Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Br[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:48]=1[N:47]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[C:46](=[O:57])[C:45]2([CH3:59])[CH3:58]>>[CH3:58][C:45]1([CH3:59])[C:44]2[C:48](=[C:40]([CH2:39][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:29])[CH2:3]3)[CH:41]=[CH:42][CH:43]=2)[N:47]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:56])[CH3:55])[C:46]1=[O:57]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: CC1(C)C(=O)N(COCC[Si](C)(C)C)c2c(CBr)cccc21
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)C3(C)C)cc1

Procedure:
Analogously to Method D, 0.600 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate (Example 10f) and 0.574 g of 7-bromomethyl-3,3-dimethyl-1-(2-trimethylsilanylethoxymethyl)-1,3-dihydroindol-2-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.16 (1:2 EtOAc-heptane); Rt=6.79.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:2]
Reactant: CCCCCCCCCCCCC(Oc1cccc([N+](=O)[O-])c1)C(=O)OCC
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCCCCCCCCCCCC(Oc1cccc(N)c1)C(=O)OCC

Procedure:
A solution of 154 g (0.39 mol) of 2-(m-nitrophenoxy)-myristic acid ethyl ester in 500 ml of ethanol is placed in an autoclave. An amount of 8 ml of Raney nickel is added. Reduction of the nitro group is carried out with hydrogen gas at an initial pressure of 10-10.5 MPa and a temperature of 65° C. After the reduction (2 h) the solvent is removed by evaporation.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41][NH:42][CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:8][C:9]5[CH:41]=[N:42][CH:43]=[CH:44][CH:2]=5)[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)Cc5cccnc5)c4)cc23)CC1
Yield: 14.3 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methyl(3-pyridinylmethyl)amine (122 mg, 1.0 mmol) for N-methylethanamine to afford 9.5 mg of the title compound (14.3%).
Reaction SMILES: F[C:2]1(F)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([F:14])([F:13])[C:5]([F:16])([F:15])[C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.Cl.C(O)(=[O:25])C>>[F:16][C:5]1([F:15])[C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[C:2](=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]1([F:14])[F:13]
Reactant: FC1(F)c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Reactant: CC(=O)O
Agent: Cl
Product: O=C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Temperature: 65 °C
Reaction time: 20 h

Procedure:
A solution of 989 mg. (0.00328 mole) of 10,11-dihydro-5,5,10,10,11,11-hexafluoro-5H-dibenzo[a,d]cycloheptene in 13.2 ml. of glacial acetic acid - 3.5 ml. of 6 N hydrochloric acid is held at room temperature for approximately 20 hours, heated in a 65° C. bath for 3 hours, again held at room temperature for about 20 hours, and finally heated in a 65° C. bath for 3 hours. The solution is concentrated under reduced pressure and the residue partitioned between benzene and water. The benzene extract is washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Sublimation of the residue at 80° C. and 0.1 mm. yields the crude product as an oily solid. Purification is effected by column chromatography on silica gel, the product being eluted with carbon tetrachloride. The fractions that show one spot of Rf 0.1 on a silica thin layer plate developed with carbon tetrachloride are combined. Evaporation of the solvent under reduced pressure leaves the white crystalline product, m.p. 76°-78° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#N)=[C:4]([F:13])[CH:3]=1.CC(C[AlH]CC(C)C)C.Cl.C([O-])(O)=[O:25].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:25])=[C:4]([F:13])[CH:3]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C#N)c1ccc(Br)cc1F
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (2.0 g, 8.3 mmol) in THF (20 mL) under nitrogen was added DIBAL-H (19 mL, 19 mmol, 1.0M in THF) dropwise at −30° C. The resulting solution was stirred at ambient temperature for 3 hours before the addition of 2 N aqueous HCl (10 mL) at 0° C. The mixture was stirred at ambient temperature for 10 minutes, then the solution was carefully basified with saturated aqueous NaHCO3 to pH 8-9, and then extracted with EtOAc (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 1-2% EtOAc/hexane) to afford the title compound) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 9.58 (s, 1H), 7.32-7.21 (m, 1H), 7.18-7.03 (m, 2H), 1.41 (s, 6H). MS ESI: [M+H]+ m/z 245.
Reaction SMILES: Br[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7](=[O:14])[N:8]([CH2:10][CH2:11][O:12][CH3:13])[CH2:9][C:4]=2[CH:3]=1.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH2:27][N:28]([CH3:33])[C:29](=[O:32])[CH:30]=[CH2:31])=[CH:24][CH:23]=[CH:22][CH:21]=2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:33][N:28]([CH2:27][C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[CH3:17])[C:29](=[O:32])/[CH:30]=[CH:31]/[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7](=[O:14])[N:8]([CH2:10][CH2:11][O:12][CH3:13])[CH2:9][C:4]=2[CH:3]=1
Reactant: COCCN1Cc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1c(C)[nH]c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: COCCN1Cc2cc(/C=C/C(=O)N(C)Cc3c(C)[nH]c4ccccc34)cnc2NC1=O
Yield: 35.4 %

Procedure:
A solution of 6-bromo-3-(2-methoxyethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one (0.86 g, 3.00 mmole), N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (see Example 1 (a), 0.68 g, 3.00 mmole), Pd(OAc)2 (0.07 g, 0.30 mmole), tri-ortho-tolylphosphine (0.18 g, 0.60 mmole) and diisopropylethylamine (1.31 mL, 7.50 mmole) in propionitrile (50 mL) was deoxygenated, then was heated at reflux under N2 overnight. The dark mixture was filtered through a pad of celite®, and the filter pad was rinsed with acetonitrile (250 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (10% EtOAc/EtOH). The title compound (0.46 g, 36%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e 434 (M+H)+.
Reaction SMILES: [O:1]1[C:19]([CH3:24])([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:2]1[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1.[H][H]>[Pt]=O.C(OCC)(=O)C>[O:1]1[C:19]([CH3:24])([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:2]1[CH2:3][CH2:4][CH:5]([CH3:18])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1
Reactant: CC(=CCOc1ccc2c(c1)OCO2)CCC1OC1(C)CC(C)C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)CC1(C)OC1CCC(C)CCOc1ccc2c(c1)OCO2

Procedure:
1.66 g. of 4-[(6,7-epoxy-3,7,9-trimethyl-2-decenyl)-oxy]-1,2-(methylenedioxy)-benzene are dissolved in 30 ml. of ethyl acetate and hydrogenated by passing hydrogen gas in the presence of 50 mg. of platinum oxide until uptake of the theoretical amount of hydrogen. The catalyst is then filtered off and the filtrate evaporated. By chromatography on slica gel in hexane/ether (9:1 parts by volume) there is obtained pure 4-[(6,7-epoxy-3,7,9-trimethyldecyl)-oxy]-1,2-(methylenedioxy)-benzene of boiling point (bulb tube) 128° C./0.03 mm Hg; nD23 = 1.5027.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(#N)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CCCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c2ccccc2c1CCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a mixture of EXAMPLE 3A (0.125 g) and triethylamine (0.21 mL) in acetonitrile (3 mL) at 0-5° C. was added methanesulfonyl chloride (0.0404 mL). After 30 minutes, the mixture was concentrated, and the concentrate was purified by flash chromatography on silica gel with 0-30% ethyl acetate/hexanes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]([OH:20])[CH3:19])[CH:5]=[C:6]([F:17])[C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.[CH:21]1(C(C2C=C(F)C=C(F)C=2)O)C[CH2:22]1>>[CH:19]1([CH:18]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([B:8]3[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:15])([CH3:16])[O:9]3)=[C:6]([F:17])[CH:5]=2)[OH:20])[CH2:22][CH2:21]1
Reactant: OC(c1cc(F)cc(F)c1)C1CC1
Reactant: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CC1(C)OB(c2c(F)cc(C(O)C3CC3)cc2F)OC1(C)C

Procedure:
Following the procedure of Intermediate 106, replacing 1-(3,5-difluorophenyl)ethanol with cyclopropyl(3,5-difluorophenyl)methanol (Intermediate 139) provided the title compound.
Reaction SMILES: O.Cl.Cl.[CH3:4][N:5]1[C:14]2[C:9](=[CH:10][C:11](N=O)=[C:12]([OH:15])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1>CO>[CH3:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: CN1CCCc2cc(N=O)c(O)cc21
Agent: Cl
Solvent: O
Solvent: CO
Product: CN1CCCc2ccc(O)cc21

Procedure:
(0.093 mole) was dissolved in a mixture of methanol 105 ml., water 70 ml., and concentrated hydrochloric acid 35 ml. and was filtered into a 500 ml. conical flask. The solution was well cooled to maintain a temperature between 0° and 5° and was rapidly stirred whilst a 10% aqueous solution of sodium nitrite 67 ml. (5% excess) mixed with methanol 67 ml. was slowly dripped in over half an hour and then stirred for another hour. The precipitate was filtered, washed with cold, dilute hydrochloric acid and air-dried to give 11.7 g. (56%) of yellow-brown fine crystals of 1-methyl-1,2,3,4-tetrahydro-6-nitroso-7-hydroxyquinoline hydrochloride.
Reaction SMILES: [NH3:1].[N:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[C:3]=[O:4]>CO>[CH2:5]([NH:2][C:3]([NH2:1])=[O:4])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCN=C=O
Reactant: N
Solvent: CO
Product: CCCCCNC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 7.0 M solution of ammonia in methanol (32 mL) was dropwise added 1-isocyanatopentane (5.0 g, 0.044 mol). After the addition, the mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to give a white solid, which was directly used for next step without further purification. LCMS calculated for C6H15N2O (M+H): 131.1; found 131.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21]O)[CH:11]=3)=[CH:9][C:2]=12.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][Br:24])[CH:11]=3)=[CH:9][C:2]=12
Reactant: OCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propan-1-ol [1 g, Example 2(a)] and carbon tetrabromide (1.59 g) in dichloromethane (40 mL) at ambient temperature was added a solution of triphenylphosphine (1.1 g) in dichloromethane (10 mL) over 2 minutes. The reaction mixture was stirred at ambient temperature for 3 hour, then stood for 18 hours and then evaporated to give the title compound which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[N:15]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:20][CH2:19][CH:18]([NH:21][C:22](N2C=CN=C2)=[O:23])[CH2:17][CH2:16]1>C(O)(C)C.C(Cl)Cl>[C:2]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:22](=[O:23])[NH:21][CH:18]2[CH2:19][CH2:20][N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:16][CH2:17]2)[CH2:13][CH2:14]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)NC2CCN(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-N-Boc-amino-piperidine (0.396 g, 1.85 mmol) in iso-propanol (5 ml) is added imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide (50 ml of a 10 mg/ml solution in DCM, 1.85 mmol) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and recrystallisation of the solid from methanol yields the title product.
Reaction SMILES: [N:1]([CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]=[N:34][NH:35][N:36]=2)[CH:27]=1)[C:5]1[CH:25]=[CH:24][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[C:13]([OH:20])[C:12]=2[CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[NH:36][N:35]=[N:34][N:33]=2)[CH:27]=1)[C:5]1[CH:25]=[CH:24][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[C:13]([OH:20])[C:12]=2[CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1
Reactant: CCCc1c(OCc2ccc(C(N=[N+]=[N-])c3cccc(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(C(N)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.5 %

Procedure:
A mixture of 1-[4-(4-{azido-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (340 mg, 0.703 mmol), triphenylphosphine (195 mg, 0.74 mmol), water (0.5 mL), and tetrahydrofuran (5 mL) is stirred at room temperature 48 hr. The mixture is filtered, the cake is washed with tetrahydrofuran (2 mL) and dried under vacuum to give the title compound 169 mg, 52%, as a white solid. 1H NMR (DMSO-d6) δ 12.86 (s, 1H), 8.9 (bs, 2H), 8.18 (s, 1H), 7.98 (d, 1H), 7.80 (d, 1H), 7.35-7.58 (m, 6H), 6.72 (d, 1H), 5.74 (s, 1H), 5.28 (s, 2H), 2.58-2.62 (m, 5H), 1.46-1.54 (m, 2H), 0.88 (t, 3H). LCMS M−1 456.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:16]1([S:22]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@@H](CCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@H](CCc1ccccc1)NS(=O)(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a suspension of homophenylalanine (Synthetech) (7 g, 39.1 mmol) in distilled water (21.5 mL) was added a 2 M aqueous NaOH (21.5 mL). After 5 minutes, the suspension had cleared and phenylsulfonyl chloride (5.48 mL, 43 mmol) was added. After 2 hours, the reaction mixture's pH was adjusted to 12 with 2 M aqueous NaOH (5 mL), and extracted with Et2O (2×100 mL). The aqueous layer's pH was adjusted to 1 with 6 M HCl (10 mL), and the product was extracted with EtOAc (100 mL), dried over MgSO4 filtered, and the solvent was removed under reduced pressure. The residue was triturated with Et2O (2×100 mL), filtered, and pumped to dryness, giving 8.74 g (70%) of phenylsulfonylhomophenylalanine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[CH2:14][CH2:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[CH2:10][CH2:11][N:12]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:13][CH2:14]1)(=[O:4])=[O:3]
Reactant: Cc1cccc(C2(CCO)CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1cccc(C2(CCOS(C)(=O)=O)CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 0 °C

Procedure:
3.8 ml of methanesulfonyl chloride are added dropwise to 21 g of 4-(2-hydroxyethyl)-4-(3-methyl-phenyl)-N-tritylpiperidine (prepared according to scheme 5) dissolved in 200 ml of methylene chloride, cooled to 0° C. The reaction mixture is left for half an hour at room temperature, washed twice with water, dried over MgSO4 and concentrated under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CC(C)(C(N)=O)S(=O)(=O)c1ccccc1Br
Product: CC(C)(C(N)=O)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-((2-bromophenyl)sulfonyl)-2-methylpropanamide. MS (ESI): mass calcd. for C20H19FN4O3S, 414.12; m/z found, 415.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 2H), 7.97 (d, J=7.9, 1H), 7.79 (m, 1H), 7.68 (m, 1H), 7.58 (m, 1H), 7.41 (s, 1H), 7.36 (d, J=7.5, 1H), 7.32-7.29 (m, 2H), 7.26 (d, J=7.9, 1H), 1.32 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[CH:32][O:28][CH:29]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccoc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (100 mg, 0.22 mmol) and 3-furanylboronic acid (54 mg, 0.48 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was purified by SCX followed by mass directed autoprep HPLC to afford the title compound (E118). MS (ES+) m/e 442 [M+H]+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]([C:17]23[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]4)[CH2:18]2)[CH2:24]3)=[O:16])[CH2:6][CH:5]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].Br[CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:45])=[O:38]>O1CCCC1>[C:40]1([CH3:45])[C:39]([C:37]([CH2:36][N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]34[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]5)[CH2:18]3)[CH2:24]4)=[O:16])[CH2:6][CH:5]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:4]2=[O:3])=[O:38])=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc2NC1=O
Reactant: Cc1ccccc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To 60% sodium hydride (128 mg) suspended in anhydrous tetrahydrofuran (30 ml), 2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine was added at room temperature under argon atmosphere. The mixture was stirred at room temperature for 30 minutes. Subsequently, 2-bromo-2′-methylacetophenone (375 mg) in anhydrous tetrahydrofuran (10 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. Ice-water (50 ml) was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Ethanol was added to the residue for solidification and collection by filtration, to thereby obtain 426 mg of the title compound as a white solid (yield: 46.6%).