Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[CH2:10][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)(C=O)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[C:44]([C:46]#[N:47])[CH:43]=[C:42]3[C:38]=2[CH:39]=[CH:40][NH:41]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(#N)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]1([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][C:9]3[S:8][C:6]4[N:7]=[C:2]([C:37]5[CH:45]=[C:44]([C:46]#[N:47])[CH:43]=[C:42]6[C:38]=5[CH:39]=[CH:40][NH:41]6)[N:3]=[C:4]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)[C:5]=4[CH:10]=3)[CH2:19][CH2:18]2)[CH2:22][CH2:21]1
Reactant: CC1(C)OB(c2cc(C#N)cc3[nH]ccc23)OC1(C)C
Reactant: O=CC1(CN2CCN(C3CC3)CC2)Cc2c(nc(Cl)nc2N2CCOCC2)S1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc(-c2nc(N3CCOCC3)c3cc(CN4CCN(C5CC5)CC4)sc3n2)c2cc[nH]c2c1
Temperature: 140 °C

Procedure:
A mixture of 2-chloro-6-(4-cyclopropyl-piperazin-1ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (217 mg), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-H-indole-6-carbonitrile (256 mg), bis(triphenylphosphine)palladium chloride (19 mg), and sodium carbonate (175 mg) in water (1.7 mL) and acetonitrile (6 mL) was heated in a microwave reactor at 140° C. for 1 hour. The reaction mixture was cooled, diluted with dichloromethane (20 mL), washed with water, dried (MgSO4) and the solvents removed in vacuo to give, after purification using flash chromatography, the title compound (59 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@:8]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])([CH3:18])[CH2:9][S:10][C:11]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12]2)[CH:7]=1.C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@@:8]2([CH3:18])[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:15](=[O:17])[C:11]3([CH2:14][CH2:13][CH2:12]3)[S:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN[C@@](C)(CSC2(C(=O)O)CCC2)c2cc(Br)ccc2F)c(OC)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)C3(CCC3)SC[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 100.9 %

Procedure:
To a solution of (R)-1-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino) propylthio)cyclobutanecarboxylic acid (1.8 g, 3.51 mmol, Eq: 1.00) and diisopropylethylamine (1.36 g, 1.84 ml, 10.5 mmol, Eq: 3.0) in ethyl acetate (70.3 ml) was added at 23° C. 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate) (3.35 g, 3.08 ml, 5.27 mmol, Eq: 1.5). The colourless reaction solution was stirred at 23° C. for 16 hours. The reaction mixture was washed with sat. NaHCO3-sol., water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the crude and pure (R)-7-(5-bromo-2-fluorophenyl)-8-(2,4-dimethoxybenzyl)-7-methyl-5-thia-8-azaspiro[3.5]nonan-9-one (1.75 g, 3.54 mmol, 101% yield) as a white foam. MS (ISP): m/z=494.0 [M+H]+ and 496.4 [M+2+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:7][CH:6]=1)C.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+]>O1CCCC1>[F:22][C:19]([F:20])([F:21])[O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[N:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1ccc(Oc2ccc(OC(F)(F)F)cc2)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
6-(4-Trifluoromethoxyphenoxy)nicotinic acid ethyl ester (7.48 g, 22.9 mmol) was dissolved in tetrahydrofuran (75 ml) and cooled to −78° C. A toluene solution (100.6 ml, 100.6 mmol) of diisobutylaluminium hydride was added thereto and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into a 1 N sodium hydroxide aqueous solution, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The organic layer was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=100:0→0:100) to afford the title compound as a colorless oil (6.15 g, 94%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][NH2:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:42][C:43]1[C:44]([C:61]2[CH:66]=[CH:65][C:64]([S:67][CH3:68])=[CH:63][CH:62]=2)=[CH:45][C:46](=[O:60])[N:47]([CH2:49][CH2:50][C@@:51]([CH3:59])([S:55]([CH3:58])(=[O:57])=[O:56])[C:52](O)=[O:53])[CH:48]=1>CN(C=O)C.CCOC(C)=O>[F:42][C:43]1[C:44]([C:61]2[CH:62]=[CH:63][C:64]([S:67][CH3:68])=[CH:65][CH:66]=2)=[CH:45][C:46](=[O:60])[N:47]([CH2:49][CH2:50][C@@:51]([CH3:59])([S:55]([CH3:58])(=[O:57])=[O:56])[C:52]([NH:17][O:16][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)=[O:53])[CH:48]=1
Reactant: CSc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2F)cc1
Reactant: NOC1CCCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
N,N-Diisopropylethylamine (450 uL, 2.45 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (192 mg, 1.64 mmol) and HATU (447 mg, 1.23 mmol) were added to a solution of (2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoic acid (339 mg, 0.82 mmol) in DMF (10 mL). The reaction was allowed to stir at rt for 18 h. The reaction mixture was diluted with EtOAc and washed with brine. The organics were dried (MgSO4), filtered and concentrated. The crude residue was purified via flash chromatography using a 40 g silica column and an eluent of EtOAc in n-heptane (0-100%) to afford the title compound (420 mg, 100%). MS (LCMS) m/z 511.4 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10]C(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21].[K].CP(Cl)(CC)=O.CN(C)C1C=CC=CC=1.[P]>C(Cl)Cl.C(O)CCC>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CCP(C)(=O)Cl
Agent: [K]
Agent: [P]
Solvent: ClCCl
Solvent: CCCCO
Solvent: CN(C)c1ccccc1
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 14.9 g of penicillin-G-potassium in 60 ml of absolute methylene chloride, 5.06 g (=40 mmols) of methylethylphosphinic acid chloride and 10 ml of dimethylaniline were added in the same manner as indicated in Example 1. The mixture was stirred for 1 hour and the solution of the mixed anhydride so prepared was converted at -5°C with 9.0 g (= 43 mmols) of phosphorus of pentachloride into the imidochloride. After addition of 60 ml of n-butanol and 2 ml of N,N-dimethylaniline, the mixture was stirred at -5°C for 30 minutes. 60 ml of ice water were added and the 6-aminopenicillanic acid was separated at pH 4. 6.47 g (= 76.4 % of the theory) of 6-aminopenicillanic acid were isolated in the form of colorless crystals having a melting point of 195°C (decomposition) which are identical with authentic 6-aminopenicillanic acid according to the IR-spectrum and the mixed melting point.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH:33]([OH:35])[CH3:34]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH:33]([OH:35])[CH3:34])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: CC(O)CN
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCC(C)O)O2
Yield: 84.2 %

Procedure:
Following the amide coupling procedure described in protocol A, 4.98 g 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (19.9 mmol), 3.99 g CDI (24.6 mmol) and 3.01 g 3-amino-2-propanol (39.9 mmol), yielded 5.15 g of 6-hydroxy-N-(2-hydroxypropyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a white powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:10][CH2:11]C)(=O)C.C(O)(=O)C.[Si:17]([O:24][C@@H:25]1[C@@H:29]([CH:30](OC)[OH:31])[O:28][C@@:27](C)([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[CH2:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CO>[Si:17]([O:24][C@@H:25]1[C@@H:29]([CH:30]([CH2:7][O:10][CH3:11])[OH:31])[O:28][C@@H:27]([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[CH2:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CCOC(C)=O
Reactant: COC(O)[C@H]1O[C@@](C)(n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: COCC(O)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
A solution of 3′-O-t-butyldimethylsilyl-5′-(R)-C,O-methylenethymidine (1.84 g, 5 mmol) and anhydrous potassium carbonate (1.38 g, 10 mmol) in methanol was stirred at room temperature for 90 h. Ethyl acetate (70 ml) was added and the mixture neutralized with acetic acid to pH 7. Solvents were evaporated and the residue was dissolved in methylene chloride (30 ml). Precipitates were filtered and the solution concentrated- The residue was purified by chromatography on silica (EtOAc-hexane, 1:1) to give 310 mg of intact starting material and 578 mg of 3′-O-t-butyldimethylsilyl-5′-C-methoxy-methylthymidine as a colorless solid.
Reaction SMILES: C(OC(=O)[C:5](=[O:16])[CH:6]([C:14]#[N:15])[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)C.C=O.C([O-])([O-])=O.[Na+].[Na+]>O>[C:14]([CH:6]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[CH2:5][OH:16])#[N:15]
Reactant: CCOC(=O)C(=O)C(C#N)c1ccc(Br)cc1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#CC(CO)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
To a mixture of 87 g (0.29 mol) 3-cyano-3-(4-bromophenyl)-2-ketopropionic acid ethyl ester, 44 ml 38% formaldehyde and 180 ml water are added dropwise within 1 hour and with stirring, at a temperature of 10°-15°, a solution of 26 g Na2CO3 in 85 ml water. The mixture is stirred further for 17 hours at room temperature and then three times extracted with 200 ml diethylether. The ether solution is washed with water, dried, evaporated and the residue kept for one hour at 60° under high vacuum. The oily residue (title compound) is chromatographed over a silica gel column with CH2Cl2 /CH3OH 97:3, Rf=0.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([CH2:11][S:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:30][C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33].O>ClCCl>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:11][S:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:9][O:10][C:32](=[O:33])[C:31]([CH3:36])([CH3:35])[CH3:30])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CSC[C@@H](CO)NC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)OC(C)(C)C)cc1
Reaction time: 6 h
Yield: 86.4 %

Procedure:
[(R)-2-hydroxy-1-(4-methoxy-benzylsulfanylmethyl)-ethyl]-carbamic acid t-butyl ester (71.3 g, 227.9 mmol) prepared in Step C was dissolved in dichloromethane (300 mL). Triethylamine (58 mL, 414.4 mmol) and trimethylacetic acid chloride (28 mL, 227.9 mmol) were added thereto, and the mixture was stirred for 6 h at 0°. Water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (81.0 g, Yield 95%).
Reaction SMILES: CO.C([NH:10][C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[C:13]([F:19])[N:12]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH2:10][C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[C:13]([F:19])[N:12]=1
Reactant: Fc1cc(F)c(NCc2ccccc2)nc1F
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(F)c(F)cc1F
Reaction time: 24 h
Yield: 81.5 %

Procedure:
To 40 ml of methanol were added 7.60 g of the crude 2-benzylamino-3,5,6-trifluoropyridine as described above together with 0.55 g of 10% palladium on carbon and 2 ml acetic acid, and the mixture was hydrogenated at 50° C. for one day. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. The precipitate was dispersed in n-hexane, and collected by filtration to obtain 3.85 g of the title compound as a colorless solid.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>CO.[OH-].[Pd+2].[OH-]>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[OH:18][CH:16]1[CH2:17][NH:14][CH2:15]1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: OC1CNC1
Reaction time: 24 h

Procedure:
1-Benzhydryl-3-hydroxyazetidine (3.0 g, 12.6 mmol) was dissolved in methanol (60 mL), and 10 mL of TFA and 10% palladium hydroxide (1.0 g) were added thereto. The mixture was stirred for 24 hours under a hydrogen stream at normal pressure. The catalyst was removed by filtration, water (100 mL) was added to the filtrate, and the mixture was washed three times with ether. The aqueous layer was concentrated under reduced pressure, and the title compound (2.33 g, 99%) was obtained as an amorphous matter.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:13]=2)[C:9]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(O)C.[Pd]>[N:1]1([C:6]2[CH:7]=[C:8]([CH2:9][NH2:10])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=3)[N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Yield: 102 %

Procedure:
To a solution of 2-pyrrolidin-1-yl-6-(4-trifluoromethyl-phenyl)-isonicotinonitrile (0.20 g, 0.61 mmol) in ethanol (20 mL) was added 1.25 M HCl in ethanol (0.50 mL, 0.63 mmol) and Pd/C (20 mg, 10 wt. %) and the system was placed under H2 atmosphere (50 atm) for 72 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure to provide the desired product (200 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:11]=3)=[CH:4][C:3]=1[Cl:30].Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1.Cl>[CH:35]([O:34][C:32](=[O:33])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[CH:11]=3)=[CH:4][C:3]=1[Cl:30])([CH3:37])[CH3:36]
Reactant: CC(C)OC(=O)Cl
Reactant: N#Cc1c(-c2ccc(N)c(Cl)c2)n(C2CCC2)c2cc(Oc3ncccn3)ccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CCC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To 2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (0.26 g, 0.6 mmol) in CH2Cl2 (0.5 mL) and pyridine (0.5 mL) was added a solution of isopropyl chloroformate in toluene (1.0M, 0.8 mL) and the mixture was stirred at room temperature overnight. The mixture was diluted with aq. HCl (1N) and extracted with CH2Cl2. The organic layer was washed with water and brine, dried, concentrated and purified on silica gel (40% EtOAc/hexane) to provide {2-chloro-4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (0.29 g, 93%) as a white solid.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[CH2:32]([O:31][CH2:30][C@H:12]([NH:11][C:8](=[O:10])[CH2:7][N:2]1[CH2:3][CH2:4][CH2:5][CH2:6]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCCC1
Agent: Cl
Product: O=C(CN1CCCC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 74.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(pyrrolidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 215, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(pyrrolidin-1-yl)acetamido)propanamide (29.4 mg, 74.8%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.92 (d, 1H), 7.60 (d, 2H), 7.27-7.31 (m, 5H), 7.21 (d, 2H), 6.99-4.03 (m, 4H), 4.72 (m, 1H), 4.52 (s, 2H), 3.70-3.75 (m, 2H), 3.12 (d, 2H), 2.55 (d, 4H), 1.72 (m 4H). MS (EI) for C28H30FN3O4. found 492.5 (MH+).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23](O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[C:43](N(C)C)=[N+:44](C)[CH3:45])C2C=CC=CC=2N=N1.Cl.CNC.N1C=CC=CC=1.CNC>CN(C)C=O.C(O)C.O>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]([N:44]([CH3:45])[CH3:43])=[O:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc(C3(C(=O)O)CCOCC3)cc2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2ccc(C3(C(=O)N(C)C)CCOCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylic acid (150 mg, 3.9 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (222 mg, 5.8 mmol), dimethylamine hydrochloride (96 mg, 1.1 mmol), pyridine (126 uL, 1.56 mmol) were combined and dissolved in dimethylformamide (2 mL). The reaction mixture was stirred at ambient temperature for 18 hours. Further O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (222 mg, 5.8 mmol) and dimethylamine in ethanol (33%) (500 μL) was added and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water (20 mL) and was then extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried using Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:ammonia (97:3:0.3) to dichloromethane:methanol:ammonia (90:10:1) to give a compound as a clear colourless oil. This was dissolved in ethyl acetate (70 mL) and washed with saturated NaHCO3 solution (2×10 mL). The organic extract was dried using Na2SO4, filtered and concentrated in vacuo to give the title compound as a clear crystalline solid (72 mg, 50%). 1H NMR (400 MHz, CD3OD) δ7.2 (d, 2H), 6.95 (d, 2H), 4.4 (m, 1H), 3.85 (m, 2H), 3.7 (m, 2H), 2.9-2.5 (m, 11H), 2.28 (m, 2H), 2.0 (m, 4H), 1.8 (m, 2H), 1.1 (d, 6H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]4=[O:39])=[CH:25][C:24]=3[F:40])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:40][C:24]1[CH:25]=[C:26]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:22][CH2:21]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CN4CCN(C(=O)OC(C)(C)C)CC4)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CN4CCNCC4)CC3)c(F)c2)C(=O)O1

Procedure:
A solution of 0.490 g of 4-[2-(4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-2-oxo-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (0.87 mmol) in 2 ml dichloromethane was treated with 2 ml of TFA. The reaction was monitored by TLC. The solvent was evaporated and the residue dissolved in water. The water layer was neutralized with ammonium hydroxide and freeze-dried.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=[CH:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:19]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20]1.[H-].[Na+].O>CN(C=O)C>[CH:19]1([O:1][C:2]2[CH:3]=[C:4]([N:10]3[C:18]4[CH:17]=[CH:16][N:15]=[CH:14][C:13]=4[N:12]=[CH:11]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(-n2cnc3cnccc32)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-n2cnc3cnccc32)cc1OC1CCCC1
Yield: 21.8 %

Procedure:
A solution of 2.05 g of 1-(3hydroxy-4-methoxyphenyl)-1H-imidazo[4,5-c]pyridine, 2.5 g of cyclopentylbromide and 665 mg of NaH in 20 ml of DMF was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate, dried to give 1.4 g of crude product. Recrystallization from CH2Cl2 gave 574 mg product. M.P.: 66°-88° C.
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:65][C:66]1[CH:74]=[CH:73][C:69]([C:70](O)=[O:71])=[CH:68][CH:67]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]3[NH:24][C:25]4[CH2:30][CH2:29][N:28]([C:70]([C:69]5[CH:73]=[CH:74][C:66]([F:65])=[CH:67][CH:68]=5)=[O:71])[CH2:27][C:26]=4[N:31]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1)[CH3:5]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccc(F)cc3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.3 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) in DMF (1 mL), was added HATU (32 mg, 84 μmol), and DIPEA (56 μL, 320 μmol). The reaction mixture was stirred at room temperature for 30 minutes. 4-Fluoro-benzoic acid (11.2 mg, 80 μmol) was added to the reaction mixture and stirring was continued for 18 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture. The resulting solid was collected by filtration, washing with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by HPLC Method B to afford 7.7 mg of the title compound.