Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH:11]=[C:10]([CH2:12]O)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:16])=O>ClCCl>[ClH:16].[CH:1]1([N:7]2[CH:11]=[C:10]([CH2:12][Cl:16])[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cnn(C2CCCCC2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCc1cnn(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.68 g of (1-cyclohexyl-1H-pyrazol-4-yl)methanol was dissolved in 20 ml of dichloromethane, and 2.0 ml of thionyl chloride was then added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain 2.15 g of 1-cyclohexyl-4-(chloromethyl)-1H-pyrazole hydrochloride.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl>[Si:15]([O:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[N:7][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: OCc1ccc(F)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6-Fluoropyridin-3-yl)methanol (9.54 g, 75.0 mmol) and imidazole (5.11 g, 75.0 mmol) were placed into a round-bottomed flask with CH2Cl2 (300 mL). tert-butyldimethylsilyl chloride (10.9 g, 72.8 mmol) was dissolved in CH2Cl2 (75 mL) and added drop-wise to the reaction mixture, which was then allowed to stir overnight at rt. The reaction was quenched by adding water (100 mL). The biphasic mixture was then separated and the aqueous layer was washed with CH2Cl2 (2×30 mL). The combined organic layer was then washed with H2O (3×50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated to give 5-((tert-butyldimethylsilyloxy)methyl)-2-fluoropyridine as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[S:14])([CH3:4])([CH3:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([N:15]=[CH:19][N:20]([CH3:22])[CH3:21])=[S:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)NCCCCNC(N)=S
Product: CN(C)C=NC(=S)NCCCCNC(=O)OC(C)(C)C
Yield: 76 %

Procedure:
The title compound was synthesised from (4-Thioureido-butyl)-carbamic acid tert-butyl ester and Dimethylformamide dimethyl acetal according to the procedure described for Example C in 76% yield. MS (m/e): 303.3 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[NH:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c[nH]c(Sc2ccc(Cl)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2ccc(Cl)cc2)c1

Procedure:
Methyl 5-(4-chlorophenylthio)pyrrole-3-carboxylate (1.4 g.) was combined with 20 ml. of methanol and 20 ml. of 1N sodium hydroxide and heated on a steam bath for 2 hours. The reaction was cooled, acidified with conc. hydrochloric acid. and the crude product which precipitated, collected by filtration. Two recrystallizations from acetone/hexane afforded purified 5-(4-chlorophenylthio)pyrrole-3-carboxylic acid (740 mg., m.p. 171°-173° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:19]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(ccn2C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-cyanoindole (1.0 g, 7.0 mmol) in dichloromethane (8 mL) was added 4-(dimethylamino)pyridine (0.171 g, 1.4 mmol), triethylamine (1.96 mL, 1.42 g, 14 mmol) and benzoyl chloride (0.89 mL, 1.08 g, 7.7 mmol). The resulting mixture was stirred for 18 hours at room temperature. The mixture was diluted with dichloromethane (80 mL) and washed consecutively with a saturated solution of sodium hydrogencarbonate (40 mL) and brine (40 mL). The organic phase was dried with magnesium sulfate (1 hour). Filtration and concentration furnished the crude material which was purified by flash chromatography on silica gel, eluting with ethyl acetate/heptanes=2:3. 1-Benzoyl-1H-indole-5-carbonitrile was obtained as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([S:5][C:6]1[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=[O:4].[H-].[Na+].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>CN(C)C=O>[CH3:1][N:2]([CH3:17])[C:3]([S:5][C:6]1[N:7]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=[O:4]
Reactant: CN(C)C(=O)Sc1nc(-c2ccccc2)c[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Sc1nc(-c2ccccc2)cn1-c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of 0.25 g (1.0 millimole) of 2-(N,N-dimethylcarbamoylthio)-4-phenylimidazole in 10 ml of N, N-dimethylformamide was added 0.04 g (1.0 millimole) of sodium hydride, and the mixture was stirred at room temperature for 1 hour. Then, 0.16 g (1.0 millimole) of 2-chloro-5-nitropyridine was added to the mixture, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and washed with water and ethyl acetate to obtain 0.27 g (yield=73%) of intended 2-(N,N-dimethylcarbamoylthio)-1-(5-nitropyridinyl)-4-phenylimidazole (compound No. 28) in the form of a yellow powder.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([P:22](Cl)(Cl)=[O:23])=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([P:22]2(=[O:23])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(P(=O)(Cl)Cl)cc1
Reactant: c1ccc(CNc2ccccc2)cc1
Product: Cc1ccc(P2(=O)c3ccccc3CN2c2ccccc2)cc1
Yield: 7 %

Procedure:
The procedure of Example 26 was employed utilizing N-benzylaniline and 4-methylphenyl phosphonic dichloride to yield 1-(4-methylphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.65 g, 7% yield) as a white solid having a melting point of 180°-181° C. and the following analysis:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CCc1ccccc1O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
5.57 g (45 mmol) of 2-ethylphenol are placed in 250 ml of chloroform in a round-bottomed flask and under a stream of nitrogen. 43.4 g (90 mmol) of tetrabutylammonium tribromide are added portionwise. The medium is stirred for 1 hour at room temperature and is then hydrolysed with saturated aqueous sodium thiosulfate solution. The organic phase is washed with water, dried over magnesium sulfate, filtered and then evaporated. 9.1 g (100%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21](O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O.O>C(OCC)(=O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([Cl:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cl)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.75 h

Procedure:
In a mixture of 120 ml of ethyl acetate and 13 g of pyridine is dissolved 12.8 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate, and 5.1 ml of thionyl chloride is added to the solution, followed by refluxing with stirring for 45 minutes. After cooling, 500 ml of water and 200 ml of ethyl acetate are added to the reaction solution, and extraction is carried out. The extract is washed with 0.1N hydrochloric acid and water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily material is purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 10 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate as a colorless oily material.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH3:16])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH3:16])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.6 %

Procedure:
Ethyl 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetate (syn isomer, 5 g.) was added to a mixture of 1 N sodium hydroxide (45.9 ml.) and ethanol (30 ml.) and stirred at room temperature for 5 hours. After removing ethanol from the resultant solution under reduced pressure, the residue was dissolved in water (60 ml.) and adjusted to pH 2.0 with 10% hydrochloric acid. The solution was subjected to salting-out, and the precipitates were collected by filtration and dried to give 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetic acid (syn isomer, 2.9 g.).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C1(C)C=CC=CC=1.C(N(CC)CC)C.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH2:3]1
Reactant: O[C@H]1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CC[C@H](O)C1
Temperature: 0 °C

Procedure:
A 0.5 g portion of (S)-3-hydroxypyrrolidine, as described in Example 42, was reconcentrated twice from toluene, dissolved in 80 ml of dichloromethane and cooled to 0° C. A 3.8 ml portion of triethylamine and 2.8 ml of benzylchloroformate were added with stirring. The reaction was stirred overnight, diluted with 300 ml of dichloromethane and extracted with 80 ml of 5% hydrochloric acid and 5% sodium bicarbonate solution. The aqueous phases were combined, saturated with sodium chloride and extracted with 3×150 ml of ethyl acetate. The organic phases were combined, dried, filtered and concentrated in vacuo. The residue was purified by chromatography (alumina) giving 940 g of (S)-3-hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester as a yellow oil [α]D26 =+21° (c, 1.054 methanol).
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.C1(C2C3C=CC=CC=3N([CH2:57][C:58](C3CCCC3)=[O:59])C(=O)N(CC(O)=O)N=2)CCCCC1.C(OC(=O)CN1C2C(=CC=C(N)C=2)C=C1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:58]([O:59][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:57]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)Cn1ccc2ccc(N)cc21
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 22, step a) and (6-amino-indol-1-yl)-acetic acid ethyl ester were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (DMSO-d6) 9.65 (1H, s), 7.67 (1H, s), 7.58-7.47 (2H, m), 7.39 (1H, d), 7.28-7.15 (3H, m), 6.97 (1H, d), 6.31 (1H, d), 4.75-4.55 (4H, m), 4.30 (1H, br d), 3.95 (1H, br d), 3.00-2.88 (2H, m), 1.98-1.40 (14H, m), 1.35-1.10 (4H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 58.53; H, 6.80; N, 10.01%; C33H37N5O5.C7H17NO5.2.0H2O requires C, 58.95; H, 7.17; N, 10.31%.
Reaction SMILES: [CH:1]([C:3]1[CH:52]=[CH:51][C:6]([C:7]([O:9][CH2:10][O:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]([NH:37][C:38]([O:40][CH2:41][C:42]3[O:43][C:44]4[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=4[CH:46]=3)=[O:39])([C:26](=[O:36])[NH:27][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])[CH3:25])=[CH:15]2)=[O:13])=[O:8])=[CH:5][CH:4]=1)=O.[OH:53][CH2:54][CH2:55][NH:56][CH2:57][CH2:58][OH:59].C(O)(=O)C.[Cl:64]CCl>>[ClH:64].[OH:53][CH2:54][CH2:55][N:56]([CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][O:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]([NH:37][C:38]([O:40][CH2:41][C:42]3[O:43][C:44]4[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=4[CH:46]=3)=[O:39])([C:26](=[O:36])[NH:27][CH:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH3:29])[CH3:25])=[CH:15]2)=[O:13])=[O:8])=[CH:51][CH:52]=1)[CH2:57][CH2:58][OH:59]
Reactant: OCCNCCO
Reactant: CC(NC(=O)C(C)(Cc1cn(C(=O)OCOC(=O)c2ccc(C=O)cc2)c2ccccc12)NC(=O)OCc1cc2ccccc2o1)c1ccccc1
Reactant: ClCCl
Solvent: CC(=O)O
Product: CC(NC(=O)C(C)(Cc1cn(C(=O)OCOC(=O)c2ccc(CN(CCO)CCO)cc2)c2ccccc12)NC(=O)OCc1cc2ccccc2o1)c1ccccc1
Product: Cl
Reaction time: 0.5 h
Yield: 42 %

Procedure:
NaHB(OAc)3 (0.212 g, 1.0 mmol, 1.4 eq.) was added in three equal portions in 10 minutes to a cloudy solution of compound 19 (0.5 g, 0.713 mmol), bis(2-hydroxyethyl)amine (0.15 g, 1.43 mmol, 2.0 eq.) and acetic acid (0.04 mL, 0.71 mmol, 1.0 eq.) in dry dichloromethane (15 mL) under N2 in an ice bath. The reaction was stirred in ice bath for 30 minutes and room temperature for 40 hours to give a white suspension. The reaction was worked up and purified as above to give compound 20g (0.24 g, 42%) as a white foam.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19](N)=[S:20]>S1(CCCC1)(=O)=O>[NH2:18][C:19]1[S:20][C:2]2[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:7]=2[N:8]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: NC(N)=S
Solvent: O=S1(=O)CCCC1
Product: Nc1nc2cc(C(F)(F)F)cc([N+](=O)[O-])c2s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
67.5 g of 4-chloro-3,5-dinitrobenzotrifluoride are slowly introduced, with stirring, into a solution of 76 g of thiourea in 250 ml of sulpholane at 100° C. The mixture is stirred at 100° C. for a further one hour. After cooling, the precipitate is filtered off with suction and dried. 35.7 g of crude 2-amino-5-trifluoromethyl-7-nitrobenzothiazole of melting point 254°-256° C. (decomposition) are obtained. Recrystallisation from pyridine/water (3/1) raises the melting point to 262°-263° C. me+ : 263.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[N:13]=2)=[CH:4][N:3]=1.[ClH:35].O1CCOCC1>CO.C1(C)C=CC=CC=1>[ClH:35].[ClH:35].[NH:26]1[CH2:27][CH:24]([N:21]2[C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]4[CH3:20])[N:13]=[C:8]([C:5]4[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=4)[C:9]=3[CH2:23][CH2:22]2)[CH2:25]1
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N(C1CN(C(=O)OC(C)(C)C)C1)CC2
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N(C1CNC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-{4-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}azetidine-1-carboxylate (760 mg, 1.62 mmol) in methanol (8 mL), was added 4 N HCl in 1,4-dioxane (8 mL, 32 mmol). The reaction was stirred at room temperature for 1 h. The mixture was diluted with toluene and the solvent was removed under reduced pressure to give a foamy residue. The residue was triturated in acetone to get a free flowing tan solid which was collected by filtration to give the title compound in quantitative yield. The material was taken directly in the next step without purification. 1H NMR (400 MHz, CD3OD) δ 8.78 (br s, 2 H), 5.32 (br s, 1 H), 4.62 (br s, 3 H), 4.34 (br s, 2 H), 4.19-3.99 (m, 4 H), 3.85-3.72 (m, 2 H), 3.64-3.46 (m, 2 H), 3.23 (br s, 2 H), 1.41 (d, J=5.5 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>O1CCCC1>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:28]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(F)c3)c2)CC1
Reaction time: 0.08 h
Yield: 109.8 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl)-polystyrene (50 mg, 0.130 mmol) in tetrahydrofuran (1 mL) was allowed to stand for 5 min. 3-fluorobenzoyl chloride (28 μL, 0.229 mmol) and tetrahydrofuran (1 mL) were added to the reaction mixture. The reaction mixture was mixed for 18 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and allowed to stand for 5 min. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 43 mg (>100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][NH:10][CH2:9][C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CNCc2cc(OC)c(N)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CCN1C(=O)CNCc2cc(OC)c(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)cc21
Temperature: 130 °C

Procedure:
The title compound was prepared from 8-Amino-1-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.095 g, 0.0004 mol), (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (0.127 g, 0.000367 mol), p-toluenesulfonic acid monohydrate (0.17 g, 0.00089 mol) and isopropyl alcohol (4 mL). The mixture was heated in a microwave at 130° C. for 30 min. The reaction was evaporated and the residue treated with a 10% sodium carbonate solution and DCM, separated, washed, dried and evcaporated to give a solid. This material was chromatographed on a silica gel prep plate with DCM/10% ammonia/methanol (10-1) giving the product as tan solid (0.041 g, 19%). Mp179-184° C.; LCMS (m/e) 545 (M); 1H-NMR (DMSO, 400 MHz) δ 9.43 (s, 1H), 8.40-8.36 (d, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.83 (s, 1H), 7.82 (s, 1H), 7.55-7.48 (t, 1H, J=7.32 Hz), 7.32-7.29 (t, 1H, J=7.83 Hz), 7.04 (s, 1H), 3.83 (s, 3H), 3.70 (s, 2H), 3.55-3.40 (m, 3H), 3.03 (s, 2H), 1.23-1.14 (d, 6H, J=6.82 Hz), 0.90-0.86 (t, 3H, J=7.08 Hz).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:52]1([CH:58]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH2:59][CH2:60][NH2:61])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)C>[C:62]1([CH:58]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:59][CH2:60][NH:61][C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)NCCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.51 g, 2.0 mmol, Example 1, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.68 mL, 3.9 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.74 g, 2.0 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; 3,3-diphenylpropylamine (0.41 g, 1.9 mmol, Aldrich, Milwaukee, Wis.) was then added. After additional 30 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo, a white solid was obtained. Recrystallization from EtOAc-hexanes afforded 0.63 g (72%) of the pure titled compound as a white solid; mp 144-145° C. APCI-MS m/z 450.3 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:4]1([CH3:7])[CH2:6][CH2:5]1)=[O:3].[CH:8]1[C:13]([CH:14]=O)=[CH:12][C:11]2[O:16][CH2:17][O:18][C:10]=2[CH:9]=1>>[CH3:7][C:4]1([C:2]([CH:1]=[CH:14][C:13]2[CH:8]=[CH:9][C:10]3[O:18][CH2:17][O:16][C:11]=3[CH:12]=2)=[O:3])[CH2:6][CH2:5]1
Reactant: CC(=O)C1(C)CC1
Reactant: O=Cc1ccc2c(c1)OCO2
Product: CC1(C(=O)C=Cc2ccc3c(c2)OCO3)CC1

Procedure:
2-(3,4-Methylenedioxyphenyl)vinyl 1-methylcyclopropyl ketone [III; Ar is 3,4-methylenedioxyphenyl, R is CH3 ] was prepared from 25.6 g. of 1-methylcyclopropyl methyl ketone and 39.3 g. of piperonal according to the procedure described above in Preparation A1, affording 29.5 g. of crystalline product.