Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:55][C@@H:56]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]3C=CC=CC=3)=[C:60]([NH:72][S:73]([CH2:76]CC3C=CC=CC=3)(=[O:75])=[O:74])[CH:59]=2)[OH:57])[CH2:26][C@H:27]([OH:54])[C:28]2[CH:33]=[CH:32][C:31]([O:34]CC3C=CC=CC=3)=[C:30]([NH:42][S:43]([CH2:46]CC3C=CC=CC=3)(=[O:45])=[O:44])[CH:29]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1.C[OH:86]>C(O)(=O)C.[OH-].[OH-].[Pd+2].ClCCl>[C:65]([OH:86])(=[O:64])[CH3:66].[C:65]([OH:86])(=[O:64])[CH3:66].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:55][C@H:56]([OH:57])[C:58]2[CH:63]=[CH:62][C:61]([OH:64])=[C:60]([NH:72][S:73]([CH3:76])(=[O:74])=[O:75])[CH:59]=2)[CH2:26][C@@H:27]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:29]=2)[OH:54])=[CH:19][CH:20]=1
Reactant: CO
Reactant: O=C(NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(OCc3ccccc3)c(NS(=O)(=O)CCc3ccccc3)c2)C[C@H](O)c2ccc(OCc3ccccc3)c(NS(=O)(=O)CCc3ccccc3)c2)cc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN(CCCCc2ccc(CCCCN)cc2)C[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of (4-{4-[4-(bis-{2-[3-(benzylmethanesulfonylamino)-4-benzyloxyphenyl]-2-(R)-hydroxyethyl}amino)butyl]phenyl}butyl)carbamic acid benzyl ester (38) (0.45 g, 0.383 mmol), palladium dihydroxide (0.12 g, 10% Pd(OH)2 on carbon, 50% wet), ten drops of acetic acid, methanol (12 mL), and dichloromethane (6 mL) was stirred at rt for 18 h under atmospheric hydrogen pressure. The catalyst was removed by vacuum filtration through a Celite pad and the filtrate was concentrated by rotary evaporation and further dried under high vacuum to give the desired amine diacetic acid salt 41 as a white solid (0.30 g, 98%): m/z (ESI) 679 [C32H42N4O6+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)(=O)[CH3:11]>CO.C(O)=O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=3[CH3:9])[CH3:20])[N:14]=2)[CH3:11])=[C:3]([CH3:9])[CH:4]=1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cc(O)ccc1N
Solvent: O=CO
Solvent: CO
Product: CC(=Nc1ccc(O)cc1C)c1cccc(C(C)=Nc2ccc(O)cc2C)n1
Reaction time: 48 h

Procedure:
4-Amino-m-cresol (450 mg) and 300 mg 2,6-diacetylpyridine were dissolved in 20 ml methanol. Four drops of formic acid were added and the solution was stirred for 2 d. The yellow solid was washed with cold methanol. Yield: 600 mg. 1H-NMR (200 MHz, CDCl3): 8.35 (d, 2H), 7.85 (t, 1H), 6.53-6.74 (6 H), 4.50 (s, 2H), 2.32 (s, 6H), 2.09 ppm (s, 6H)
Reaction SMILES: [C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:30]/[O:31][CH:32]([F:34])[F:33])/[C:27](O)=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:36][C@@H:37]1[C:60](=[O:61])[N:39]2[C:40]([C:48]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=3)=[O:49])=[C:41](/[CH:44]=[CH:45]\[CH2:46][Cl:47])[CH2:42][S:43][C@H:38]12>>[C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:30]/[O:31][CH:32]([F:33])[F:34])/[C:27]([NH:36][C@@H:37]2[C:60](=[O:61])[N:39]3[C:40]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=4)=[O:49])=[C:41](/[CH:44]=[CH:45]\[CH2:46][Cl:47])[CH2:42][S:43][C@H:38]23)=[O:28])[N:22]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(COC(=O)C2=C(/C=C\CCl)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: O=C(O)/C(=N\OC(F)F)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Product: COc1ccc(COC(=O)C2=C(/C=C\CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(F)F)c4nsc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 88.8 %

Procedure:
In the same manner as described in Experiment 3, 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-difluoromethoxyiminoacetic acid (2.00 g) was reacted with p-methoxybenzyl 7β-amino-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate hydrochloride (1.795 g) to obtain the object product (3.17 g).
Reaction SMILES: Cl[CH:2]1[C:6]([CH3:8])([CH3:7])[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[C:13]([C:10]1[CH:11]=[CH:12][C:4]2[O:3][CH:2]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:6]([CH3:8])([CH3:7])[C:5]=2[CH:9]=1)#[N:14]
Reactant: CC1(C)c2cc(C#N)ccc2OC1Cl
Reactant: C1COCCN1
Product: CC1(C)c2cc(C#N)ccc2OC1N1CCOCC1
Temperature: 0 °C

Procedure:
2-Chloro-5-cyano-2,3-dihydro-3,3-dimethylbenzofuran (4.1 g), prepared as in Example 45 was heated under reflux at about 130° C. in morpholine (20 ml) for 4 hours. Addition to ice-water, followed by extraction with diethyl ether, gave, after water washing, drying over sodium sulphate and running down, 3.3 g of crude title product. Recrystallisation from isopropanol gave 2.3 g of pure product, mp 105°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOCC>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)COc1ccccc1Cl
Temperature: 80 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
To a solution of 2-chlorophenol (2.06 mL, 19.9 mmol) in DMF (40 mL) is added potassium carbonate (3.03 g, 21.9 mmol) and ethyl bromoacetate (2.3 mL, 20.7 mmol), and the mixture is stirred at 80° C. for 18 h. Et2O is added, and the mixture is washed with water, brine, dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is purified by chromatography in silica gel; elution with EtOAc: dichloromethane:hexane (10:5:85) gives 4.17 g of the product 465. 1H NMR (CDCl3) δ 7.38 (d, 1H), 7.21 (t, 1H), 6.92 (t, 1H), 6.84 (d, 1H), 4.70 (s, 2H), 4.27 (q, 2H), 1.29 (t, 3H); MS: m/z 215, 217 (M++1).
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[N:12]=[C:11]([CH2:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][N:8]=1)([CH3:6])([CH3:5])[CH3:4]>C(Cl)(Cl)Cl.O1CCOCC1>[Br:1][CH:13]([C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[N:12]=1)[C:14](=[O:16])[CH3:15]
Reactant: BrBr
Reactant: CC(=O)Cc1ccnc(C(C)(C)C)n1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(=O)C(Br)c1ccnc(C(C)(C)C)n1
Temperature: 12.5 °C

Procedure:
Bromine (3.25 g, 20.7 mmol) in chloroform (20 ml) is added dropwise over 5 hours to a stirred solution of 1-(2-tert-butyl-pyrimidin-4-yl)-propan-2-one (4.0 g, 20.7 mmol) in dioxane (300 ml) maintained at 10-15° C. When the addition is complete the solvent is removed in vacuo to give the titled compound as a hydrobromide salt.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].Cl[CH2:13][C:14]([CH3:17])([OH:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[OH:16][C:14]([CH3:17])([CH3:15])[CH2:13][O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C#N)cc(C)c1OCC(C)(C)O
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g, 13.5 mmol) and 1-chloro-2-methyl propan-2-ol (8.85 g, 81.5 mmol) in ethanol (50 mL) was added potassium carbonate (7.5 g, 54 mmol) and water (5 mL). The reaction mixture was stirred at reflux for 24 h and cooled to room temperature. The precipitated solid was filtered off and washed with water. The solid was dissolved in ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.9 g, 97%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:43][C:44]1[C:48]2[CH2:49][NH:50][CH2:51][CH2:52][C:47]=2[S:46][C:45]=1[C:53]([O:55][CH2:56][CH3:57])=[O:54]>CN(C)C=O>[CH3:43][C:44]1[C:48]2[CH2:49][N:50]([C:7]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=3)=[O:9])[CH2:51][CH2:52][C:47]=2[S:46][C:45]=1[C:53]([O:55][CH2:56][CH3:57])=[O:54]
Reactant: CCOC(=O)c1sc2c(c1C)CNCC2
Reactant: Cn1cccc1C(=O)O
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: CCOC(=O)c1sc2c(c1C)CN(C(=O)c1cccn1C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-methylpyrrole-2-carboxylic acid (12.5 mg, 0.1 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.048 g, 0.11 mmol) and N,N-diisopropylethylamine (52.2 μL, 0.3 mmol) in N,N-dimethylformamide (1 mL, 12.9 mmol) was stirred at room temperature for 15 minutes. A solution of ethyl 3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (22.5 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL) was then added and the reaction was further stirred at room temperature overnight. The solution was evaporated to dryness and the residue obtained was partitioned between DCM (2 mL) and half-saturated aqueous sodium bicarbonate solution (2 mL). Upon separation of the layers, the aqueous layer was extracted with additional DCM (2 mL) and the combined organic layers were concentrated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=[N:19][N:20]([CH2:23][C:24](O)=[O:25])[C:21]=1[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[Cl:16][C:17]1[C:18]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=[N:19][N:20]([CH2:23][C:24]([N:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([C:14]#[N:15])[CH2:9][CH2:10]2)=[O:25])[C:21]=1[CH3:22]
Reactant: N#CC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Cc1c(Cl)c(-c2ncco2)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(-c2ncco2)nn1CC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 75 mg of 4-(4-chloro-phenyl)-piperidine-4-carbonitrile (0.34 mmol, 1.0 equiv), 90 mg of (4-chloro-5-methyl-3-oxazol-2-yl-pyrazol-1-yl)-acetic acid (0.37 mmol, 1.00 equiv), 194 mg HATU (0.51 mmol, 1.5 equiv), 189 μL TEA (1.36 mmol, 4.00 equiv) and 2 mL NMP. A stir bar was placed in the vial and the reaction mixture stirred overnight at room temperature. The crude reaction mixture was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield 1-[2- (4-chloro-5-methyl-3-oxazol-2-yl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carbonitrile: MS (ES) M+H expected=444.3, found=444.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:2]1.[H-].[Na+].I[CH3:23]>C1COCC1>[CH3:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:2]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CCNC(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
To a solution of tert-butyl (2-(1H-indol-3-yl)ethyl)carbamate (4.70 g, 18.01 mmol) in anhydrous THF (50 mL) was added sodium hydride (800 mg, 20 mmol, 60% in mineral oil) at 0° C. under nitrogen. After the resulting reaction mixture was stirred at room temperature for 15 min, iodomethane (2.84 g, 20 mmol) in THF (15 mL) was added slowly at 0° C. The resulting mixture was stirred at room temperature for 3 h and quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under vacuum gave the crude product, which was purified by silica gel column chromatography (0.6% MeOH in DCM) to afford the title compound (4 g, 14.6 mmol, 80% yield) as a brown solid. MS (ESI) m/z 275.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH:4]=[C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]2=O)[CH2:3][CH2:2]1.B.CO.Cl>C1COCC1>[CH:1]1([CH2:4][CH:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: O=C1Nc2ccccc2C1=CC1CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc2c(c1)NCC2CC1CC1
Temperature: 25 °C

Procedure:
1.0 g (5.4 mmol) 3-cyclopropylmethylene-1,3-dihydro-indol-2-one were placed in 50 mL THF. 12 mL (12 mmol) 1M borane in THF was slowly added dropwise. The reaction mixture was refluxed for 3 h. After cooling to RT 10 mL methanol and 15 mL semi-concentrated aqueous hydrochloric acid solution were successively added dropwise and then the mixture was refluxed for 3 h. After cooling to RT it was extracted with EtOAc. The aqueous phase was made alkaline with aqueous 4M sodium hydroxide solution and extracted once again with EtOAc. The organic phase was dried, filtered and evaporated down.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:19][O:18][CH:17]([CH2:20][C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:31][C:32]1[O:33][C:34]([C:40]([F:43])([F:42])[F:41])=[C:35]([C:37](O)=[O:38])[N:36]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:31][C:32]1[O:33][C:34]([C:40]([F:43])([F:41])[F:42])=[C:35]([C:37]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH:14]4[CH2:19][O:18][CH:17]([CH2:20][C:21]([O:23][CH2:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[O:22])[CH2:16][CH2:15]4)=[CH:12][CH:13]=3)=[CH:4][CH:3]=2)=[O:38])[N:36]=1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: Nc1ccc(-c2ccc(C3CCC(CC(=O)OCc4ccccc4)OC3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2ccc(-c3ccc(C4CCC(CC(=O)OCc5ccccc5)OC4)cc3)cc2)c(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
To a solution of benzyl 2-(5-(4′-amino-[1,1′-biphenyl]-4-yl)tetrahydro-2H-pyran-2-yl)acetate (118 mg, 0.294 mmol) in DMF (2 ml) at room temperature was added 2-methyl-5-(trifluoromethyl)oxazole-4-carboxylic acid (74.5 mg, 0.382 mmol) and DIPEA (0.103 ml, 0.588 mmol) and the reaction was stirred at room temperature for 10 min then was added HATU (145 mg, 0.382 mmol). The reaction was stirred at room temperature for 30 min. The reaction was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10 to 50% EtOAc/Heptane) to give the title compound 138 mg (yield 81%). MS (ESI) m/z 579.4 (M+1). Retention time 1.69 min (condition A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:12]
Reactant: O=C(O)Cc1cc(Br)ccc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(Br)ccc1F
Temperature: 64 °C

Procedure:
To a solution of 5-bromo-2-fluorophenylacetic acid (5 g) in MeOH (200 mL) is added concentrated sulfuric acid (2 mL) and the solution is heated at 64° C. for 16 hours. The solution is evaporated iii vacuo and the residue is taken up in EtOAc and washed with 10% sodium bicarbonate, brine and dried over sodium sulfate. The solution is filtered and evaporated in vacuo to afford (5-bromo-2-fluoro-phenyl)-acetic acid methyl ester (5.1 g). 1H NMR (300 MHz, CDCl3) □7.3-7.5 (m, 2H); 6.9 (m, 1H); 3.9 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.O=S(Cl)Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:9]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[F:16])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1F
Reactant: Nc1ccc(Br)nc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Nc1ccc(Br)nc1C(=O)Nc1ccccc1F
Temperature: 130 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
A mixture of 3-amino-6-bromopicolinic acid (250 mg, 1.152 mmol) and SOCl2 (5 mL) in toluene (10 mL) was stirred at 130° C. for 2 h, then evaporated and dissolved in tetrahydrofuran (20 mL). 2-fluoro-phenylamine (256 mg, 2.3 mmol) was added dropwise maintaining the temperature at 5° C. The reaction mixture was heated to 90° C. for 15 h. The mixture was cooled to room temperature and quenched with saturated aqueous K2CO3 (10 mL) and extracted with ethyl acetate (10 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with column chromatograph (PE:EtOAc=3:1) to give 3-amino-6-bromo-N-(2-fluorophenyl)picolinamide (160 mg, yield: 45%). MS (M+H)+: 311/313.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH3:7][NH:8][C@H:9]1[CH2:28][N:13]2[C:14]3[C:19]([C:20]([CH2:21][C:22]([O:24]CCC)=[O:23])=[C:12]2[CH2:11][CH2:10]1)=[CH:18][CH:17]=[CH:16][CH:15]=3>>[CH:1]1([C:4]([N:8]([CH3:7])[C@H:9]2[CH2:28][N:13]3[C:14]4[C:19]([C:20]([CH2:21][C:22]([OH:24])=[O:23])=[C:12]3[CH2:11][CH2:10]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[O:6])[CH2:3][CH2:2]1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)C1CC1
Product: CN(C(=O)C1CC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from cyclopropanecarboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 327.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[C:20]([Cl:40])[CH:19]=1>>[Cl:40][C:20]1[CH:19]=[C:18]([N:11]2[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]2(=[O:15])=[O:16])[CH:23]=[CH:22][C:21]=1[C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=2[CH3:39])[CH2:28][CH2:27]1)=[O:25]
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)cc3Cl)CC2)c(C)c1
Yield: 22.8 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (586 mg) described in Preparation Example 1 and (4-bromo-2-chlorophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (990 mg) described in Preparation Example 131 and by the reaction and treatment in the same manner as in Example 32, the title compound (265 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]23[CH2:15][C@H:14]2[CH2:13][CH2:12][S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:9]3)[CH:7]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]34[CH2:15][C@H:14]3[CH2:13][CH2:12][S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:9]4)[CH:7]=2)=[O:33])=[N:30][CH:31]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)C[C@H]2CCS1
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)C[C@H]2CCS1
Yield: 50 %

Procedure:
Prepared in an analogous manner as described for intermediate rac-A9a from tert-butyl (1S,7S)-1-(5-amino-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (intermediate (−)-A8a) (85 mg, 0.24 mmol) and 5-chloro-2-pyridinecarboxylic acid to give the tert-butyl (1S,7S)-1-(5-(5-chloropicolinamido)-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (70 mg, 50% yield) as a light yellow oil. MS (ISP): m/z=391.0 [(M-Boc+H)+] and 393.1 [(M-Boc+2+H)+].
Reaction SMILES: Cl.[CH:2](N)=[NH:3].[NH2:5][C:6]1[NH:7][C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[C:23]([Cl:26])[CH:22]=[CH:21]3)=[CH:9][C:10]=1[C:11]([O:13]CC)=O>CC(O)C>[ClH:26].[Cl:26][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[C:16]([C:8]3[NH:7][C:6]4[N:5]=[CH:2][NH:3][C:11](=[O:13])[C:10]=4[CH:9]=3)[CH:17]=[CH:18][CH:19]=2)[N:24]=1
Reactant: N=CN
Reactant: CCOC(=O)c1cc(-c2cccc3ccc(Cl)nc23)[nH]c1N
Agent: Cl
Solvent: CC(C)O
Product: O=c1[nH]cnc2[nH]c(-c3cccc4ccc(Cl)nc34)cc12
Temperature: 100 °C
Yield: 178 %

Procedure:
Formamidine hydrochloride (0.296 g, 3.67 mmol) and ethyl 2-amino-5-(2-chloroquinolin-8-yl)-1H-pyrrole-3-carboxylate (0.232 g, 0.735 mmol) were combined in 3 mL IPA, sealed, and heated to 100° C. overnight. An additional 1 mL IPA was added, and the reaction resealed and heated to 110° C. for 24 additional hours. The reaction was cooled, diluted with IPA, and filtered, rinsing 2×IPA. The solid was collected and dried in vacuo to give 6-(2-chloroquinolin-8-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one hydrochloride (0.218 g, 0.654 mmol, 89% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (1H, br. s.), 8.53 (1H, d, J=8.6 Hz), 8.23-8.30 (1H, m), 8.00 (1H, dd, J=7.9, 1.1 Hz), 7.92 (1H, s), 7.66-7.77 (2H, m), 7.49 (1H, s), 7.01-7.26 (2H, m). m/z (ESI, +ve) 296.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=[O:6].[CH2:28]([Mg]Br)[CH3:29]>O1CCCC1.C(OC)(C)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:28][CH3:29])[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCC(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (1.00 g, 2.7 mmol) in tetrahydrofuran (20 ml) at 0° C. was added ethylmagnesium bromide soln in t-butylmethyl ether. (4.0 ml, 4.0 mmol) dropwise over 5 min. The reaction was allowed to stir 20 min at 0° C. The reaction was quenched with NH4Cl aq. sat soln. The solid was removed by filtration. The filtrate was concentrated and purified by silica gel chromatography: ISCO, 120 g column, 20-30% EtOAc/Hex, followed by 40% (3% EtN3 in EtOAc)/Hex to give 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propan-1-ol. MS (ESI) m/z: Calculated: 404.1; Observed: 405.1 (M++H).