Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[F:11][C:12]([F:33])([F:32])[C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]3)[NH:22][CH:23]=2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[F:33][C:12]([F:11])([F:32])[C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[C:21]([C@H:24]3[CH2:25][CH2:26][C@H:27]([CH2:30][NH:31][S:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)(=[O:9])=[O:8])[CH2:28][CH2:29]3)[NH:22][CH:23]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC[C@H]1CC[C@H](c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine-3-sulfonyl chloride (0.34 mmol) was added to a solution of C-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexyl}-methylamine (0.31 mmol) and triethylamine (0.62 mmol) in CH2Cl2 (5 mL). The mixture was stirred overnight at room temperature, diluted with CH2Cl2, washed with saturated NaHCO3, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (90:10 CH2Cl2/MeOH) to give Pyridine-3-sulfonic acid trans-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-amide.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)O)[CH3:3].[ClH:14].S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[ClH:17].[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[Cl:14])[CH3:3]
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)CCC(Cl)c1ccccc1

Procedure:
A solution containing 442 g. of N,N-dimethyl 3-phenyl-3-hydroxypropylamine in 5 l. of chloroform was saturated with dry gaseous hydrogen chloride. 400 ml. of thionyl chloride were then added to the chloroform solution at a rate sufficient to maintain reflux. The solution was refluxed an additional 5 hours. Evaporation of the chloroform andd other volatile constituents in vacuo yielded N,N-dimethyl 3-phenyl-3-chloropropylamine hydrochloride which was collected by filtration, and the filter cake washed twice with 1500 ml. portions of acetone. The washed crystals weighed about 500 g. and melted at 181°-3° C. with decomposition. An additional 30 g. of compound were obtained from the acetone wash by standard crystallization procedures. The structure of the above compound was verified by NMR and titration.
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:45]=2[S:51]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][C:54]=2[C:60]2[CH:65]=[CH:64][C:63]([Cl:66])=[C:62]([N+:67]([O-])=O)[CH:61]=2)=[O:52])=[CH:40][C:39]=1[N+:70]([O-])=O>>[NH2:67][C:62]1[CH:61]=[C:60]([C:54]2[CH:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:53]=2[S:51]([C:45]2[CH:46]=[CH:47][C:48]([CH3:50])=[CH:49][C:44]=2[C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[C:39]([NH2:70])[CH:40]=2)=[O:52])[CH:65]=[CH:64][C:63]=1[Cl:66]
Reactant: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(Cl)c([N+](=O)[O-])c2)c(-c2ccc(Cl)c([N+](=O)[O-])c2)c1
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(Cl)c(N)c2)c(-c2ccc(Cl)c(N)c2)c1
Yield: 88 %

Procedure:
Following the procedure described in Example 2 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of (4-chloro-3-nitrophenyl)-4-methylphenyl sulfoxide, the title compound is obtained: M.P.=119°-121° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH:11]=O)=[CH:7][C:6]=1[O:15][CH3:16])([CH3:3])[CH3:2].[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]>>[CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH:11]=[C:21]2[S:17][C:18](=[O:23])[NH:19][C:20]2=[O:22])=[CH:7][C:6]=1[O:15][CH3:16])([CH3:3])[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: COc1cc(C=CC=O)ccc1OC(C)C
Product: COc1cc(C=CC=C2SC(=O)NC2=O)ccc1OC(C)C
Yield: 61 %

Procedure:
According to the same manner as that described in Example 1, 4-isopropoxy-3-methoxycinnamaldehyde was condensed with 2,4-thiazolidinedione to give 5-(4-isopropoxy-3-methoxycinnamylidene)-2,4-thiazolidinedione (yield: 61%). This product was recrystallized from ethyl acetate-hexane. Yellow prisms, mp: 230-231° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C:5]=1[C:20]1[N:24]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1.I[CH3:34].O>C1COCC1>[CH3:34][N:6]1[C:5]([C:20]2[N:24]([C:25]3[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=3)[N:23]=[CH:22][CH:21]=2)=[C:4]([CH3:3])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]1=[O:19]
Reactant: CI
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
Sodium hydride (10 mg of a 60% dispersion in mineral oil, 0.25 mmol) was added to a stirred suspension of 4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (70 mg, 0.17 mmol) in THF (2.0 mL) under a nitrogen atmosphere. This resulted in degassing and the formation of a yellow solution. Iodomethane (0.031 mL, 0.5 mmol) was added and the mixture was stirred for 3 h. Water (10 mL) was added and the mixture was extracted with DCM (2×10 mL). The combined organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography (2 g Si II SPE eluted with 0-50% EtOAc in DCM in 10% increments). Concentration of the appropriate fractions in vacuo gave the title compound which was freeze-dried from acetonitrile/water to afford a fluffy white solid (50 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C@:7]([CH3:20])([C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])[CH2:6][CH2:5]2.[O:22]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:22][C@@:7]([CH3:20])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:21])[C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(C(=O)NCCO)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CC[C@](C)(O)C(=O)NCCO)=C(C)C1=O
Yield: 90.5 %

Procedure:
Oxidation as described in protocol B, using 3.50 g (11.93 mmol) of (S)-6-hydroxy-N-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 13.73 g CAN (25.06 mmol) yielded 3.341 g of (S)-2-hydroxy-N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:25][C:26]1[N:27]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[CH:28]=[CH:29][N:30]=1)[C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])(=[O:5])=[O:4].[CH2:38]([N:41]([CH2:49][CH2:50][CH3:51])[CH:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1)[CH2:39][CH3:40]>>[CH3:35][N:34]([CH3:36])[S:31]([N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[CH2:25][N:12]([CH2:11][C:7]1[N:6]([S:3]([N:2]([CH3:37])[CH3:1])(=[O:4])=[O:5])[CH:10]=[CH:9][N:8]=1)[C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20]([CH:45]1[CH2:46][CH2:47][CH:42]([N:41]([CH2:49][CH2:50][CH3:51])[CH2:38][CH2:39][CH3:40])[CH2:43][CH2:44]1)[CH2:19][CH2:18]2)=[O:14])(=[O:33])=[O:32]
Reactant: CCCN(CCC)C1CCC(=O)CC1
Reactant: CN(C)S(=O)(=O)n1ccnc1CN(Cc1nccn1S(=O)(=O)N(C)C)C(=O)c1ccc2c(c1)CCNC2
Product: CCCN(CCC)C1CCC(N2CCc3cc(C(=O)N(Cc4nccn4S(=O)(=O)N(C)C)Cc4nccn4S(=O)(=O)N(C)C)ccc3C2)CC1
Yield: 75.2 %

Procedure:
The same operation as in Example 2 was performed, except for using the compound (150 mg) obtained in Example 31 and 4-(dipropylamino)cyclohexanone (269 mg), and then the obtained crude product was purified by silica gel chromatography (dichrolomethane:methanol:28% aqueous ammonia=1:0:0→80:10:1) to obtain the title compound (150 mg) having the following physical properties.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:20]1[C:21]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])=[N:22][CH:23]=[CH:24][N:25]=1>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:20]4[C:21]([N:26]5[CH2:30][CH2:29][CH2:28][C:27]5=[O:31])=[N:22][CH:23]=[CH:24][N:25]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCN1c1nccnc1Cl
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1c1nccnc1Oc1ccc2c(c1)CCN(C1CCC1)CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (103 mg, 0.47 mmol) was dissolved in dry dimethylformamide (3 ml), cooled to 0° C. and treated with sodium hydride (60% in mineral oil, 20 mg, 0.49 mmol). The mixture was allowed to warm to room temperature over 40 minutes. A solution of 1-(3-chloro-2-pyrazinyl)-2-pyrrolidinone (D46) (103 mg, 0.52 mmol) in dry dimethylformamide (1 ml) was added and the mixture stirred at room temperature for 2 hours and heated at 80° C. for 2.5 hours. The mixture was allowed to cool to room temperature and applied to a SCX column and washed with methanol then a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo and resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (86 mg); MS (ES+) m/e 379 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH:14]([C:25]2([C:30]([OH:32])=O)[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(=O)C(Cl)=O.C[Si]([NH:43][OH:44])(C)C>C(Cl)Cl>[OH:44][NH:43][C:30]([C:25]1([CH:14]([S:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:13])=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:32]
Reactant: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C2(C(=O)O)CCCC2)cc1OC
Reactant: C[Si](C)(C)NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C2(C(=O)NO)CCCC2)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
1-[1-(3,4-Dimethoxyphenylsulfonyl)-5-phenylpentyl]cyclopentane carboxylic acid (0.69 g, 1.5 mmol) is dissolved in CH2Cl2 (6 mL), cooled to 0° C. and 2 M oxalyl chloride in CH2Cl2 (2.2 mL, 4.4 mmol) is added. The reaction is warmed and stirred at room temperature 2 hours. The solvent is removed in vacuo and the residue azeotroped with chloroform (2×10 mL). The residue is dissolved in CH2Cl2 (2 mL) and cooled to 0° C. Trimethylsilylhydroxylamine (0.52 mL, 4.5 mmol) is added over 1 minute and this mixture is stirred 5 minutes. Then the ice bath is removed and the reaction stirred at room temperature overnight. The solvent is removed in vacuo and CH2Cl2 (20 mL) added and the solution washed with 1 N HCl (20 mL). The solution is dried over MgSO4 and the solvent removed in vacuo to give 1-[1-(3,4-Dimethoxyphenylsulfonyl)-5-phenylpentyl]cyclopentanecarboxylic acid hydroxyamide (0.48 g, 67%): 1H NMR (300 MHz, CD3OD) δ 7.44 (dd, J=8.3, 2.0 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.22-7.05 (m, 4H), 6.98 (d, J=7.0 Hz, 2H), 3.89 (s, 3H), 3.87 (m, 4H), 2.38 (t, J=7.4 Hz, 2H), 2.35-2.25 (m, 1H), 1.96-1.63 (m, 10H), 1.34-1.27 (m, 2H), 1.21-1.10 (m, 1H), 1.00-0.88 (m, 1H); MS (EI) m/e 476 (M+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCC(C(=O)NC(CCCc3ccccc3)CCCc3ccccc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 108 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-4-carbonyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (70) (1.84 g; 3.12 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 1.25 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.65 g) as a white solid. ESMS:MH+ 490.4
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16][C:15]=1[NH2:21].CCN(CC)CC>O=S(Cl)Cl>[NH2:21][C:15]1[N:16]=[CH:17][C:18]([NH:20][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:19][N:14]=1
Reactant: Nc1cnc(N)nc1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(N)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-methyl-5-nitrobenzoic acid (659 mg, 3.64 mmol) was heated to reflux in SOCl2 (6 mL) for 1 h. After cooling to room temperature and concentrating to dryness, the crude acid chloride was taken up in CH2Cl2 (25 mL). Pyrimidine-2,5-diamine 7 (400 mg, 3.64 mmol) was added to the solution and the mixture was allowed to stir at rt over night. The mixture became a thick white suspension. NEt3 (700 □L, 4.73 mmol) was added. After 2 h, a thick-white suspension remained. The mixture was filtered through a Buchner funnel and washed with copious amounts of CH2Cl2 to remove NEt3HCl salt, affording N-(2-aminopyrimidin-5-yl)-2-methyl-5-nitrobenzamide 8 as an off-white solid.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[NH:5])#[N:2].[OH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.Cl>C(#N)C.O>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][NH:6][C:4]([NH:3][C:1]1[O:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:2]=1)=[NH:5]
Reactant: O=C(CO)c1ccccc1
Reactant: COc1ccccc1CNC(=N)NC#N
Agent: Cl
Solvent: CC#N
Solvent: O
Product: COc1ccccc1CNC(=N)Nc1nc(-c2ccccc2)co1
Temperature: 45 °C
Yield: 10.6 %

Procedure:
The cyclization of 0.60 g (2.94 mmol) N-cyano-N′-(2-methoxybenzyl)guanidine with 0.44 g (2.94 mmol) 2-hydroxyacetophenone was performed in 20 ml acetonitrile and water (1:1). The pH value of the mixture was adjusted with 1 N hydrochloric acid to pH 1.5 and the mixture was then heated in the microwave at 45° C. (100 Watt) for 4.5 hours. After workup and purification, analogously to. 190.2, 0.10 g of pure product was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][S:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=[O:45])=[O:44])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][S:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=[O:44])=[O:45])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCS(=O)(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCS(=O)(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (No. 6804464; 56.1 mg, 0.0748 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure. To the residue was added dichloromethane, and the solvent was again distilled off under reduced pressure. This operation was repeated twice. The residue was then purified by HPLC (water with 0.05% TFA-acetonitrile with 0.05% TFA) to obtain (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoic acid (No. 5513214; 36.2 mg, 74% yield, white powder).
Reaction SMILES: [C:1]1([C:7]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][C:14]3[C:10](=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:12][N:13]=3)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1.O>CN(C)C=O>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([N:13]2[C:14]3[C:10]([CH:9]=[CH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:15]=3)=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:12]2)=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)c1[nH]nc2c1C=CC(c1ccccc1)(c1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=C2C=CC(c3ccccc3)(c3ccccc3)C=C2N(c2ccc([N+](=O)[O-])cc2)N1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 1 g of ethyl 6,6-diphenyl-6,7-dihydro-2H-indazole-3-carboxylate in 5 cm3 of dimethylformamide is added dropwise to a suspension of 0.151 g of sodium hydride (at 60% in oil) in 4 cm3 of dimethylformamide. After stirring the mixture for one and a half hours in the region of 20° C., 0.46 cm3 of 1-fluoro-4-nitrobenzene is added and the reaction mixture is stirred in the region of 80° C. for about two hours. A further 0.26 cm3 of 1-fluoro-4-nitrobenzene is added to the mixture, cooled to the region of 20° C. After stirring for two hours in the region of 80° C., the mixture is slowly cooled to the region of 20° C. and 10 cm3 of water are added. The mixture is extracted three times with 75 cm3 of ethyl acetate, and the combined organic phases are washed with twice 75 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/ethyl acetate (90/10 by volume)], 0.34 g of ethyl 1-(4-nitrophenyl)-6,6-diphenyl-1H-indazole-3-carboxylate is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[S:37]([CH3:36])(=[O:39])=[O:38])=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)CCCCN(Cc1ccc(CNC(=O)OC(C)(C)C)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (198.3 mg) obtained in Example 23-4 was dissolved in anhydrous dichloromethane (4.0 ml) and added with triethylamine (0.142 ml) and methanesulfonyl chloride (0.060 ml), and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the resultant was washed with water and dried with anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (192.0 mg) as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[CH3:7][C:8]([C:11]1[N:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][N:12]=1)([CH3:10])[CH3:9]>>[CH3:10][C:8]([C:11]1[N:12]=[CH:13][C:14]([CH2:17][C:18]([O:20][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])=[O:19])=[CH:15][N:16]=1)([CH3:7])[CH3:9]
Reactant: CC(C)(C)c1ncc(CC(=O)O)cn1
Reactant: CC(C)=CCO
Product: CC(C)=CCOC(=O)Cc1cnc(C(C)(C)C)nc1

Procedure:
Prepared according to the esterification process described in Example 19, Method 1 from 3-methylbut-2-en-1-ol and 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]acetic acid
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C12(NC3C(C(N)=O)=CN=C(S(C)(=O)=O)N=3)CC(C1)C2.[NH2:38][C@@H:39]1[CH2:44][CH2:43][CH2:42][C@H:41]([OH:45])[CH2:40]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([NH:38][C@@H:39]4[CH2:44][CH2:43][CH2:42][C@H:41]([OH:45])[CH2:40]4)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: CS(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Reactant: N[C@@H]1CCC[C@H](O)C1
Agent: CS(=O)(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(N[C@@H]2CCC[C@H](O)C2)nc1NC12CC(C1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a mixture of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylsulfinyl)pyrimidine-5-carboxamide and 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (300 mg) and (1S,3R)-3-aminocyclohexanol (152 mg, 1.32 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) in NMP (10 mL) was added DIEA (426 mg, 3.3 mmol). The resulting mixture was stirred at 100° C. overnight. The reaction mixture was purified by preparative HPLC to give the desired product (230.2 mg, 0.73 mmol, yield 66%). 1H NMR (400 MHz, CD3OD) δ ppm 8.29 (s, 1H), 3.91-3.89 (m, 1H), 3.69-3.62 (m, 1H), 2.50 (s, 1H), 2.29-2.25 (m, 1H), 2.20 (s, 6H), 1.97-1.83 (m, 3H), 1.41-1.21 (m, 4H); MS (ESI) m/z=318.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH2:17][CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH2:17][CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: N=C(N)NN
Reactant: CCc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1n[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 204 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-ethyl-4,5,6,7-tetrahydroindazol-4-one (0.44 g), aminoguanidine hydrochloride (0.19 g), concentrated hydrochloric acid (0.24 ml), water (0.24 ml) and ethanol (40 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated. The resulting crystals were recrystallized from ethanol-water to give 6-(2-chlorophenyl)-3-ethyl-4-guanidinoimino-4,5,6,7-tetrahydroindazole hydrochloride (Compound 27) (0.6 g) as colorless crystals.