Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:4]1[C@@H:9]([C:10](=[O:12])[NH2:11])[N:8]([CH2:13][C:14](OCC)=[O:15])[CH2:7][CH2:6][N:5]1[CH2:19][C:20]([O:22]CC)=O)(=[O:3])[NH2:2]>CCO.CC[O-].[Na+]>[C:1]1(=[O:3])[C@H:4]2[C@H:9]3[C:10](=[O:12])[NH:11][C:14](=[O:15])[CH2:13][N:8]3[CH2:7][CH2:6][N:5]2[CH2:19][C:20](=[O:22])[NH:2]1
Reactant: CCOC(=O)CN1CCN(CC(=O)OCC)[C@@H](C(N)=O)[C@H]1C(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CN2CCN3CC(=O)NC(=O)[C@H]3[C@H]2C(=O)N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Method A. The diester diamide 11 (0.65 g, 1.88 mmol) was added to a solution of Na (0.173 g) in 7 mL of absolute EtOH at room temperature under argon. The resulting suspension in NaOEt was heated at 85° C. for 6 hours, during which time the reaction mixture became turbid. Following stirring at room temperature for 14 hours, the solvent was removed under reduced pressure, and the residual solid was dissolved in 3 mL of H2O. The aqueous solution was acidified (concentrated HCl, pH 2), and the crystalline compound obtained upon cooling in the refrigerator was filtered, washed with 5 mL of cold H2O followed by 5 mL of ethanol, and dried: yield 0.333 g (70%); mp 282°-284° C. dec. This compound was identical in all respects with the cis tricyclic compound 2 prepared from diamide 7 as previously described.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.O.[NH2:11][NH2:12]>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8](=[N:11][NH2:12])[NH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C#N)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(N)=NN)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
11.97 g (101.4 mmol) 6-methylpyridine-2-carbonitrile are dissolved in 25 mL ethanol. After addition of 36.3 mL (304.05 mmol) hydrazine hydrate (w=30%) the reaction mixture is stirred for 24 hours at room temperature. The precipitated product (K1=1.45 g) has been filtered off and the filtrate is evaporated to ⅓ of its volume. After dilution with water the reaction mixture is extracted three times with ethyl acetate. The combined organic extracts are washed with brine and dried (Na2SO4). The solvent has been removed yielding a K2 (11.11 g) of the desired product. The overall yield is 78.9%.
Reaction SMILES: [CH3:1][NH2:2].[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8][C:7]=2[CH:6]=[CH:5][C:4]=1[S:16](Cl)(=[O:18])=[O:17]>S1(CCCC1)(=O)=O.O>[CH3:1][NH:2][S:16]([C:4]1[CH:5]=[CH:6][C:7]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]=2[CH:3]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccc2sc3ccccc3c2c1
Reactant: CN
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CNS(=O)(=O)c1ccc2sc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A large excess of aqueous methylamine was added to a suspension of dibenzo[b,d]thiophene-2-sulfonyl chloride (2.83 g) in sulfolane (15 ml) and the mixture was stirred at RT for 3 h. The reaction mixture was diluted with water, and the precipitate was recovered, washed with water, dried and purified by silica gel chromatography eluting with a gradient of ethyl acetate:DCM of 0:100 to 10:90 to give the title compound (1.79 g, 64%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[CH:3]1[NH:14]C(=O)OCC1C=CC=CC=1.Br.CC(O)=O>CCOCC>[NH2:14][CH:3]1[C:2]([CH3:1])([CH3:25])[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]1=[O:13]
Reactant: CC1(C)Sc2ccccc2NC(=O)C1NC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC1(C)Sc2ccccc2NC(=O)C1N
Yield: 80.6 %

Procedure:
Benzyl 2,2-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-ylcarbamate (0.67 g, 1.88 mmol, Eq: 1.00, WO96/11940) and 33% HBr/HOAc (9 μl, 54.7 mmol, Eq: 29) were combined to give a yellow solution. After 75 min. the mixture was diluted with 100 mL Et2O. The resulting precipitate was collected by filtration, washed with Et2O and added to 100 mL of aq. NaHCO3. The mixture was extracted with EtOAc and DCM. The combined extracts were dried over Na2SO4, filtered and the filtrate concentrated to give the title compound as a white solid (0.3370 g, 81%) which was used without purification. MS m/z 379.0 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:24][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 110 °C

Procedure:
To 600 μL of 2-fluoro-nitrobenzene, 6 mL of DMSO are added 1.7 g of 4-(benzyloxy)aniline (1.5 equivalents) and 1.02 g of potassium tert-butanolate (1.6 equivalents). The whole is heated to 110° C. for 1 h 30. The medium is then hydrolyzed and extracted several times with ethyl acetate. The organic phases are washed with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and then concentrated under reduced pressure. A silica gel chromatography of the residue (cyclohexane/ethyl acetate: 99/1) allows 754 mg of the desired product to be isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[N:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[N:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[C:31](=[O:35])[N:30]([C:27]2[CH:26]=[CH:25][C:24]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:29][CH:28]=2)[CH:34]=[N:33]1)[CH3:12]
Reactant: O=c1[nH]ncn1-c1ccc(-n2cccn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](n1ncn(-c2ccc(-n3cccn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 4-[4-(1H-1-pyrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 11 to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(1H-1-pyrazolyl )phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 19).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:12])[CH2:9][CH2:10][S:11][C:6]=2[C:5]([Cl:13])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br.Cl>C(Cl)Cl>[Br:18][C:3]1[CH:4]=[C:5]([Cl:13])[C:6]2[S:11][CH2:10][CH2:9][C:8](=[O:12])[C:7]=2[C:2]=1[Cl:1]
Reactant: BrBr
Reactant: O=C1CCSc2c(Cl)ccc(Cl)c21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCSc2c(Cl)cc(Br)c(Cl)c21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A solution of 45.18 g (0.19 mol) of the title compound of Step B in 400 mL of methylene chloride was added dropwise at room temperature under nitrogen to a mixture of 64.6 g (0.48 mol) of aluminum chloride in 400 mL of methylene chloride. After stirring for 15 min, 10.5 mL (0.20 mol) of bromine was added dropwise and the mixture was refluxed for 10 min. The mixture, while still warm, was poured into 550 g of ice containing 110 mL of concentrated hydrochloric acid, and the resulting mixture was extracted with diethyl ether (2×500 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to dryness to yield 57.37 g of the title compound of Step C as a solid melting at 89-90° C. 1H NMR (CDCl3): δ3.0 (m,2H), 3.3 (m,2H), 7.7 (s,1H).
Reaction SMILES: [Br:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].[C:16]1(=[O:20])[CH2:19][CH2:18][CH2:17]1>O1CCCC1>[Br:1][C:2]1[C:7]([C:16]2([OH:20])[CH2:19][CH2:18][CH2:17]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC1
Reactant: Brc1cccnc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2cccnc2Br)CCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
2,3-Dibromopyridine (2.30 g, 9.7 mmol) in tetrahydrofuran (10 mL) was added to a solution of isopropyl magnesium chloride/lithium chloride (1M in tetrahydrofuran, 10 mL, prepared according to the method of Krasovskiy and Knochel, Angew. Chem. Int. Ed. 2004, 43, 3333-3336) at approximately −15° C. under nitrogen. This mixture was cooled to −78° C. and cyclobutanone (0.74 mL, 9.9 mmol) added. It was stirred for 1 hour before allowing to warm to 0° C. for a further 1 hour then quenched with saturated ammonium chloride solution. Water (150 mL) was added and extracted with diethyl ether (2×75 mL). These extracts were washed with water and brine then dried (MgSO4), filtered and the solvent removed in vacuo. Purification by flash column chromatography eluting with a 0-10% diethyl ether/dichloromethane gradient gave 1-(2-bromopyridin-3-yl)cyclobutanol (0.57 g, 26%). 1H NMR (400 MHz, CDCl3) δ 8.28 (1H, dd, J=1.9, 4.7 Hz), 7.68 (1H, dd, J=1.9, 7.6 Hz), 7.30-7.26 (1H, m), 3.00 (1H, s), 2.70-2.60 (2H, m), 2.55-2.47 (2H, m), 2.30-2.16 (1H, m), 1.77-1.65 (1H, m); m/z (ES+) 228, 230 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][N:13](CC1C=CC(OC)=CC=1OC)[C:12](=[O:27])[C:11]1[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:10]2=1)=[O:5])[CH3:2].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][NH:13][C:12](=[O:27])[C:11]1[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1CN(Cc1ccc(OC)cc1OC)C(=O)c1cc(OC)ccc1-2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncn2c1CNC(=O)c1cc(OC)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2,4-Dimethoxy-benzyl)-8-methoxy-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (9.8 g, 22 mmol) was suspended in CH2Cl2 (50 mL), cooled in ice, and diluted sowly with trifluoroacetic acid (50 mL). The resulting clear solution was treated at 5° C. with trifluoromethanesulfonic acid (3.8 mL, 44 mmol). The now red solution was stirred at rt for 2 h, evaporated to dryness, and the residue extracted with CH2Cl2 (500 mL), and 2×10% NaHCO3 (500 mL). The crude product (ca. 10 g) was digested with hot ethyl acetate (100 mL), allowed to cool, and the white crystals (5.6 g, 85%) were filtered off. mp 240° C. m/z 301 (M).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][C@@H:26]2[CH2:38][O:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:24])=[CH:18][CH:17]=1>CO>[ClH:1].[ClH:1].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH:26]2[CH2:38][O:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:24])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(O)cc2)[C@@H](COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1ccc(O)cc1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 88 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of (R)-tert-butyl 4-(4-hydroxyphenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (182 mg, 0.335 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 118 mg (88%) of the title compound as a white solid. LC-MS: RT=2.11 min, [M+H]+=329.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[C:39]([CH2:40][N:41]2[CH2:61][CH2:60][C:44]3([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]4[N:53]=[C:54]([CH:57]([CH3:59])[CH3:58])[S:55][CH:56]=4)=[O:51])[CH2:45]3)[CH2:43][CH2:42]2)=[CH:38][CH:37]=[CH:36][C:27]=1[CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33](O)=[O:34].CCN(C(C)C)C(C)C.[CH3:71][O:72][CH:73]([O:83][CH3:84])[CH2:74][NH:75][CH:76]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]1>CN(C=O)C>[CH:76]1([N:75]([CH2:74][CH:73]([O:83][CH3:84])[O:72][CH3:71])[C:33](=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28][C:27]2[CH:36]=[CH:37][CH:38]=[C:39]([CH2:40][N:41]3[CH2:42][CH2:43][C:44]4([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]5[N:53]=[C:54]([CH:57]([CH3:59])[CH3:58])[S:55][CH:56]=5)=[O:51])[CH2:45]4)[CH2:60][CH2:61]3)[C:26]=2[F:25])[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]1
Reactant: COC(CNC1CCCCCC1)OC
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4F)CC3)C2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(CN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1F)C1CCCCCC1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of HATU (0.143 g) in DMF (0.5 mL) was added to a solution of 3-(2-fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid [Example 7, step d] (0.133 g), Hunig's base (0.22 mL) and N-(2,2-dimethoxyethyl)cycloheptanamine [WO 2008075025] (0.050 g) in DMF (0.5 mL). The resulting dark solution was stirred overnight at RT. The solvent was evaporated and the residue partitioned between ethyl acetate (25 mL) and 20% aqueous brine (25 mL). The organic layer was separated and washed with 20% aqueous brine (2×25 mL). The organic solution was evaporated and the residue purified by silica gel chromatography, elution gradient 65:30:5 to 47.5:47.5:5 isohexane:ethyl acetate:triethylamine. The fractions containing the product were combined and evaporated to give the subtitled compound as an oil. Yield 0.165 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[C:19]1([C:25]2[C:29]3[CH:30]=[CH:31][C:32]([OH:37])=[C:33]([CH2:34][CH2:35][CH3:36])[C:28]=3[O:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH:11]([O:37][C:32]1[CH:31]=[CH:30][C:29]2[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:26][O:27][C:28]=2[C:33]=1[CH2:34][CH2:35][CH3:36])[CH3:12]
Reactant: COC(=O)Cc1ccc(OCCCCBr)c(F)c1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Product: CCCc1c(OC(C)CCOc2ccc(CC(=O)OC)cc2F)ccc2c(-c3ccccc3)coc12

Procedure:
Using the method of Example 27, step A, using methyl 3-floro-4-(4-bromobutyloxy)-phenylacetate and 3-phenyl-6-hydroxy-7-propylbenzofuran (Example 5, Step B) as the starting material, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:18]=[CH:17][C:16](I)=[CH:15][C:12]=1[C:13]#[N:14].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:16]2[CH:17]=[CH:18][C:11]([F:10])=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cncc(Cl)c1
Reactant: N#Cc1cc(I)ccc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: N#Cc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 60 °C
Yield: 90.3 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (77 mg, 0.11 mmol), copper (I) iodide (42 mg, 0.22 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (300 mg, 2.2 mmol) to a solution of 2-fluoro-5-iodobenzonitrile (650 mg, 2.6 mmol) in triethylamine (4.6 mL, 33 mmol) and heat at 60° C. for 6 h. Cool to room temperature and concentrate. Purify by silica gel chromatography, eluting with 50:50 dichloromethane:hexanes to 90:10 dichloromethane:ethyl acetate, followed by a second silica gel chromatography eluting with 95:5 to 75:25 hexanes:ethyl acetate, to give the title compound as an off-white solid (510 mg, 91%).
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][C:2]1=[O:11].Cl.NC1(CCC(O)=O)CCCCC1.[P:25]([OH:28])([OH:27])[OH:26].P(Cl)(Cl)Cl>O>[NH2:1][C:5]1([CH2:4][CH2:3][C:2]([OH:11])([P:25]([OH:28])(=[O:26])[OH:27])[P:25]([OH:28])(=[O:27])[OH:26])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C1CCC2(CCCCC2)N1
Reactant: OP(O)O
Agent: Cl
Agent: NC1(CCC(=O)O)CCCCC1
Solvent: ClP(Cl)Cl
Solvent: O
Product: NC1(CCC(O)(P(=O)(O)O)P(=O)(O)O)CCCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
19.1 g. 1-Aza-spiro(4,5)decan-2-one (prepared as described in J. Org. Chem., 22, 832) are boiled for 90 hours in 190 ml. concentrated hydrochloric acid. After cooling, the reaction mixture is filtered and evaporated and the residue is reprecipitated with methanol/diethyl ether. There are obtained 17.5 g. (68% of theory) of the hydrochloride of 3-(1-aminocyclohexyl)-propionic acid; m.p. 183° C. sinters; 188°-192° C. melts with decomposition. 7 g. thereof are mixed with 5.5 g. phosphorous acid and, after melting at 80° C., mixed dropwise with 5.9 ml. phosphorus trichloride. After stirring for 8 hours at 80° C., 43 ml. 6N hydrochloric acid are added thereto, the temperature is increased to 100° C. and stirring continued for a further 8 hours. The yellowish suspension is then filtered hot, the filtrate is evaporated and the residue, a colourless oil, is stirred into 2 liters of acetone. The precipitate obtained is filtered off with suction and washed with acetone and diethyl ether. There are obtained 4.6 g. (43% of theory) of product which are dissolved in a little water. Purification takes place by fractionation on an Amberlite IR-120 column (H+ form). The individual fractions are tested electrophoretically for purity. After combining the pure fractions, the aqueous solution is again evaporated and again precipitated with acetone. There are obtained 2.9 g. (27% of theory) of white crystals; m.p. 143° C. sinters, 155°-158° C. foaming up; Mrel =0.29.
Reaction SMILES: Cl.C[O:3][C:4]1[CH2:9][N:8]([CH3:10])[CH2:7][CH2:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]([O:28][CH:29]([CH3:31])[CH3:30])[CH:12]=1>C1COCC1>[CH3:10][N:8]1[CH2:7][CH2:6][CH:5]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:13]([O:28][CH:29]([CH3:30])[CH3:31])[CH:12]=2)[C:4](=[O:3])[CH2:9]1
Reactant: COC1=C(c2ccc(NC(=O)OCc3ccccc3)c(OC(C)C)c2)CCN(C)C1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C2CCN(C)CC2=O)ccc1NC(=O)OCc1ccccc1
Temperature: 50 °C
Yield: 99.4 %

Procedure:
30 ml of a 6N aqueous hydrochloric acid solution are added to a solution of 1.77 g of benzyl [4-(5-methoxy-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate in 60 ml of THF. The reaction medium is heated at 50° C. for 2 h 30 and then evaporated to dryness. The residue is taken up in 15 ml of water, 5 ml of a saturated aqueous sodium carbonate solution and 50 ml of ethyl acetate. The two phases are separated, and the aqueous phase is washed with twice 15 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated, so as to give 1.7 g of benzyl [4-(1-methyl-3-oxopiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate in the form of a brown gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17]C)=[O:16])[CH:9]=2)=[CH:4][CH:3]=1.Cl.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([OH:17])=[O:16])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1-c1cc(-c2ccc(Cl)cc2)on1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccccc1-c1cc(-c2ccc(Cl)cc2)on1
Yield: 95.3 %

Procedure:
A mixture of 2.8 g of methyl 2-[5-(4-chlorophenyl)3-isoxazolyl]benzoate, 12 ml of concentrated HCl, and 14 ml of acetic acid was held at reflux for 4 hours, cooled, diluted with water, and filtered to give 2.55 g (95%) of white solid, mp 174-176° C. Recrystallization of the solid gave 2.18 g of solid, mp 175.5-177.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N([O-])=O.[Na+].[BrH:16]>O>[Br:16][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Br
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 4-chloro-3-nitro-phenylamine (17.2 g, 0.1 mol) in 260 mL HBr (48%) at 0° C. was added dropwise NaNO2 (13.8 g, 0.2 mol) in water. The reaction mixture was stirred for 1 h at 0° C. then CuBr (24 g, 0.17 mol) was added in portions to the mixture and stirred for an additional 1 h. Water was added, the mixture allowed to warm to room temperature and was then extracted with EtOAc. The crude product was purified by silica gel column chromatography to give the title compound (13 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:18]=3)=[C:15]3[N:10]([C:11](SC)=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH:42]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:18]=3)=[C:15]3[N:10]([C:11]([NH:47][CH:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3cccc(Cl)c3)nn12
Reactant: NC1CCCC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1cccc(-c2nn3c(NC4CCCC4)nccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64.6 %

Procedure:
To a cold (0° C.) solution of 4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine (40 mg, 0.0915 mmol) in dichloromethane (3 mL) was added m-chloroperoxybenzoic acid (24 mg, 0.139 mmol). The reaction mixture was stirred 1.5 hours at 0° C. then diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration provided a crude oil which was heated in cyclopentylamine (2 mL, 20 mmol) at 85° C. in a sealed tube for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 3:1 hexanes:ethyl acetate) provided 2-(3-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-amine (28 mg, 65%) as a beige solid. Rf 0.27 (3:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.09 (d, 1H), 7.78 (d, 1H), 7.71 (s, 1H), 7.51–7.35 (m, 4H), 6.41 (d, 1H), 6.30 (d, 1H), 5.15 (d, 1H), 4.53 (m, 1H), 4.29 (m, 1H), 2.20 (m, 2H), 2.04 (m, 2H), 1.83–1.50 (m, 12 H); MS m/z 474 (M+1).
Reaction SMILES: [S].[CH3:2][CH:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([CH:11]2[CH:16]=[CH:15][N:14](C(OCC(Cl)(Cl)Cl)=O)[CH:13]=[CH:12]2)[S:4]1>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:2][CH:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:4]1
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SC(C)C(=O)N1
Agent: [S]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC1=C(c2ccncc2)SC(C)C(=O)N1
Temperature: 140 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
Sulfur sublimed (0.7 g) was added to a solution of 2,5-dimethyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (1.5 g) in dimethylformamide (20 ml) and the mixture was stirred at 140° C. for 2 hours. Then, the mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was dissolved in 2N hydrochloric acid and the insoluble matter was removed by filtration. The filtrate was adjusted to pH 7-8 by 2N aqueous sodium hydroxide. The precipitated crude crystals were chromatographed on silica gel (Wakogel C-200) column, using chloroform-methanol (=20:1) as an eluant to give pale yellow crystals. These crude crystals were dissolved in chloroform, were washed with water and were dried over magnesium sulfate. The solvent was removed under reduced pressure to give the titled compound (0.43 g, yield 52%) as white crystals.