][N:12]2[CH2:11][CH2:10][Cl:9]
Reactant: O=Cc1ccncc1
Reactant: Nc1nc(N)c2ncn(CCCl)c2n1
Product: Nc1nc(NCc2ccncc2)nc2c1ncn2CCCl

Procedure:
6-amino-9-(2-chloroethyl)-2-[(4-pyridylmethyl)amino]-purine was prepared from 4-pyridinecarboxaldehyde and 9-(2-chloroethyl)-2,6-diamino-purine according to the procedure described in example 12 step B. The crude product was purified by flash chromatography (DCM/MeOH 99.5/0.5→80:20) to give the desired product as white solid.
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8]C)=[O:6])C.[NH2:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]1>CO>[CH3:20][C:14]1([CH3:21])[CH2:13][CH:12]([NH:11][C:4](=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: CO
Product: COC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1

Procedure:
Methyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate was prepared from diethyloxalate and 4-amino-2,2,6,6-tetramethylpiperidine according to the first step in Example III, Method B. The ethyl ester undergoes ester interchange in methanol to form the methyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3](=[O:18])[C:4]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH3:1][C:2]([CH3:20])([CH3:19])[C:3](=[O:18])[CH:4]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH:5]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)[S:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)C(=O)C(=Cc1ccc(F)cc1)n1cncn1
Solvent: CCO
Product: CC(C)(C)C(=O)C(C(Sc1ccccc1)c1ccc(F)cc1)n1cncn1
Reaction time: 1 h
Yield: 90.5 %

Procedure:
27.3 g (0.1 mol) of 4,4-dimethyl-1-(4-fluorophenyl)-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one (E,Z isomer mixture) and 11 g (0.1 mol) of thiophenol were stirred with 100 ml of ethanol at room temperature. After 1 hour, the crystals which had separated out were filtered off and dried. 34.7 g (91% of theory) of 4,4-dimethyl-1-(4-fluorophenyl)-1-phenylthio-2-(1,2,4-triazol-1-yl)-pentan-3-one, of melting point 175° C., were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH2:24](B(O)O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(Cl)cc3)c2c1O
Reactant: OB(O)Cc1ccccc1
Product: CCOC(=O)c1nc(Cc2ccccc2)c2snc(-c3ccc(Cl)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-3-(4-chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and benzylboronic acid: MS (m/z) 425.1 (M+1).
Reaction SMILES: [CH2:1]([C@@H:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C@H:17]3[CH2:26][CH2:25][C@@:19]4([NH:23]C(=O)[O:21][CH2:20]4)[CH2:18]3)[CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH2:23][C@:19]1([CH2:20][OH:21])[CH2:25][CH2:26][C@H:17]([C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][C@H:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:15][C:14]=3[CH:13]=2)[CH2:18]1
Reactant: CCCCCC[C@@H]1CCc2cc([C@H]3CC[C@]4(COC(=O)N4)C3)ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCCC[C@@H]1CCc2cc([C@H]3CC[C@](N)(CO)C3)ccc2C1
Temperature: 100 °C
Yield: 78.2 %

Procedure:
To a mixture of (5R,7S)-7-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one (400 mg, 1.125 mmol) in dioxane (30 mL) was added aqueous NaOH (1N, 20 mL). The reaction mixture was heated at 100° C. for 3 days, cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried with MgSO4, filtered and concentrated. The crude material was purified on a silica gel cartridge (24 g) using an 20% (2N NH3/MeOH) in DCM/DCM gradient (0-75% of 20% (2N NH3/MeOH) in DCM over 13 CV) to afford 290 mg of ((1R,3S)-1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol. HPLC retention time=10.09 min (Condition H); LC/MS M+1=330; 1H NMR (400 MHz, methanol-d4) δ 7.03-6.91 (m, 3H), 3.54-3.41 (m, 2H), 3.01 (tt, J=11.1, 7.2 Hz, 1H), 2.87-2.69 (m, 3H), 2.34 (dd, J=16.2, 10.5 Hz, 1H), 2.20 (dd, J=13.0, 7.5 Hz, 1H), 2.07-1.84 (m, 3H), 1.83-1.60 (m, 3H), 1.60-1.48 (m, 1H), 1.47-1.25 (m, 11H), 1.00-0.88 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.Br[CH2:19][CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][CH2:20][Cl:21])=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: ClCCBr
Reactant: Clc1nc(NC2CCCCC2)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCn1cnc2c(NC3CCCCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Chloro-6-cyclohexylamino-purine (4 mmol), 1-bromo-2-chloroethane (8 mmol) and potassium carbonate (8 mmol, water free) in DMF (20 ml) are heated up to 45° C. and the mixture is stirred at this temperature for 5 hours. After cooling to RT the mixture is poured on water and extracted 3 times with ethyl acetate. The combined organic phases are washed twice with brine and the extract is dried over sodium sulfate and evaporated. The residue is dissolved in diethylether and pentane is added. The solid material formed is filtered of and dried (vacuum). A white powder with mp. 150-152° C., Rf=0.17 (CH2Cl2/MeOH=20:1) is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH2:5][C:4]([CH3:20])([CH3:19])[NH:3]1.[CH:22]1([C:25]2[C:30]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][C:28]([NH2:36])=[C:27]([F:37])[CH:26]=2)[CH2:24][CH2:23]1>CC(O)C>[CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:36][C:28]3[CH:29]=[C:30]([N:31]4[CH:35]=[N:34][N:33]=[N:32]4)[C:25]([CH:22]4[CH2:23][CH2:24]4)=[CH:26][C:27]=3[F:37])[N:10]=2)[CH2:5][C:4]([CH3:20])([CH3:19])[NH:3]1
Reactant: Nc1cc(-n2cnnn2)c(C2CC2)cc1F
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2C(N)=O)CC(C)(C)N1
Solvent: CC(C)O
Product: CC1(C)CC(Nc2nc(Nc3cc(-n4cnnn4)c(C4CC4)cc3F)ncc2C(N)=O)CC(C)(C)N1
Temperature: 100 °C
Yield: 45.4 %

Procedure:
A mixture of 4-(2,2,6,6-tetramethylpiperidin-4-ylamino)-2-chloropyrimidine-5-carboxamide (178 mg, 0.570 mmol, 1 equiv), 4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzenamine (150 mg, 0.684 mmol, 1.2 equiv), and PTSA monohydrate (230 mg, 1.20 mmol, 2.1 equiv) in IPA (6 mL) were heated to 100° C. overnight giving a precipitate. The precipitate was collected by vacuum filtration and rinsed with IPA. The solid was taken in EtOAc then adjusted to ca. pH 12-14 with 1N NaOH. The aqueous and organic layers were partitioned. The aqueous layer was extracted with EtOAc (2×150 mL). The combined organics were washed with 1N NaOH (1×150 mL), dried (Na2SO4), filtered, and concentrated to give the desired product (128 mg, 50%) as a solid.
Reaction SMILES: Cl.[S:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[C:7](=[S:9])=[S:8].C([O-])(=O)C.[Zn+2:14].C([O-])(=O)C>N1C=CC=CC=1>[S:2]1[CH2:6][CH2:5][N:4]([C:7]([S-:9])=[S:8])[CH2:3]1.[S:2]1[CH2:6][CH2:5][N:4]([C:7]([S-:9])=[S:8])[CH2:3]1.[Zn+2:14]
Reactant: C1CSCN1
Reactant: S=C=S
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: c1ccncc1
Product: S=C([S-])N1CCSC1

Procedure:
While cooling and stirring 250 g. of pyridine, 175 g. (1.40 moles) of thiazolidine hydrochloride [preparation described by S. Ratner and H. Clarke, J. Am. Chem. Soc. 59, 200 (1937)] was added. After it had dissolved, 106.4 g. (1.40 mole) of carbon disulfide was added dropwise, followed by 128.5 g. (0.70 mole) of anhydrous zinc acetate. The resulting reaction mixture was stirred at 40° - 50° C for 2 hours. The precipitate was filtered at 5° - 10° C. The crude solid was water-washed and finally freed of pyridine by vacuum-drying at 120° C to give 147.8 g. of the desired product. It gradually decomposed starting at ca. 200° C without a definite final decomposition point. A small sample washed with hot benzene had the following analysis:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:5][NH:6][C:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.[ClH:31].[CH2:32]([O:34][C:35]([CH:37]1[C:46]2[C:41](=[CH:42][C:43]([O:49][CH3:50])=[C:44]([O:47][CH3:48])[CH:45]=2)[C:40]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([O:60][CH3:61])[CH:53]=2)=[N:39][CH2:38]1)=[O:36])C>>[CH3:1][O:2][C:3]([CH:4]1[C:20]2[C:25](=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[N:6][CH2:5]1)=[O:30].[ClH:31].[CH3:32][O:34][C:35]([CH:37]1[C:46]2[C:41](=[CH:42][C:43]([O:49][CH3:50])=[C:44]([O:47][CH3:48])[CH:45]=2)[C:40]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([O:60][CH3:61])[CH:53]=2)=[N:39][CH2:38]1)=[O:36]
Reactant: COC(=O)C(CNC(=O)Cc1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)C1CN=C(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Agent: Cl
Product: COC(=O)C1CN=C(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21

Procedure:
The hydrochloride of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline carboxylic acid methyl ester was prepared by treating 2-(3,4-dimethoxyphenyl)-3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid methyl ester via the method described for the preparation of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinolinecarboxylic acid ethyl ester hydrochloride. Crystallization from methanol provided analytically pure 3,4-dihydro6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinolinecarboxylic acid methyl ester, hydrochloride, mp 199°-200°.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([CH3:15])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[NH2:16][C:17]1[C:18]([CH3:24])=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1.O>C(O)COCCO>[CH3:24][C:18]1[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:17]=1[N:16]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH3:15])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1cc(O)ccc1N
Reactant: Cc1cccc2c1=NC(=O)C1CCOC=21
Solvent: OCCOCCO
Solvent: O
Product: Cc1cc(O)ccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Temperature: 250 °C
Yield: 68.5 %

Procedure:
4-Oxo-6-methyl-2,3-dihydrofuro[3,2-c]quinoline (201 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol in a pressure tube and 4-amino-m-cresol (308 mg, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted in 20 ml of salt water and the aqueous layer was extracted by methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 210 mg of desired compound as solid in 81% of yield.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH:19]1[S:25][C:24]([CH3:27])([CH3:26])[CH2:23][NH:22][C:21]2[N:28]([CH3:32])[N:29]=[C:30]([CH3:31])[C:20]1=2.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH:19]1[S:25][C:24]([CH3:27])([CH3:26])[CH2:23][N:22]([CH:5]=[O:7])[C:21]2[N:28]([CH3:32])[N:29]=[C:30]([CH3:31])[C:20]1=2
Reactant: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)SC(C)(C)CN2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)SC(C)(C)CN2C=O
Temperature: 50 °C
Reaction time: 24 h
Yield: 64.3 %

Procedure:
To acetic anhydride (5 mL, 53 mmol), was added formic acid (2.83 mL, 75 mmol). The resulting mixture was heated for about 15 min at about 50° C. To this mixture (after cooling to about 0° C.), was added 4-(2,4-dichlorophenyl)-1,3,6,6-tetramethyl-7,8-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepine (50 mg, 0.14 mmol, Ex. D.4). The reaction mixture was stirred, for about 24 h, at rt. Subsequently, 5% aqueous sodium bicarbonate (25 mL) and ethyl acetate (50 mL) were added. The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate), to afford 4-(2,4-dichlorophenyl)-1,3,6,6-tetramethyl-4,7-dihydropyrazolo[3,4-e][1,4]thiazepine-8-carbaldehyde (35 mg, 0.09 mmol, 65%), as a white solid. LC-MS (Table 1, Method a) Rt=4.53/4.71 min (rotamers), m/z 384 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (3H, s) 1.49 (3 H, s) 1.65 (3 H, br s) 3.58-3.85 (2 H, br s) 3.73 (3 H, s) 5.48 (1 H, s) 7.11 (1 H, br s) 7.20 (1 H, br s) 7.44 (1 H, br s) 8.45 (1 H, s) (Major) 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (3H, br s) 1.34 (3 H, br s) 1.93 (3 H, s) 3.41 (1 H, d, J=14.2 Hz) 3.69 (3 H, s) 3.76 (1 H, d, J=14.2 Hz) 5.54 (1 H, s) 7.12 (1 H, br s) 7.20 (1 H, br s) 7.39 (1 H, br s) 8.23 (1 H, br s) (Minor).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23]Br>O>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2
Reactant: Clc1cccc(Cl)c1CBr
Reactant: Cc1ccc2cccc(O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)cccc3Cl)c2n1
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a mixture of sodium hydride (40% in oil, 24 mg) and N,N-dimethylformamide (1 ml) was added 8-hydroxy-2-methylquinoline (80 mg) in an ice-water bath. The mixture was stirred for 30 minutes at the same temperature and then 2,6-dichlorobenzyl bromide (120 mg) was added therein. The reaction mixture was stirred at ambient temperature for 1 hour. To this mixture was added water (0.5 ml) in an ice-water bath. The precipitates were corrected by vacuum filtration and washed with water (3 ml) to give 8-(2,6-dichlorobenzyloxy)-2-methylquinoline (117 mg) as a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[C:19]([Cl:35])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[CH3:44][NH:45][CH2:46][CH2:47][OH:48].O>CN(C)C=O>[Cl:35][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:45]([CH2:46][CH2:47][OH:48])[CH3:44])=[C:7]([O:36][CH3:37])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34])=[O:25]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCBr
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCN(C)CCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea, 59 mg), potassium carbonate (138 mg), and 2-(methylamino)ethanol (0.040 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 58 mg (yield 100%) of the title compound.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:51]=[C:52]([Cl:54])[CH:53]=1)[O:31][C:32]1[C:33]([CH2:49][CH3:50])=[N:34][N:35]([CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:36]=1[CH2:37]O>ClCCl>[Br:1][CH2:37][C:36]1[N:35]([CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[N:34]=[C:33]([CH2:49][CH3:50])[C:32]=1[O:31][C:30]1[CH:29]=[C:28]([Cl:27])[CH:53]=[C:52]([Cl:54])[CH:51]=1
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CO)c1Oc1cc(Cl)cc(Cl)c1
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(CBr)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
Bromine (16011,3.12 mmol) was added dropwise to a stirred solution of triphenylphosphine (820 mg, 3.12 mmol) and imidazole (213 mg, 3.12 mmol) in dichloromethane (15 ml) at room temperature under nitrogen. A solution of the alcohol of Example 135 (1.12 g, 2.60 mmol) in dichloromethane (5 ml) was then added to the reaction. The reaction was stirred at room temperature for 2 hours, diluted with dichloromethane (50 ml), washed with brine (20 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to provide the title compound (969 mg) as a white foam.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([O:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH3:32]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:37][CH2:36][CH2:35][CH2:34][O:33][CH2:31][CH3:32])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: CCOCCCN
Agent: Cl
Product: CCOCCCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 24.2 mg (0.23 mmol) of 3-ethoxypropylamine are reacted together by general method E. 17.8 mg (28.9% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[C:7]#[N:8].C(O)C>CO.Cl.[Fe]>[NH2:10][C:5]1[CH:4]=[C:3]([C:13]([F:14])([F:15])[F:16])[C:2]([CH3:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: Cc1cc(C#N)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1cc(C#N)c(N)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Iron powder (37.42 g, 670 mmol) was added in small portions to a stirred suspension of finely grinded 5-methyl-2-nitro-4-trifluoromethyl-benzonitrile from step 3 (34.58 g, 150 mmol) in methanol (75 mL) and 37% HCl (93 mL). The internal temperature was kept between 40 and 60° C. by external water bath cooling. The resulting brown solution was stirred for 1 h at 50° C., giving a green suspension. The mixture was poured into ice cold water (600 mL), the precipitated solid was filtered off and washed with water to give a green solid, which was dissolved in boiling ethanol (700 mL), activated carbon (ca. 10 g) was added and the mixture was refluxed for 1 h. The hot solution was filtered and the solvent was evaporated in vacuum to leave the title compound as a brown-yellow solid (23.55 g, 78%), which was used without further purification. MS (EI) 200.1 [M].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:27](=[O:28])[CH2:26][O:25][CH3:24])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (60 mg), methoxyacetyl chloride (23 mg), and 36 μL of triethylamine in dichloromethane was stirred for 1 h. The reaction mixture was evaporated to give N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-methoxyacetamide. 70 mg of the crude N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-methoxyacetamide was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 17.3 mg of 120. MS (Q1) 501 (M)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]1[CH2:12][CH:11]2[CH2:13][CH:4]1[C:5]1[CH:10]2[CH2:9][CH2:8][CH2:7][CH:6]=1.[H][H]>[Pd].CO>[F:1][C:2]([F:14])([F:15])[CH:3]1[CH2:12][CH:11]2[CH2:13][CH:4]1[CH:5]1[CH:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: FC(F)(F)C1CC2CC1C1=CCCCC12
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)C1CC2CC1C1CCCCC21
Reaction time: 0.75 h

Procedure:
A 400 ml autoclave is charged with 177 g of the thus purified octahydro-2-trifluormethyl-1,4-methanonaphthalene, methanol (100 ml, Burdick & Jackson, HPLC grade), and palladium on activated carbon (1.5 g containing 10% Pd, Alfa products, powder). The autoclave is closed and sealed, then it is shaken under 50 psig hydrogen pressure for 20 minutes at room temperature. The hydrogen pressure is increased to 200 psig for 10 minutes at room temperature followed by 600 psig at 70° C. for 45 minutes. The decahydro-2-trifluormethyl-1,4-methanonaphthalene product is purified by distillation at reduced pressure. The crude product is treated with sulfuric acid as described in Example 2.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:4]([S:9]([OH:12])(=[O:11])=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[F:15]F>C(#N)C>[F:15][N+:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:1])[F:14])[C:4]=1[S:9]([O-:12])(=[O:11])=[O:10]
Reactant: O=S(=O)(O)c1ncccc1C(F)(F)F
Reactant: FF
Solvent: CC#N
Product: O=S(=O)([O-])c1c(C(F)(F)F)ccc[n+]1F

Procedure:
To a mixture of 3-(trifluoromethyl)pyridine-2-sulfonic acid (115 mg, 0.5 mmol) and acetonitrile (20 ml) in a flask on a cooling bath kept at -10° C., a mixed gas of 10% fluorine/90% nitrogen was introduced at a flow rate of 15 ml/min. The total amount of the fluorine gas was 1.5 mmol. Thereafter, the nitrogen gas alone was introduced for 30 minutes. After the reaction mixture was concentrated, ethyl acetate was added to the residue. The precipitated crystal was recovered by filtration to obtain N-fluoro-3-(trifluoromethyl)pyridinium-2-sulfonate (84.6 mg, 0.345 mmol). Yield, 69%. Melting point, 180°-196° C. (with decomposition).