Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:15]([S:19](Cl)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]>C(Cl)Cl>[CH2:15]([S:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)Nc1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
9.9 ml of aniline (10.1 g, 108.4 mmol) and 15 ml of triethylamine (11.0 g, 108.4 mmol) were dissolved at 50° C. in 108 ml of methylene chloride. Again at 50° C. 14.1 ml of n-butanesulfonyl chloride (17.0 g, 108.4 mmol) were added dropwise to this solution over the course of 1 h. After 15 minutes of stirring at 50° C. the reaction mixture was extracted twice with 100 ml of water. The resultant crude product in solution in 150 ml of methylene chloride was extracted with 150 ml of 1 N NaOH. The aqueous phase was adjusted to a pH of 1–2 using concentrated HCl and was extracted twice with 100 ml of methylene chloride. Drying over magnesium sulphate and removal of the methylene chloride by distillation gave 17.0 g of the target compound, whose constitution was verified by NMR spectroscopy.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]([CH2:57][C:58](O)=[O:59])#[N:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:58](=[O:59])[CH2:57][C:55]#[N:56])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: N#CCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and cyanoacetic acid as starting materials in 41% yield. LCMS for C27H28ClN8O2 (M+H)+: m/z=531.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15]CC)=O)=[CH:7][N:6]([CH3:18])[C:5]=2[CH:4]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:13]([C:8]2[C:9](=[O:12])[C:10]3[S:11][C:3]([CH2:2][OH:1])=[CH:4][C:5]=3[N:6]([CH3:18])[CH:7]=2)=[O:15])=[CH:22][CH:21]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C)c2cc(CO)sc2c1=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CO)cc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Ethyl 2-(hydroxymethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (250 mg, 0.94 mmol) was suspended in 4-chlorobenzylamine (2.0 mL, 16.4 mmol). The mixture was stirred at 80° C. for 16 hours before it was quenched with a mixture of 1.0 M hydrochloric acid (25 mL) and ice (5 g). The mixture was stirred at room temperature for 1 hr. The solid ppt. was collected by vacuum filtration and washed thoroughly with 50 mL of water. Drying in vacuo left a white solid (0.26 g).
Reaction SMILES: [CH2:1]([Si:6]1(C2C=CC=CC=2)[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([OH:25])=[C:20]([F:26])[CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:33][C@@H:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:35]O>>[CH2:1]([Si@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([F:26])[C:21]([O:25][CH2:35][C@H:34]([F:33])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:22]([F:24])[CH:23]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCCCC[C@H](F)CO
Reactant: CCCCC[Si]1(c2ccccc2)CCC(c2ccc(-c3cc(F)c(O)c(F)c3)cc2)CC1
Product: CCCCCCCC[C@@H](F)COc1c(F)cc(-c2ccc([C@H]3CC[Si@H](CCCCC)CC3)cc2)cc1F

Procedure:
The general procedure of Example 1 was repeated using 4-(4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)phenyl) -2,6-difluorophenol and (S)-2-fluoro-1-decanol, thereby obtaining the intended compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:16]>CN(C)C=O.O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH2:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=C(CBr)c1ccccc1
Reactant: CC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(COC1CCN(C(C)=O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
N-Acetyl-4-hydroxypiperidine (13.6 g.) in dimethylformamide (50 ml.) was added dropwise to a stirred suspension of sodium hydride (10 g. 50% dispersion in mineral oil) in dimethylformamide (50 ml.) under nitrogen. The mixture was stirred at room temperature for 3 hours then α-(bromomethyl)styrene (20 g.) in dimethylformamide (50 ml.) was added dropwise. The mixture was stirred at room temperature for 4 hours, then diluted with water and extracted with chloroform (3×200 ml.). The combined chloroform extracts were dried (Na2SO4), evaporated in vacuo, and distilled to give N-acetyl-4-(2-phenylallyloxy)piperidine (25 g.), b.p. 170°-180° C./0.3 mm. with an n.m.r. spectrum in accordance with this structure.
Reaction SMILES: C(OC(N(C(OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[CH3:46][O:47][CH2:48][CH2:49][NH2:50]>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([NH:50][CH2:49][CH2:48][O:47][CH3:46])=[O:38])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: COCCN
Product: COCCNC(=O)c1cc(N2CCCC2=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (150 mg) described in Example 769 and 2-methoxyethylamine (84 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (68 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2([C:11](OCC)=[O:12])[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[N:17]=2)[N:3]=1.CC(C)([O-])C.[K+].O.C(O)(=O)C>C1COCC1>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[CH2:25][N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:4]2[N:5]=[CH:6][C:7]3[C:8]4([CH2:9][CH2:10]4)[C:11](=[O:12])[NH:1][C:2]=3[N:3]=2)=[N:17]1
Reactant: CCOC(=O)C1(c2cnc(-c3nn(Cc4ccc(F)cc4F)c4ncccc34)nc2N)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C1Nc2nc(-c3nn(Cc4ccc(F)cc4F)c4ncccc34)ncc2C12CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The intermediate from Step b) was taken up in 20 ml of THF, 109 mg (0.974 mmol) of potassium tert-butoxide were added under an atmosphere of argon and the mixture was stirred at RT for 2 h. Water was added, and the pH of the reaction mixture was adjusted to pH=5 with acetic acid. The mixture was stirred at RT for 10 min and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase:acetonitrile/water with 0.1% formic acid, gradient 50:50→70:30). This gave 101 mg of the title compound (25% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH2:40][NH2:41]>COCCOC.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:41][CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][CH2:29][NH2:28])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: NCCCNCCCCNCCCN
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Solvent: CN(C)C=O
Product: NCCCNCCCCNCCCNC(=O)Cc1ccc(O)c(F)c1
Reaction time: 48 h

Procedure:
According to the General Procedure using 3-fluoro-4-hydroxyphenylacetic acid (85 mg, 0.50 mMol), dicyclohexylcarbodiimide (106 mg, 0.31 mMol), and spermine (512 mg, 2.53 mMol) in DME/DMF (4 ml, 3:1), activation during 2 h and coupling over 48 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 12-19 and was homogeneous when monitored by tlc on silica (CH2Cl2 /MeOH/NH4OH, 4:2:1), Rf =0.19, (39 mg, 22%), lyophilisation gave 30 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, 2H2O) 1.6-2.2 (m, 8H, 4×CH2 --CH2), 2.85-3.2 (m, 10H, 5×CH2 --N), 3.4 (t, J=7, 2H, CON2H--CH2 --CH2), 3.6 (s, 2H, Ar--CH2 --CO), 6.8-7.1 (m, 2H, 2×ArH 5,6), and 7.1 (d, 3 J H--F=11, H, ArH 2)ppm.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][C@H:22]1[CH2:26][O:25][C:24](=[O:27])[NH:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:28][C:29]1[N:34]=[C:33](F)[CH:32]=[CH:31][N:30]=1>CN(C=O)C>[Si:3]([O:20][CH2:21][C@H:22]1[CH2:26][O:25][C:24](=[O:27])[N:23]1[C:31]1[CH:32]=[CH:33][N:34]=[C:29]([F:28])[N:30]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Fc1ccnc(F)n1
Reactant: CC(C)(C)[Si](OC[C@H]1COC(=O)N1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@H]1COC(=O)N1c1ccnc(F)n1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
Sodium hydride (34 mg, 0.84 mmol, 1.5 equiv) was carefully added to a solution of (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one (200 mg, 0.563 mmol) in DMF (2.8 mL). The mixture was stirred at room temperature for 20 minutes and then 2,4-difluoropyrimidine (0.072 mL, 0.84 mmol, 1.5 equiv) was added (bubbling). The yellow suspension was stirred for minutes and the reaction was then carefully quenched with saturated aqueous ammonium chloride (5 mL). Water (20 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 30%) provided (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (0.185 g, sticky colorless oil) in 73% yield. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=5.8, 2.2 Hz, 1H), 8.12 (dd, J=5.8, 3.4 Hz, 1H), 7.58 (m, 2H), 7.48-7.32 (m, 6H), 7.23 (m, 2H), 4.80 (m, 1H), 4.65 (dd, J=8.6, 3.0 Hz, 1H), 4.55 (m, 1H), 4.18 (dd, J=11.1, 3.5 Hz, 1H), 3.83 (dd, J=11.1, 2.1 Hz, 1H), 1.04 (s, 9H). MS m/z 452.3 (M+H)+; Rt-1.15 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(=CC([O:49][C:50]([F:53])([F:52])[F:51])=CC=2)OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2cc(OC(F)(F)F)ccc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(OC(F)(F)F)ccc4c3=O)cc2)CCC1
Yield: 100 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-2-phenyl-7-trifluoromethoxy-chromen-4-one was reacted to give the title compound as a beige solid (83 mg, 100%). LCMS (Method B): RT=5.11 min, [M+Na]+=574.
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10](=[O:19])[NH:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N:34]1[C:43]2[C@@H:42]([NH2:44])[CH2:41][CH2:40][CH2:39][C:38]=2[CH:37]=[CH:36][CH:35]=1>O1CCCC1.C(Cl)Cl>[C:5]([O:9][C:10](=[O:19])[NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:44][C@@H:42]2[C:43]3[N:34]=[CH:35][CH:36]=[CH:37][C:38]=3[CH2:39][CH2:40][CH2:41]2)[CH2:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: N[C@H]1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N[C@H]2CCCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Acetic acid (2.9 mL, 50.7 mmol), (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester (4.32 g, 20.2 mmol) and sodium triacetoxyborohydride (7.56 g, 35.7 mmol) were added to a solution of (S)-5,6,7,8-tetrahydro-quinolin-8-ylamine (2.86 g, 19.3 mmol) in tetrahydrofuran (78 mL) and the mixture was stirred at 25° C. for 3.5 h. The mixture was diluted with methylene chloride (500 mL) and washed with saturated sodium bicarbonate (600 mL). The aqueous layer was extracted with methylene chloride (2×150 mL). The combine organic layers were dried (Na2SO4) and concentrated. The crude mixture of isomers was purified by column chromatography on silica gel with methanol/methylene chloride (4:96) to afford the trans-isomer [4-((S)-5,6,7,8-tetrahydro-quinolin-8-ylamino)-trans-cyclohexyl]-carbamic acid tert-butyl ester as a white solid (2.01 g, 30%). 1H NMR (CDCl3) δ 1.06-1.39 (m, 4H), 1.69 (s, 9H), 1.65-1.80 (m, 2H), 1.90-2.14 (m, 5H), 2.16-2.25 (m, 1H), 2.29 (bs, 1H), 2.56-2.71 (m, 1H), 2.72-2.88 (m, 2H), 3.43 (bs, 1H), 3.92 (t, 1H, J=6.3 Hz), 4.39 (bs, 1H), 7.04 (dd, 1H, J=7.9, 4.5 Hz), 7.35 (d, 1H, J=7.5 Hz), 8.38 (d, 1H, J=4.5 Hz).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:21]=[C:20]4[C:14]([CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19]4)=[N:13]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1.CO>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:21]=[C:20]4[C:14]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)=[N:13]3)=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(N4CCCC4)cc3)nc2CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1cc(-n2cc3c(n2)CCNCC3)ccc1N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 2-[4-(1-pyrrolidinyl)phenyl]-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 44) (79 mg, 0.21 mmol) in dioxan (3 ml) was added 4M hydrochloric acid in dioxan (2 ml). The resulting mixture was stirred at room temperature, under argon, overnight. The reaction mixture was diluted with methanol and then purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (D45). MS (ES+) m/e 283 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([CH2:15][N:16]([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27]O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CS(OS(C)(=O)=O)(=O)=O>C1COCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]2[CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][O:1][C:2]3([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])[CH2:4][CH2:3]3)[CH2:15]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(CO)c2ccccc2)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OCC2c2ccccc2)cc1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-[[(2-hydroxy-1-phenyl-ethyl)-[(4-methoxyphenyl)methyl]amino]methyl]piperidine-1-carboxylate (1.0 g, 2.13 mmol) in THF (10 mL) was added DIEA (1.1 mL, 6.38 mmol) followed by an addition of a solution of methylsulfonyl methanesulfonate (1.1 g, 6.38 mmol) in THF (2 mL) under an atmosphere of nitrogen at 0° C. The reaction mixture was warmed to room temperature and then heated at 40° C. for 16 hours. The reaction mixture was quenched with water and the aqueous layer was extracted with DCM. The organic layer was washed with a sat. solution of NaHCO3, followed by washing with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0 to 100% DCM in hexanes as eluent to obtain tert-butyl 8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (0.5 g, 51%). ESI-MS m/z calc. 452.6. Found 453.5 (M+1)+; Retention time: 1.62 minutes (3 min run).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([O:15][C@@H:16]1[C@@H:29]([OH:30])[C@@H:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:27]([CH2:39][OH:40])[O:26][C@H:17]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>N1C=CC=CC=1>[CH2:8]([O:15][C@@H:16]1[C@@H:29]([OH:30])[C@@H:28]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@@H:27]([CH2:39][O:40][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[O:26][C@H:17]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](O)[C@H]1OCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](O)[C@H]1OCc1ccccc1
Reaction time: 1.17 h
Yield: 90.2 %

Procedure:
Under nitrogen gas atmosphere, pivaloyl chloride (4.2 ml, 35.7 mmol) was added to a solution of Compound 13 (7.3 g, 16.2 mmol) in pyridine (50 ml) at 0° C., and the mixture was stirred for 70 minutes. Methanol was added to the reaction mixture, and the mixture was stirred for 40 minutes, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=6:1) to obtain Compound 14 (7.81 g, 90%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1)(=[O:5])=[O:4].Cl.C(O[C:26](=N)[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)C>CCO>[F:21][C:2]([F:20])([F:1])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]2[NH:18][C:26]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:31][CH:30]=3)=[N:19][C:14]=2[CH:13]=1)(=[O:4])=[O:5]
Reactant: Nc1ccc(-c2ccccc2S(=O)(=O)C(F)(F)F)cc1N
Reactant: CCOC(=N)COc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: O=S(=O)(c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
A mixture of 2′-trifluoromethanesulfonyl-biphenyl-3,4-diamine (0.042 g, 0.133 mmol) and 2-(4-trifluoromethyl-phenoxy)-acetimidic acid ethyl ester hydrochloride (0.045 g, 0.159 mmol, Example 1.1) in EtOH (4 mL) was stirred at room temperature for 12 hours. The reaction was concentrated to give a residue, which was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the product as brown oil (0.065 g, 98%). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.25 (d, 1H, J=7.6 Hz), 7.92 (td, 1H, J=8.4 Hz, J=1.6 Hz), 7.77 (td, 1H, J=8.4 Hz, J=1.2 Hz), 7.65-7.54 (m, 3H), 7.27-7.20 (m, 4H), 7.14 (d, 1H, J=8.4 Hz), 5.45 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H15F6N2O3S: 501.4 (M+H), Found 501.2.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])[N:10]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=1)[C:9]2=[O:38])(=O)C.[OH-].[Na+].CCCCCC.C(O)(=O)C>CO>[CH2:16]([C:11]1[N:10]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:34][N:35]=[N:36][N:37]=3)=[CH:25][CH:26]=2)[C:9](=[O:38])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH2:5][OH:4])[CH:7]=2)[N:12]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1nc2ccc(COC(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1nc2ccc(CO)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 94.7 %

Procedure:
A solution of 0.2 g (0.38 mmol) of the product of Example 63 was dissolved in 5 mL of MeOH and was treated with 1 mL of 1N NaOH (1.0 mmol) and stirred over night. The resulting solution was extracted with EtOAc (3×10 mL). The organic phase was washed with water (2×5 mL) and brine (1×5 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluting with 80:19:1 EtOAc: hexane:acetic acid to give 0.17 g (0.36 mmol) of a white foam, 93% yield. 1H-NMR (CD3OD): 0.88 (t, 3H, J=7.38 Hz), 1.41 (m, 2H), 1.48 (m, 2H), 2.73 (3 line m, 2H, J=8.03 Hz), 4.60 (s, 2H), 5.38 (bs, 2H), 7.08 (m, 4 H), 7.20 (m, 1H), 7.50 (m, 2H), 7.61 (m, 2H), 7.77 (dd, 1H, J=2.0, 9.0 Hz), 8.17 (s, 1H). FABMS m/e: 467 (M+ +1) calc. for C27H26N6O2
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH3:12][S:13]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])(=[O:15])=[O:14]
Reactant: COC(=O)c1ccccc1O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1OS(C)(=O)=O
Reaction time: 20 h
Yield: 92.8 %

Procedure:
A solution of methyl salicylate (200 g, 1310 mmoles) and methanesulfonyl chloride (210 g, 1830 mmoles) in toluene (600 ml), cooled at 5÷10° C. and under inert atmosphere (nitrogen), is slowly added (about 1 hour) with triethylamine (192 g, 1900 mmoles). The mixture is stirred for 20 hours, then poured into water (1500 ml) and the phases are separated. The aqueous phase is extracted twice with 250 ml of toluene. The combined organic phases are washed twice with 250 ml of water, dried over sodium sulfate, then evaporated under vacuum to a residue which is recrystallized from isopropanol (590 ml) to yield methyl 2-(methanesulfonyloxy)benzoate (280 g, 99.8% purity, 89% yield).