Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][CH:6]([C:11](=O)[CH2:12][CH3:13])[C:7](=O)[CH2:8][CH3:9].[NH2:19][NH2:20].[CH2:21]([OH:23])[CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:11]([CH2:12][CH3:13])=[N:19][N:20]([CH2:22][CH2:21][OH:23])[C:7]=1[CH2:8][CH3:9]
Reactant: CCC(=O)C(Oc1cc(Cl)cc(Cl)c1)C(=O)CC
Reactant: NN
Reactant: CCO
Product: CCc1nn(CCO)c(CC)c1Oc1cc(Cl)cc(Cl)c1

Procedure:
3,5-Dichlorophenol (501 mg, 3.07 mmol), potassium carbonate (467 mg, 3.38 mmol) and finally sodium iodide (461 mg, 3.07 mmol) were added sequentially to a stirred solution of the chloroketone of Preparation 2 (500 mg, 3.07 mmol) in acetone (15ml), at room temperature and under nitrogen, producing an orange/red suspension. The mixture was heated under reflux for 22½ hours producing a yellow suspension. After cooling the mixture was diluted with water (10 ml) and the acetone was removed under reduced pressure in a fumehood (caution: possible residual lachrymator). The residue was diluted with 2M hydrochloric acid and extracted with dichloromethane (1×20 ml, 2×10 ml). The combined organic layers were washed with brine (20 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave crude 4-(3,5-dichlorophenoxy)-3,5-heptanedione as an orange oil (777 mg). A portion of the crude 4-(3,5-dichlorophenoxy)-3,5-heptanedione (250 mg, ca. 0.865 mmol) was dissolved in ethanol (8.6 ml) and treated with 2-hydroxethyl hydrazine (65 μL, 0.951 mmol). The resulting solution was heated under reflux for 16 hours producing a red solution. After cooling, the mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (20 ml). The resulting solution was washed with 2M hydrochloric acid (10 ml), 1N sodium hydroxide solution (10 ml) and brine (10 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave an orange oil (102 mg). The crude product was purified by flash chromatography on silica gel eluting with methanol:dichloromethane (5:95, by volume) to provide the title compound (23 mg) as an orange oil which solidified to a waxy solid on standing.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[CH3:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:10]([C:11]3[CH:19]=[CH:18][C:14]([CH3:15])=[CH:13][CH:12]=3)[O:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: Cc1ccc(C(=O)O)cc1
Product: Cc1ccc(-c2nc3ccc(Br)cc3o2)cc1

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 4-methyl-benzoic acid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[O:20]([CH2:27]C(O)=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:31]([N:33]1[C:45]2[CH:44]=[CH:43][C:42]([NH2:46])=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH3:32]>>[CH2:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH2:27][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:9]([C:17]([NH:46][C:42]2[CH:43]=[CH:44][C:45]3[N:33]([CH2:31][CH3:32])[C:34]4[C:39]([C:40]=3[CH:41]=2)=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:19])[CH2:10]1)[CH3:16]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)COc1ccccc1
Product: CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)COc2ccccc2)C1

Procedure:
Following the general method as outlined in Example 2, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, phenoxyacetic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained after column chromatography as an off-white solid as a mixture of E/Z-isomers. The isomers were then separated using column chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][C:17]2[NH:21][N:20]=[C:19]([CH:22]3[CH2:24][CH2:23]3)[CH:18]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.O=S(Cl)Cl.[CH3:29]O>>[ClH:1].[Cl:1][C:2]1[C:3]([NH:16][C:17]2[NH:21][N:20]=[C:19]([CH:22]3[CH2:23][CH2:24]3)[CH:18]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([C:13]([O:15][CH3:29])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)n[nH]3)n2)s1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)n[nH]3)n2)s1
Product: Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(5-chloro-4-(3-cyclopropyl-1H-pyrazol-5-ylamino)pyrimidin-2-yl)thiophene-2-carboxylic acid (Compound 156) (50 mg, 0.138 mmol) in methanol (5 mL) was added SOCl2 (0.5 mL) dropwise. The mixture was stirred at 70° C. for 2 hrs. LCMS showed that the reaction is over. The solvent was removed in vacuum to the target product Methyl 5-(5-chloro-4-(3-cyclopropyl-1H-pyrazol-5-ylamino)pyrimidin-2-yl)thiophene-2-carboxylate hydrochloride (Compound 154) as HCl salt (25 mg, 44%). LC-MS (m/z)=376 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.77-0.81 (m, 2H), 1.00-1.05 (m, 2H), 1.95-2.02 (m, 1H), 3.86 (s, 3H), 6.43 (s, 1H), 7.81-7.84 (m, 2H), 8.51 (s, 1H), 9.67 (s, 1H).
Reaction SMILES: C(O)(=O)CCC(O)=O.[NH2:9][C:10]1[C:27]([Cl:28])=[CH:26][C:13]([C:14]([NH:16][CH:17]2[CH2:21][N:20](CC)[N:19]([CH2:24][CH3:25])[CH2:18]2)=[O:15])=[C:12]([O:29][CH3:30])[CH:11]=1.CO.Cl[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:9][C:10]1[C:27]([Cl:28])=[CH:26][C:13]([C:14]([NH:16][CH:17]2[CH2:18][N:19]([CH2:24][CH3:25])[N:20]=[CH:21]2)=[O:15])=[C:12]([O:29][CH3:30])[CH:11]=1
Reactant: CCN1CC(NC(=O)c2cc(Cl)c(N)cc2OC)CN1CC
Agent: O=C(O)CCC(=O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCN1CC(NC(=O)c2cc(Cl)c(N)cc2OC)C=N1
Temperature: -20 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of 8.90 g (0.020 mole) of 4-amino-5-chloro-N-(1,2-diethyl-4-pyrazolidinyl)-2-methoxybenzamide succinate in 400 ml of reagent grade methanol, cooled to -20° C. and under nitrogen atmosphere was added dropwise 80 ml of 5% aqueous sodium hypochlorite over a 20 min period while maintaining the reaction mixture at -20° C. The reaction mixture was stirred for an additional one hour period at 0° C. then diluted with one liter of chloroform. The diluted mixture was washed with 500 ml of water. The aqueous layer was extracted with 200 ml of chloroform. The combined chloroform layers were dried over sodium sulfate and concentrated in vacuo. The crude product was partially purified by column chromatography on a silica column (eluted with ethyl acetate:hexane:methanol, 4.5:4.5:1). Further purification was effected by high pressure liquid chromatography, using the same solvent system as eluant. On evaporation, the residue was triturated with cold diethyl ether to give 1.90 g (32.0%) of title product, m.p. 132.5°-134.0° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][OH:10])[N:3]=1.[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([N+]([O-])=O)[C:15]=1[C:16]#[N:17])([O-:13])=[O:12]>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][O:10][C:18]2[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[C:15]=2[C:16]#[N:17])[N:3]=1
Reactant: Cc1cc(C)n(CCO)n1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: Cc1cc(C)n(CCOc2cccc([N+](=O)[O-])c2C#N)n1
Yield: 90.7 %

Procedure:
Prepared as in Example 215c from 2-(3,5-dimethyl-1H-pyrazol-1-yl)ethanol and 2,6-dinitrobenzonitrile in 90.7% yield. MS 287 (MH+).
Reaction SMILES: C(Cl)(=[O:3])C.[O:5]1C[CH2:8][CH2:7][CH2:6]1.C([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])C>>[OH:5][C@H:6]1[CH2:7][CH2:8][CH2:16][C@@H:15]1[NH:12][C:13](=[O:3])[CH3:14]
Reactant: C1CCOC1
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Product: CC(=O)N[C@H]1CCC[C@@H]1O

Procedure:
In addition, this intermediate can be acetylated with acetyl chloride in a solvent such as tetrahydrofuran in the presence of an acid scavenger, such as triethylamine, to give (S,S)-(+)-N-(2-hydroxycyclopentyl)acetamide. Treatment of this acetamide derivative with thionyl chloride results in the ring-closed intermediate (S,R)-4,5,6,6a-tetrahydro-2-methyl-3aH-cyclopentoxazole hydrochloride which is converted into (R,S)-(-)-2-aminocyclopentanol hydrochloride when allowed to reflux in the presence of dilute hydrochloric acid. This intermediate can then be used in any of the above schemes, preferably using the ergoline acid and carbonyldiimidazole, to give the (S,R) compound of this invention.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC[N:30]([CH:34]([CH3:36])C)[CH:31]([CH3:33])C.CN1C(=O)[CH2:41][CH2:40][CH2:39]1>>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1[N:30]1[CH2:31][CH2:33][C:40]([CH3:41])([CH3:39])[CH2:36][CH2:34]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(C)CC3)n2n1
Temperature: 50 °C
Yield: 76 %

Procedure:
To a solution of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (300 mg, 0.613 mmol) and 4,4-dimethylpiperidine, HCl (138 mg, 0.920 mmol) in NMP (3 mL) was added DIEA (0.321 mL, 1.839 mmol) and the mixture was heated at 50° C. for 72 h. At this point LCMS indicated completion of reaction. Mixture was cooled to room temperature and purified by prep-HPLC to afford (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (220 mg, 0.464 mmol, 76% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.03 (s, 1H), 5.99 (s, 1H), 4.47 (q, J=7.1 Hz, 2H), 4.30-4.11 (m, 2H), 3.21-2.98 (m, 4H), 2.65 (s, 3H), 1.70-1.62 (m, 2H), 1.59-1.50 (m, 2H), 1.46 (t, J=7.1 Hz, 3H), 1.26 (s, 9H), 1.25-1.22 (m, 3H), 1.14 (s, 6H). LCMS (M+H)=475.2.
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:11][C@H:10]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.C(OC(Cl)=O)C.[CH2:35]([CH:42]([NH2:50])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:43]([CH:42]([NH:50][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@@H:10]1[CH2:11][C@@H:9]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCCCCCCC[C@H]1C[C@H]1CCCCCCCC(=O)O
Reactant: NC(Cc1ccccc1)Cc1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC[C@H]1C[C@H]1CCCCCCCC(=O)NC(Cc1ccccc1)Cc1ccccc1
Reaction time: 1 h

Procedure:
To a cooled solution of 2.0 g (cis)-2-octylcyclopropanoctanoic acid in 70 ml methylene chloride at -20° is added first 0.707 g triethylamine and then dropwise 0.732 g ethylchloroformate. The reaction mixture is then allowed to come to room temperature and stirred for 1 hours. Then 1.5 g of 1-benzyl-2-(phenyl)ethylamine is added, and the reaction mixture stirred for 16 hours. The reaction mixture is then extracted a few times with 2 N hydrochloric acid, then with 2 N aq. sodium hydroxide sol. and washed several times with saturated aq. sodium chloride. The organic phase is then dried over anh. sodium sulphate filtered and evaporated i.v. to dryness to obtain a residue, which upon crystallization from pentane yields the title product (m.p. 40°-45°).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18][NH2:19])[CH3:16])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[Br:20][C:21]1[C:22]([OH:34])=[C:23]([CH:32]=O)[C:24]2[CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]=2[CH:29]=1.[BH4-].[Na+].CCOCC>C(O)C.C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18][NH:19][CH2:32][C:23]2[C:22]([OH:34])=[C:21]([Br:20])[CH:29]=[C:28]3[C:24]=2[CH2:25][CH2:26][C:27]3([CH3:31])[CH3:30])[CH3:16])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: CN(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC1(C)CCc2c1cc(Br)c(O)c2C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCO
Product: CN(CCNCc1c(O)c(Br)cc2c1CCC2(C)C)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A mixture of 1.82 g (6.32 mmol) of 3,5-diamino-N-[2-[(2-aminoethyl)methylamino]ethyl]-6 -chloropyrazinecarboxamide (A) and 1.70 g (6.32 mmol) of 6-bromo-1,1-dimethyl-5-hydroxyindan-4-carboxaldehyde (B) in 70 ml of ethanol and 10 ml of methylene chloride was stirred at ambient temperature for 1 h. Sodium borohydride (0.29 g, 7.58 mmol) was added and the reaction mixture stirred for 15 min. The solution was evaporated and the residue was partitioned between water and methylene chloride The organic phase was dried and evaporated. The residue was chromatographed on silica gel (150 g) using 0.2:3:96.8 (v/v/v) ammonium hydroxide:methanol:methylene chloride as eluent. There was obtained 2.62 g (4.84 mmol, 77%) of the title compound after trituration with ether: mp 134°-136° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:49]=[N+:50]=[N-:51].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][N:49]=[N+:50]=[N-:51])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCOS(C)(=O)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCN=[N+]=[N-])C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 98.0 mg of (2S,4R,5R)-2-(2-methanesulfonyloxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 18b) in N,N-dimethylformamide are added 94 mg of sodium azide and the resulting mixture is stirred for 24 hours at room temperature. The reaction mixture is diluted with water, extracted with tert-butyl methyl ether, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.47 (EtOAc-heptane 1:1); Rt=5.65.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)=[CH:14][C:13]2=[O:29])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:31]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:62][C@@H:63]([CH2:93]O)[CH2:64][N:65]1[CH:69]=[CH:68][C:67]([NH:70]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:66]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:26])[F:27])[CH:19]=3)=[CH:14][C:13]2=[O:29])[C:9]([NH:70][C:67]2[CH:68]=[CH:69][N:65]([CH2:64][C:63]([OH:62])([CH3:93])[CH3:31])[N:66]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC(F)(F)F)c2)=CC1=O
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3cccc(OC(F)(F)F)c3)=CC2=O)n1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 21.2 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethoxy-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (250 mg, 0.6 mmol) in dichloromethane (12 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (344 mg, 1.8 mmol) and N,N-diisopropylethylamine (387 mg, 3.0 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (275 mg, 1.9 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 93 mg, 0.6 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[2-oxo-4-(3-trifluoromethoxy-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide (70 mg, 21%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ PPM 0.81-1.09 (m, 2H), 1.15 (s, 6H), 1.16-1.32 (m, 3H), 1.60-1.97 (m, 8H), 3.60 (s, 1H), 3.93 (s, 2H), 4.08 (d, J=18.1 Hz, 1H), 4.28 (d, J=18.1 Hz, 1H), 4.88 (dd, J=9.0, 6.6 Hz, 1H), 5.02 (s, 1H), 6.67 (d, J=2.1 Hz, 1H), 7.07 (s, 1H), 7.10-7.16 (m, 2H), 7.29 (d, J=2.1 Hz, 1H), 7.44 (t, J=8.3 Hz, 1H), 8.49 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH:32]([S:40]([Cl:43])(=[O:42])=[O:41])=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[ClH:43].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:40](/[CH:32]=[CH:33]/[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:42])=[O:41])=[C:3]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Product: Cl
Product: O=S(=O)(/C=C/c1ccccc1)Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
The compound was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and beta-styrenesulfonylchloride (55 mg, 0.27 mmol) to give before Boc-deprotection 12 mg as purple solid. M+1 513.6 Calcd 512.15. 1HNMR δ 7.78-7.38 (m, 10H), 7.20 (d, 1H), J=15.4 Hz), 7.10 (d, 1H), 6.98 (d, 1H), J=15.4 Hz), 6.56 (dd, 1H), 6.44 (d, 1H), 3.62 (app t, 2H), 3.41 (app t, 2H), 3.23 (app t, 2H), 3.15 (app t, 2H), 2.09-2.01 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.O=[C:11]([CH2:15][CH3:16])[C:12]([OH:14])=[O:13].[O-][CH2:18][CH3:19].[Na+].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:16][C:15]1[C:11]([C:12]([O:14][CH2:18][CH3:19])=[O:13])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CC[O-]
Reactant: Nc1ccccc1C=O
Reactant: CCC(=O)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2ccccc2cc1C
Temperature: 0 °C

Procedure:
A solution of 2-aminobenzaldehyde, 2-oxobutyric acid (13.5 g, 132 mmol), and sodium ethoxide (13.5 g, 198 mmol) in ethanol (331 mL) was refluxed for 20 h. After being cooled to 0° C., 96% sulfuric acid (10.6 mL, 97.9 mmol) was added. The reaction mixture was refluxed for 20 h. After being cooled to 0° C., the reaction mixture was basified to pH 8-9 with saturated sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 2:1) to give ethyl 3-methylquinoline-2-carboxylate. MS (APCI): m/z 218 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH2:24][OH:25])[N:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:33]1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.IC.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH2:24][O:25][CH3:33])[N:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4nc(CO)cs4)ccc3n(C)c21
Reactant: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COCc1csc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)n1
Reaction time: 0.08 h

Procedure:
120 mg (0.286 mmol) of compound from Example 100 above, 3-(4-fluorophenyl)-6-(4-hydroxymethylthiazol-2-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 3 ml of DMF. 17 mg (0.429 mmol) of 60% NaH and a spatula of dibenzo-18-crown-6 are added. After stirring for 5 minutes, 27 μl (0.429 mmol) of iodomethane are added. The mixture is allowed to stir for 4 h at ambient temperature. A saturated NaHCO3 solution is added, the mixture is extracted with EtOAc and then with CH2Cl2 and the organic phase is concentrated to dryness without drying. The residue is taken up in MeOH, and the white precipitate is filtered off and washed with MeOH and then with a minimum amount of Et2O.
Reaction SMILES: C1(N([C@H]2CC[C@H](COC)CC2)C(=O)NC2SC(SC[C:17](O)=[O:18])=CN=2)CCCCC1.[CH:30]1([NH:37][C@H:38]2[CH2:44][CH2:43]C[C@H:41]([CH2:45][O:46][CH3:47])[CH2:40][CH2:39]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C([O:50][C:51](=[O:62])[C:52]([S:55][C:56]1[S:60][C:59]([NH2:61])=[N:58][CH:57]=1)([CH3:54])[CH3:53])C>>[CH:30]1([N:37]([C@H:38]2[CH2:39][CH2:40][C@H:41]([CH2:45][O:46][CH3:47])[CH2:43][CH2:44]2)[C:17](=[O:18])[NH:61][C:59]2[S:60][C:56]([S:55][C:52]([CH3:54])([CH3:53])[C:51]([OH:50])=[O:62])=[CH:57][N:58]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC[C@H]1CCC[C@H](NC2CCCCCC2)CC1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1
Product: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)C2CCCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cycloheptyl-(trans-4-methoxymethyl-cycloheptyl)-amine and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester to give the title compound.