Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:41]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][CH2:37][NH:38][C:39]=4[CH:40]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:41]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][CH2:37][N:38]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[O:9][C:10]([CH3:13])=[N:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:39]=4[CH:40]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCCC3
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D11) and 2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10) using a similar procedure to Example 1 as a white solid (62%). This was converted to its oxalate salt which was obtained as a white solid (mp 187-188° C.) and hydrochloride salt (mp 176-180° C.).
Reaction SMILES: C[CH2:2][N:3]([CH2:6]C)[CH2:4]C.CN(C)[CH2:10][CH:11](OCCCCCCCC/C=C\C/C=C\CCCCC)[CH2:12][O:13][C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C[C@@]12[C@@:84](O)([C:85]([CH2:87][OH:88])=O)[CH2:83][CH2:82][C@H:81]1[C@@H:80]1[CH2:90][CH2:91][C:92]3[C@@:98](C)([C@H:79]1[C:77](=O)[CH2:76]2)[CH:97]=[CH:96][C:94](=O)[CH:93]=3>ClCCl>[CH3:2][N:3]([CH3:6])[CH2:4][CH:12]([O:13][C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:10][O:88][CH2:87][CH2:85][CH2:84][CH2:83][CH2:82][CH2:81][CH2:80][CH2:90]/[CH:91]=[CH:92]\[CH2:93]/[CH:94]=[CH:96]\[CH2:97][CH2:98][CH2:79][CH2:77][CH3:76]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOC(COC(=O)CCC(=O)O)CN(C)C
Reactant: CCN(CC)CC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCCC(CN(C)C)OC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NEt3 (100 μL, 0.74 mmol, 1.0 equiv) was added dropwise to a dry dichloromethane solution (10 mL) of 4-(3-(dimethylamino)-2-((9Z,12Z)-octadeca-9,12-dienyloxy)propoxy)-4-oxobutanoic acid and the resultant was stirred for 15 minutes under argon at room temperature. PyBOP (0.48 g, 0.93 mmol, 1.25 equiv) was added in one portion and the resultant was stirred for 10 minutes. Prednisone (0.32 g, 0.89 mmol, 1.2 equiv) was added to the mixture and the resultant was stirred at room temperature for 18 hours and then concentrated to provide a thick yellow oil, (90% pure). Purification by flash column chromatography (5-15% MeOH in chloroform and (0-15% MeOH in EtOAc) provided the desired product
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[C:5]([Br:8])=[CH:6][CH:7]=1.C(O)(=O)C.[C:15]1([C:21]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]2[C:3]=1[N:10]=[C:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:9]2
Reactant: Nc1c(Br)ccc(Br)c1N
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc12
Yield: 86 %

Procedure:
Preparation procedure: 3,6-dibromo-o-phenylene diamine (1.0 g, 3.7 mmol) is added to an acetic acid (20 mL) solution of benzil (0.39 g, 1.84 mmol) at 120° C. The resulting solution is mixed homogeneously and reflux for 12 hours. The reaction solution is poured into water, neutralized with sodium bicarbonate, extracted with chloroform, washed with saturated brine water, and dried over anhydrous sodium sulfate. The solvents are removed using a rotary evaporator. The crude product is subjected to column chromatography to give a white solid, which is then recrystallized in chloroform/n-hexane to afford a white solid powder (yield 86%), MALDI-TOF-MS (m/z): 440.1 (M+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:17]2[N:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=2[CH2:13][C:12]1=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.CC(C)([O-])C.[K+].[N:40](OCCC(C)C)=[O:41]>O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:17]2[N:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=2[C:13](=[N:40][OH:41])[C:12]1=[O:26])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)CCON=O
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)Cc2ccccc2-c2cccnc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCn1c(=O)c(=NO)c2ccccc2c2cccnc21
Temperature: 20 °C
Reaction time: 0.38 h
Yield: 89 %

Procedure:
Combine 5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7H-pyrido[2,3-d][3]benzazepin-6-one (30.0 g, 0.08 mol) and toluene (300.0 mL), cool the reaction mixture to −10-0° C. Add potassium tert-butoxide (18.2 g, 0.16 mol), isoamyl nitrite (13.34 g, 0.11 mol) and then stir for 3-5 hours. Transfer the reaction mixture to a cool (0-5° C.) biphasic solution of ethyl acetate (210 mL) and water (510 mL) and stir for 15-30 minutes. Warm the reaction mixture to 15-25° C. and separate the layers. Extract the aqueous layer with additional ethyl acetate (120 mL) and methyl tert-butyl ether (120 mL) and combine the organic layers. Concentrate the organic under reduced pressure to a solution volume of approximately 60-90 mL and then add toluene (240 mL) and ethyl acetate (75 mL). Filter the solution through silica gel (45.0 g), rinse the silica gel with a mixture of toluene (210 mL) and ethyl acetate (60 mL), and concentrate the filtrate under reduced pressure to a volume of approximately 75 mL. Add heptane (120 mL) and concentrate the mixture to a volume of approximately 60 mL and filter the resulting solids. Wash the filter cake with heptane (25 mL) and dry under vacuum to provide the title compound (28.3 g, 72.5%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:8][CH2:9][CH3:10])[CH:3]([OH:7])[CH2:4][C:5]#[CH:6].[CH2:12]([Si:14](Cl)([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].N1C=CN=C1>CN(C)C=O>[CH2:12]([Si:14]([O:7][CH:3]([C:2]([CH3:11])([CH3:1])[CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13]
Reactant: C#CCC(O)C(C)(C)CCC
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(O[Si](CC)(CC)CC)C(C)(C)CCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture containing 3 parts of 5,5-dimethyl-1-octyn-4(RS)-ol, 3.3 parts of triethylsilyl chloride, 3.4 parts of imidazole and 5 parts by volume of dimethylformamide is stirred at room temperature for about 1 hour, then is partitioned between water and ether. The ether solution is separated, washed several times with water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to afford 5,5-dimethyl-1-octyn-4(RS)-ol triethylsilyl ether.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH3:13].[Cl:14][C:15]1[N:16]=[C:17](Cl)[C:18]2[CH:23]=[CH:22][S:21][C:19]=2[N:20]=1>C1COCC1.O>[Cl:14][C:15]1[N:16]=[C:17]([O:3][C:4]2[C:5]([CH3:13])=[CH:6][C:7]([C:8]#[N:9])=[CH:10][C:11]=2[CH3:12])[C:18]2[CH:23]=[CH:22][S:21][C:19]=2[N:20]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: Clc1nc(Cl)c2ccsc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2sccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
A stirred suspension of NaH (85 mg, 2.12 mmol) in dry THF (12 mL) was added 4-hydroxy-3,5-dimethyl benzonitrile (311 mg, 2.12 mmol) and stirred at room temperature for 30 min under Argon. The reaction mixture was added to a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (434 mg, 2.12 mmol) in dry THF (10 mL) and heated at 50° C. for 2 h, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (5:1) to give the product as a white solid (188 mg, 28%):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:30][CH:29]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (227 mg, 1.13 mmol) in THF (4.0 mL) at room temperature was added NaH (100 mg, 4.5 mmol). Stirring was continued for 10 min. To this solution was added 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (200 mg, 0.56 mmol) and the resulting mixture was stirred at 50-55° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography using 30% ethyl acetate in hexanes to provide 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:27]=[CH:26][C:9]([C:10]([N:12]([C@H:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH:24]=O)[CH:20]=4)[CH2:15]3)[CH3:13])=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C1COCC1.[O:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35][CH2:34]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:27]=[CH:26][C:9]([C:10]([N:12]([CH3:13])[C@H:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH2:24][NH:40][CH2:39][CH:36]5[CH2:37][CH2:38][O:33][CH2:34][CH2:35]5)[CH:20]=4)[CH2:15]3)=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: NCC1CCOCC1
Reactant: CN(C(=O)c1ccc(OCC2CC2)cc1)[C@H]1CCc2cc(C=O)ccc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C(=O)c1ccc(OCC2CC2)cc1)[C@H]1CCc2cc(CNCC3CCOCC3)ccc2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 4-cyclopropylmethoxy-N—((S)-6-formyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylbenzamide (0.20 g), THF (5 ml), C-(tetrahydropyran-4-yl)methylamine (63 mg) and acetic acid (33 mg) was added polymer-bound sodium cyanoborohydride (0.55 mmol), and the suspension was shaken at room temperature for 12 hours. The polymer was filtered off with suction and the filtrate was concentrated. The residue was purified by preparative HPLC. The product was thus obtained with the monoisotopic molecular weight of 462.29 (C28H38N2O3); MS (ESI): 463.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24].CC[O:31][C:32]([CH3:34])=[O:33]>>[CH3:2][CH2:1][O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:21]1[C@H:22]([C:23]([OH:25])=[O:24])[CH2:26][CH2:27][CH2:28]1)=[O:20])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5].[CH:34](/[C:32]([OH:31])=[O:33])=[CH:6]/[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCOC(C)=O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Product: O=C(O)/C=C\C(=O)O
Yield: 77 %

Procedure:
In ES patent 2,004,804 the preparation of carboxyalkyldipeptides useful as ACE inhibitors is disclosed. N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine is treated with 1,1-carbonyldiimidazole in EtOAc and subsequently with L-proline and enalapril maleate is obtained with a 77% yield.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1>>[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH:20][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH:28][CH2:27][C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)[CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: NCc1cccnc1
Product: Cc1ccc(CNc2ccc3cc(NCc4cccnc4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=345.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 3-picolylamine.
Reaction SMILES: [ClH:1].[C:2]1([N:8]2[CH2:13][CH2:12][N:11](CCCCN3C(=O)C4C=CC=C5C=4C(=CC=C5)C3=O)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:48](=[O:49])[C:47]2[CH:50]=[CH:51][CH:52]=[C:45]3[C:46]=2[C:41](=[CH:42][CH:43]=[CH:44]3)[C:40]1=[O:53].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]3[C:48](=[O:49])[C:47]4[CH:50]=[CH:51][CH:52]=[C:45]5[C:46]=4[C:41](=[CH:42][CH:43]=[CH:44]5)[C:40]3=[O:53])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccc2)CC1
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCN1CCN(c2ccccc2)CC1

Procedure:
Following the procedure of part (b) of example 34 but substituting 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, one obtains 2-[5-(4-phenyl-1-piperazinyl)pentyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C@H:7]2[NH:14]C(=O)OC(C)(C)C.CO.Cl>CC(OC)(C)C.O>[Cl:1][C:2]1[C:3]([F:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C@H:7]2[NH2:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2c1ccc(F)c2Cl
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O
Solvent: CO
Product: CC1(C)C[C@@H](N)c2ccc(F)c(Cl)c2O1
Reaction time: 2 h
Yield: 92.6 %

Procedure:
The crude (R)-tert-butyl 8-chloro-7-fluoro-2,2-dimethylchroman-4-ylcarbamate (4.47 g, 13.5 mmol), MeOH (36 mL), and concentrated HCl (4 mL) were heated to 50° C. After 2 hours, complete deprotection was observed by LCMS. The reaction mixture was cooled, stirred for 8 hours, and then diluted with MTBE (60 mL) and water (40 mL). The mixture was partitioned and the organic layer was extracted with water (50 mL). The aqueous layer was basified with 2N NaOH (40 mL) and extracted with dichloromethane (2×40 mL). The organic extracts were dried (Na2SO4), filtered, and concentrated to give the title compound (2.87 g, 12.50 mmol, 92%). MS (ESI+) m/z 230 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(C1C=CC([C:28]2[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=2)=CC=1)CCCCCCCC.C(C1C=CC(C2C=CC(C(O)=O)=CC=2)=CC=1)CCCCCCCCC.[CH2:62]([C:73]1[CH:78]=[CH:77][C:76]([C:79]2[CH:84]=[CH:83][C:82]([C:85]([OH:87])=[O:86])=[CH:81][CH:80]=2)=[CH:75][CH:74]=1)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72].C(OC1C=C(C(O)=O)C(C2C=CC=CC=2)=CC=1)CCCCCCCCC>>[CH2:62]([C:73]1[CH:74]=[CH:75][C:76]([C:79]2[CH:84]=[CH:83][C:82]([C:85]([O:87][C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:10][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:2]([F:11])([F:12])[F:1])=[O:35])=[CH:30][CH:29]=3)=[O:86])=[CH:81][CH:80]=2)=[CH:77][CH:78]=1)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72]
Reactant: CCCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCCC(O)C(F)(F)F
Reactant: CCCCCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CCCCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)O)c1
Agent: CCCCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: CCCCCCCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(CCCCCC)C(F)(F)F)cc3)cc2)cc1

Procedure:
Example 1s were repeated except that optically active 1,1,1-trifluoro-2-octanol was used in place of the 1,1,1-trifluoro-2-decanol used in example 1,1, and 4'-n-nonylbiphenyl-4-carboxylic acid, 4'-n-decylbiphenyl-4-carboxylic acid and 4'-n-undecylbiphenyl-4-carboxylic acid were used in place of the 4-n-decyloxybiphenylcarboxylic acid to obtain the titled compounds, respectively.
Reaction SMILES: CS(C)=O.[C:5]([N:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>C(N(CC)CC)C>[O:16]=[C:14]1[CH2:15][N:12]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Temperature: 50 °C
Yield: 61.7 %

Procedure:
A DMSO (10 mL) solution of a sulfur trioxide-pyridine complex (2.2 g; Ald) was added to a triethylamine (4 mL) solution of 1-Boc-3-(hydroxy)azetidine (500 mg; CNH) at room temperature and the resulting mixture was stirred 50° C. for 2 and half hours. The resulting mixture was stirred for approx. 10 minutes at room temperature, then the reaction mixture was poured into ice water (40 mL) and extracted with ethyl acetate (40 mL), the organic layer was dried, and the solvent was evaporated under reduced pressure to give the title compound (305 mg).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][N:9]=[C:10]=[O:11].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14]C=1>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>[C:1]1([O:7][C:10](=[O:11])[NH:9][CH3:8])[C:6]2[CH:16]3[CH2:15][CH:14]([CH2:12][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: CN=C=O
Reactant: Oc1ccccc1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: CNC(=O)Oc1cccc2c1C1CCC2C1
Reaction time: 96 h

Procedure:
##STR8## The phenol IV (1.3 g.) was dissolved in benzene (10 ml.), and methyl isocyanate (0.6 g.) and dibutyltin diacetate (two drops) added. The solution was allowed to stand at room temperature for 4 days, then petroleum ether was added to precipitate the carbamate VI, (1.6 g.), m.p. 160°-164° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:49][N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][N:53]3[CH2:54][CH2:55][CH2:56][N:50]([CH3:49])[CH2:51][CH2:52]3)=[CH:14][CH:15]=2)[N:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C=O)cc4)c4ccccc43)cn12
Reactant: CN1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CN5CCCN(C)CC5)cc4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To an orange solution of Intermediate 176b (0.188 mmol) and N-methyl homopiperazine (43 mg, 0.38 mmol) in DCM (3 mL) was added sodium triacetoxyborohydride (60 mg, 0.28 mmol) and the mixture stirred at RT for 1 h. Water (3 mL) was added and the mixture shaken. The aqueous was extracted with DCM (3 mL) then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave a brown gum. Flash chromatography (silica 12 g, 7-11% [2M NH3 in MeOH] in DCM) gave the title compound as a yellow solid (102 mg, 73%). LCMS (Method 3): Rt 2.84 min, m/z 745 [MH+]. 1H NMR (300 MHz, CDCl3): 0.91 (3H, d, J=6.2 Hz), 1.34 (9H, s), 1.40-1.55 (2H, m), 1.62-1.99 (7H, m), 2.15-2.02-2.14 (2H, m), 2.21-2.30 (1H, m), 2.33 (3H, s), 2.55-2.69 (8H, m), 2.90 (1H, ddd, J=12.1, 9.3, 4.1), 3.04 (1H, dt, J=12.1, 4.2 Hz), 3.23-3.32 (1H, m), 3.58 (2H, s), 5.09 (1H, td, J=8.9, 5.2 Hz), 5.19 (1H, t, J=3.9 Hz), 6.04 (1H, br d, J=8.6 Hz), 6.33 (1H, s), 6.94 (1H, dd, J=9.9, 2.1 Hz), 7.22 (1H, br s), 7.25-7.39 (7H, m), 7.43 (1H, d, J=2.2 Hz), 7.47 (2H, m).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH3:14])=[C:7]([NH:15][CH:16]([CH3:20])[CH:17]([CH3:19])[CH3:18])[N:6]2[N:21]=[CH:22][C:23]([C:24](Cl)=[O:25])=[C:5]2[N:4]=1.C(OCC)(=O)C>O1CCCC1>[Cl:2][C:3]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH3:14])=[C:7]([NH:15][CH:16]([CH3:20])[CH:17]([CH3:19])[CH3:18])[N:6]2[N:21]=[CH:22][C:23]([C:24]([NH2:1])=[O:25])=[C:5]2[N:4]=1
Reactant: N
Reactant: Cc1ccsc1-c1c(Cl)nc2c(C(=O)Cl)cnn2c1NC(C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccsc1-c1c(Cl)nc2c(C(N)=O)cnn2c1NC(C)C(C)C
Temperature: 22 °C
Reaction time: 16 h

Procedure:
At room temperature, 15 ml of concentrated aqueous ammonia were added to 4.0 g (10 mmol) of 5-chloro-7-(1,2-dimethylpropylamino)-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]pyrimidine-3-carbonyl chloride in 30 ml of tetrahydrofuran. The mixture was stirred at 22° C. for 16 hours, and 50 ml of ethyl acetate were then added. The organic phase was separated off, dried over sodium sulphate and concentrated under reduced pressure. This gave 3.0 g of 5-chloro-7-(1,2-dimethyl-propylamino)-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide (logPs=3.5; content according to HPLC: 94%)
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.[CH3:44][O:45]C[C@@H]1CCCN1>>[CH3:44][O:45][CH2:6][C@@H:5]1[CH2:4][CH2:3][CH2:2][N:1]1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:8]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCCC3)n2)c1
Reactant: COC[C@@H]1CCCN1
Agent: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: COC[C@@H]1CCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B18 was prepared following the procedure reported for B1 using A1 and (S)-2-(methoxymethyl)pyrrolidine. MS (ES) C16H22N6O3S requires: 378. found: 379 (M+H)+.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36][CH3:37].[Cl:38][C:39]1[C:40]2[C:50]([F:51])=[CH:49][CH:48]=[C:47]([F:52])[C:41]=2[S:42][C:43]=1[C:44](Cl)=[O:45]>>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:44]([C:43]2[S:42][C:41]3[C:47]([F:52])=[CH:48][CH:49]=[C:50]([F:51])[C:40]=3[C:39]=2[Cl:38])=[O:45])[CH2:16][C:17]2[CH:18]=[C:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36][CH3:37])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)[CH3:28])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: CSc1ccccc1Br
Product: COc1ccc(-c2ccccc2SC)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (300 mg, 0.76 mmol) was coupled to 2-bromothioanisole (156 mg, 0.77 mmol) using Method A. The crude reaction mixture was reacted with acid chloride 8 (246 mg, 0.92 mmol) using Method D to give the title compound.