Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-])=O)[CH:12]=2)[CH2:7]1)=[O:4]>CCOC(C)=O.[Pd]>[NH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH2:14]2
Reactant: O=C(NC1Cc2ccc([N+](=O)[O-])cc2C1)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC(NC(=O)C(F)(F)F)C2
Yield: 98.5 %

Procedure:
2,2,2-Trifluoro-N-(5-nitro-2,3-dihydro-1H-inden-2-yl)acetamide (245 mg, 0.89 mmol) was dissolved in EtOAc and stirred vigorously for 15 h. with 5% Pd/C (70 mg) under hydrogen atmosphere (1 atm). The reaction was filtered through celite and the solvent was removed under vacuum. Filtration yielded 214 mg (98%) of the desired amine as a brown powder. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (d, J=7.1 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.39 (s, 1H), 6.34 (d, J=8.1 Hz, 1H), 4.83 (s, 2H), 4.43 (m, 1H), 3.01 (m, 2H), 2.71 (m, 2H); ES-LC/MS (M+H)+=245.11.
Reaction SMILES: F[C:2]1[C:20]2[C:19](=[O:21])[C:18]([C:22]([OH:24])=[O:23])=[CH:17][N:7]3[C@H:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:25][CH2:26][CH2:27][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:3]=1[F:35].[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1>CS(C)=O>[F:35][C:3]1[C:4]([NH:25][CH2:26][CH2:27][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:5]2[O:10][CH2:9][C@@H:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:7]3[CH:17]=[C:18]([C:22]([OH:24])=[O:23])[C:19](=[O:21])[C:20]([C:2]=1[NH:43][CH2:42][C:41]1[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=1)=[C:6]23
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1cn2c3c(c(NCCNc4ccccn4)c(F)c(F)c3c1=O)OC[C@H]2c1ccccc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2c(F)c(NCCNc3ccccn3)c3c4c2c(=O)c(C(=O)O)cn4[C@H](c2ccccc2)CO3)cc1
Temperature: 0 °C
Yield: 76.4 %

Procedure:
A solution of (R)-8,9-difluoro-2,3-dihydro-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (432 mg, 0.903 mmol) and 4-methoxybenzylamine (400 μL, 4.51 mmol) in DMSO (4 mL) was stirred at 150° C. for 2 h. The reaction mixture was added portionwise at 0° C. with ice-water and the resulting precipitate was combined by filtration, washed with water. The cake washed with EtOH and collected by filtration and then dried to give (R)-9-fluoro-2,3-dihydro-8-(4-methoxybenzylamino)-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (411 mg, 78%) as a pale yellow solid.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH:15]1[C:25]2[CH2:24][CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[CH:20]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].CO>C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:33]3[CH2:32][CH2:31][CH:30]([CH:20]4[C:19]5[CH:18]=[CH:17][CH:16]=[CH:15][C:25]=5[CH2:24][CH2:23][C:22]5[CH:26]=[CH:27][CH:28]=[CH:29][C:21]4=5)[CH2:35][CH2:34]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc2c(c1)CCc1ccccc1C2C1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(C2c3ccccc3CCc3ccccc32)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 89% overall yield. FDMS m/e=466 (M+ of free base). α[D]589 =-10.02(c=0.72, methanol).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#[N:12])=[C:9]2[C:5]([C:6]([CH:13]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1(P(=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N>[C:11]([C:10]1[C:2]([F:1])=[CH:3][CH:4]=[C:5]2[C:9]=1[NH:8][CH:7]=[C:6]2/[CH:13]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:12]
Reactant: N#Cc1c(F)ccc2c(C=O)c[nH]c12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)/C=C/c1c[nH]c2c(C#N)c(F)ccc12
Yield: 58.3 %

Procedure:
To a mixture of 6-fluoro-3-formyl-1H-indole-7-carbonitrile (D142) (3 g) in CH3CN (30 mL) was added ethyl (triphenylphosphoranylidene)acetate (11.1 g). The reaction was heated to reflux overnight. After the mixture was filtered, the filtrate was concentrated and purified by column chromatography to afford ethyl (2E)-3-(7-cyano-6-fluoro-1H-indol-3-yl)-2-propenoate (D143) (2.4 g) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH:15]=[CH2:16])[CH:8]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2]
Reactant: C=CCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O

Procedure:
A solution of 3-(3-allyl-4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (330 mg, 0.97 mmol) in absolute EtOH (5 mL) was treated with 5% Pd/C and then the mixture was evacuated three times with N2. The reaction mixture was hydrogenated at 1 atm with an H2-filled balloon for 24 h before filtering the mixture over celite and rinsing with EtOH. The product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.22 (t, J=7.6 Hz, 2H), 7.99-6.95 (m, 3H), 6.82 (m, 2H), 6.68 (d, J=8.0 Hz, 1H), 4.20 (q, J=6.8 Hz, 2H), 3.24 (A of AB, J=13.6 Hz, 1H), 3.08 (B of AB, J=13.6 Hz, 1H), 2.55 (t, J=7.6 Hz, 2H), 1.62 (sextet, J=7.6 Hz, 2H), 1.41 (s, 3H), 1.23 (t, J=6.8 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([OH:33])([C:25]([F:26])([F:27])[F:28])[C:29]([F:30])([F:31])[F:32])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[CH:8][C:2]=1[Cl:1]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(CC2CCNCC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1Cl
Yield: 93.5 %

Procedure:
2-Chloro-4-(piperidin-4-ylmethyl)aniline (0.445 mmol, 100 mg), 2-(4-(bromomethyl)-phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.445 mmol, 150 mg) and potassium carbonate (0.890 mmol, 123 mg) were combined and stirred at room temperature in acetonitrile (5 mL) for 1.5 hours. The reaction mixture was filtered and filtrate was concentrated under vacuum. The residue was purified by SCX chromatography to give the title compound (200 mg). MS (ESI) m/z 480.9 [M+H]+
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])(C)(C)C>C(Cl)Cl>[NH2:14][C@@H:15]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17]
Reactant: CN(C)C(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 130.4 %

Procedure:
Trifluoroacetic acid (1 mL, 10 mmol) was added to a solution of tert-butyl[(1S)-1-(biphenyl-4-ylmethyl)-2-(dimethylamino)-2-oxoethyl]carbamate (50 mg, 0.1 mmol) in methylene chloride (2 mL). The reaction was stirred for 2 h., and was concentrated under reduced pressure to give the crude product (2S)-2-amino-3-biphenyl-4-yl-N,N-dimethylpropanamide (35 mg, 97%). Analytical LCMS (M+H)+: m/z=269.0.
Reaction SMILES: C([O:8][C:9]1[C:40]([CH3:41])=[CH:39][C:12]([CH2:13][C@@H:14]([CH2:18][C:19](=[O:38])[N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:22][CH2:21]2)[C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[CH3:42])C1C=CC=CC=1.[H][H]>C(Cl)Cl.[Pd]>[OH:8][C:9]1[C:40]([CH3:41])=[CH:39][C:12]([CH2:13][C@@H:14]([CH2:18][C:19](=[O:38])[N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)[C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[CH3:42]
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Product: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O

Procedure:
A suspension of 2.41 g (4.23 mmol) (S)-2-(4-benzyloxy-3,5-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 300 mg 10% Pd/C in 50 mL DCM was hydrogenated at RT and 3447 hPa hydrogen pressure until the theoretical amount of hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac. The residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.CO[CH:10]1[CH2:14][CH2:13][CH:12](OC)O1.[OH-].[Na+]>C(O)(=O)C>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[N:1]1[CH:10]=[CH:14][CH:13]=[CH:12]1
Reactant: Nc1cnccn1
Reactant: COC1CCC(OC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1ccn(-c2cnccn2)c1
Temperature: 105 °C

Procedure:
A mixture of 43 g (0.5 mole) 2-aminopyrazine and 66 g (0.5 mole) 2,5-dimethoxytetrahydrofuran is placed in a 1-liter 3-neck flask equipped with a stirrer, addition funnel, thermometer and condenser, and 200 ml glacial acetic acid is added dropwise with stirring while maintaining the temperature below 20°C. The reaction mixture is refluxed at 105°C for 30 minutes and, after cooling, it is made basic by the addition of 325 ml of 30% aqueous sodium hydroxide and steam-distilled.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[Cu](C#N)[C:28]#[N:29]>CN(C)C=O.[Cl-].[NH4+].[OH-].[NH4+]>[C:28]([C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1)#[N:29]
Reactant: N#C[Cu]C#N
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc2c(s1)-c1cc(C#N)ccc1OC2)c1ccc(F)cc1F
Yield: 79.3 %

Procedure:
A solution of 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp (33.7 mg, 0.0772 mmol, 1 equiv) and copper cyanide (22 mg, 0.24 mmol, 3.2 equiv) in N,N-dimethylformamide (1 mL) was heated at 250° C. in the microwave for 30 min. The reaction mixture was diluted with 9:1 saturated aqueous ammonium chloride solution/ammonium hydroxide (10 mL). The resulting mixture was extracted with dichloromethane (3×5 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (11:4/hexanes:ethylacetate) provided 161bp as a white solid (23.4 mg, 79%). 1H NMR (500 MHz, CDCl3) δ 7.40-7.42 (m, 2 H), 7.32 (m, 1 H), 6.99 (t, J=8.1 Hz, 1 H), 6.92 (m, 1 H), 6.88 (s, 1 H), 5.23 (s, 2 H), 3.40 (s, 3 H). LCMS (ESI) m/z: 383.1
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH2:17]([C:11]1[CH:12]=[CH:13][C:14]([C:7]([CH2:8][C:2]([CH3:1])([CH3:10])[CH2:3][C:4]([OH:6])=[O:5])=[O:9])=[CH:15][CH:16]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCc1ccccc1
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCc1ccc(C(=O)CC(C)(C)CC(=O)O)cc1
Temperature: 25 °C

Procedure:
First, 3,3-dimethylglutaric anhydride (25 g, 0.176 moles) is heated with 1-phenylheptane (150 ml) and anhydrous aluminium chloride (51.6 g, 0.387 moles) at 90°-100° C. for 1 hour. The reaction mixture is cooled to room temperature, poured into a mixture of ice water (500 ml) and concentrated hydrochloric acid (100 ml), and extracted with ether (3×150). The combined ether extracts are dried over anhydrous magnesium sulfate and filtered. Ether is removed under reduced pressure and the resulting solution chromatographed on silica gel (hexane and then hexane:ether:acetic acid at 80:20:1) to yield 4-(4-heptylbenzoyl)-3,3-dimethyl butanoic acid (17.67 g), m.p. 41°-42° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C)C=O>[Si:14]([O:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[N:7][CH:6]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cnc(Cl)nc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cnc(Cl)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 104.8 %

Procedure:
To a solution of 20.2 g (0.154 mol) of 2-chloro-5-hydroxypyrimidine in 150 ml of N,N-dimethylformamide, 15.8 g (0.232 mol) of imidazole and 26.8 g (0.178 mol) of tert-butyldimethylsilyl chloride were added, and the reaction mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with n-heptane three times. The obtained organic phases were combined, washed with 0.01 N sodium hydroxide aqueous solution, water and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to provide 39.5 g of the title compound as a white solid (yield: 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](Cl)[CH:5]=1.O1CCCC1.[Br-].[F:18][C:19]1([F:27])[CH2:24][CH2:23][CH:22]([CH2:25][Zn+])[CH2:21][CH2:20]1>C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:18][C:19]1([F:27])[CH2:24][CH2:23][CH:22]([CH2:25][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=2)[C:3]([O:2][CH3:1])=[O:11])[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: FC1(F)CCC(C[Zn+])CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(CC2CCC(F)(F)CC2)c1
Temperature: 60 °C
Yield: 76.6 %

Procedure:
To methyl-2-chloroisonicotinate (1.664 g, 9.7 mmol) and bis(tri-tert-butylphosphine)palladium(0) (198 mg, 0.38 mmol) under nitrogen was added tetrahydrofuran (10 mL). To the resulting solution was added freshly prepared ((4,4-difluorocyclohexyl)methyl)zinc(II) bromide (14.55 mmol, 0.5 M in 29 mL DMA) and the resulting brown mixture heated to 60° C. for 4 h. The reaction mixture was diluted with ethyl acetate and washed with satd NaHCO3 (2 times), satd NH4Cl and brine. The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and added onto an SCX-2 cation exchange column. The column was washed with DCM, MeOH and then eluted with NH3/MeOH. The NH3/MeOH layer was evaporated leaving methyl 2-((4,4-difluorocyclohexyl)methyl)isonicotinate (2 g, 67%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 1.30-1.46 (m, 2H), 1.58-1.79 (m, 4H), 1.87-2.14 (m, 3H), 2.82 (d, 2H), 3.96 (s, 3H), 7.65-7.73 (m, 2H), 8.70 (d, 1H). MS m/z 270 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.O1CCOCC1.[CH:37]1([CH2:40][Mg]Br)[CH2:39][CH2:38]1>C1COCC1>[CH:37]1([CH2:40][CH:22]([C:20]2[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:29])([F:30])[F:28])[N:17]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[N:21]=2)[OH:23])[CH2:39][CH2:38]1
Reactant: Br[Mg]CC1CC1
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(O)CC3CC3)n2)ccc1-n1cnc(C)c1

Procedure:
2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidine-4-carbaldehyde (92 mg, 0.22 mmol) was coevaporated with dioxane and dissolved in THF (5 mL). The solution was cooled on an ice bath and (cyclopropylmethyl)magnesium bromide was added over 30 min. The mixture was quenched by addition of an ammonium chloride (aq, sat). The organic phase was separated and aquous phase was extracted with ethyl acetate (2×5 mL). The combined organic phase was dried over sodium sulfate and filtered through a short pad of silica. The solvents were removed and the residue was purified by preparative HPLC to give the title compound as a dry film 17 mg (16%).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:42]>C1COCC1>[Br:42][CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)CC(Cc1nc(CO)co1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(Cc1nc(CBr)co1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
To a solution of ethyl (±)-4-(4-hydroxymethyl-1,3-oxazol-2-yl)-3-phenylbutanoate (1.3 g, 4.49 mmole) in dry THF (20 mL) was added PPh3 (1.41 g, 5.39 mmole) then CBr4 (1.79 g, 5.39 mmole) at 0° C. After 20 min, the mixture was warmed to RT. After 2 hr, the mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (20% EtOAc/hexanes) to give the title compound (1.38 g, 87%) as a colorless oil: MS (ES) m/e 352 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[OH:7][C@H:8]([CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C@H:9]([CH3:20])[O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.I[C:30]1[C:31]([O:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=1>C(O)C.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>[CH3:37][O:36][C:31]1[C:30]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C@@H:9]([CH3:20])[C@H:8]([OH:7])[CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:12][CH:13]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: COc1ncccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ncccc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1
Temperature: 25 °C

Procedure:
Prepared according to the method described in Example 21b) from 2M aqueous sodium carbonate (2.0 ml), (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (Example 21a), 0.508 g), 3-iodo-2-methoxypyridine (0.730 g, J. Org. Chem., 1988 53(12), 2740), and tetrakis(triphenylphosphine)palladium(0) (0.216 g) in ethanol (10 ml). The mixture was heated at reflux for 6 hours. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give an oil, which was further purified by normal phase HPLC eluting with 2-propanol:dichloromethane (3:97) to give the title compound as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:7](N)([NH2:10])(=[O:9])=[O:8]>O1CCOCC1>[N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NS(N)(=O)=O
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCOCC1

Procedure:
Morpholine (5 ml) and sulfamide (11 g) in 1,4-dioxane (100 ml) were heated at reflux for 48 h. The solvent was evaporated under reduced pressure and the resulting solid partitioned between EtOAc and water. The organic phase was collected and the aqueous phase was further extracted with EtOAc (×4). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo. The solid residue was triturated with Et2O and filtered to give the subtitle compound as a white crystaline solid. Yield: 2.1 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[C:8]([C:10]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])([CH:12]2[CH2:24][C:15]3[NH:16][C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=4[C:14]=3[CH2:13]2)[F:11])[O:7][N:6]=1)=O.[OH-].[NH4+:35]>CCO>[C:28]1([S:25]([C:10]([CH:12]2[CH2:24][C:15]3[NH:16][C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=4[C:14]=3[CH2:13]2)([F:11])[C:8]2[O:7][N:6]=[C:5]([C:3]([NH2:35])=[O:2])[N:9]=2)(=[O:27])=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Yield: 86 %

Procedure:
To a stirred solution of 70 mg (0.14 mmol) of (RS,SR)-5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazole-3-carboxylic acid methyl ester in 3 mL of EtOH, were added 0.5 mL of an ammonium hydroxide solution (25% in water) and stirred over night. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried over Na2SO4, filtered and evaporated. Recrystallisation in Et2O afforded 60 mg (86%) of (RS,SR)-5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazole-3-carboxylic acid amide as a light orange crystals, MS: 475 (MH+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[NH2:17][C@H:18]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[CH3:36][CH:35]([CH3:37])[C:34]([NH:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][C@H:18]([NH:17][C:2]([NH:1][C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[CH:6][CH:5]=3)=[O:3])[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:26][CH2:25]2)[CH:28]=1)=[O:38]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Nc3ccc(Oc4ccccc4)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1-isocyanato-4-phenoxybenzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 591.3 (M+H)+.