Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:5]=1Br.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22]>>[CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:5]=1[CH:21]([OH:22])[C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COC(OC)c1cc2c(cc1Br)OCO2
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(C(O)c2cc3c(cc2C(OC)OC)OCO3)c1
Yield: 79 %

Procedure:
2-bromo-4,5-methylenedioxybenzaldehyde dimethylacetal and 3-methyoxybenzaldehyde are reacted in the same manner as described in Example 1-(1), whereby 2-(3-methoxy-α-hydroxybenzyl)-4,5-methylenedioxybenzaldehyde dimethylacetal is obtained as pale yellow syrup. Yield: 79%
Reaction SMILES: C([C:3]1[C:4]([C:29]([F:32])([F:31])[F:30])=[N:5][N:6]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[N:23][CH:24]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][CH:17]=[N:16][CH:15]=2)=[CH:10][CH:9]=1)C.BrC1C=CC(C2(CC)N(C3C=CC(S(N)(=O)=O)=NC=3)NC(C(F)(F)[F:56])=C2)=CC=1>>[F:56][C:3]1[C:4]([C:29]([F:31])([F:30])[F:32])=[N:5][N:6]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:26])=[O:27])=[N:23][CH:24]=2)[C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:18][CH:17]=[N:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(-c2cncs2)cc1
Reactant: CCC1(c2ccc(Br)cc2)C=C(C(F)(F)F)NN1c1ccc(S(N)(=O)=O)nc1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(F)c2-c2ccc(-c3cncs3)cc2)cn1

Procedure:
The title compound was prepared according to the procedure of step 1 in the Example 10 using 5-[4-fluoro-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (Example 8, step 1), instead of 5-[5-(4-bromophenyl)-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:49][C@@H:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@@H:51]1[NH2:56]>CN(C)C=O>[NH2:49][C@H:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@H:51]1[NH:56][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=1[S:2][CH3:1]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: CSc1cc(C(F)(F)F)ccc1C(=O)O
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: CSc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
2-Methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate C, 590 mg, 2.5 mmol) was dissolved in 10 mL dimethylformamide. N,N-Diisopropyl ethyl amine (646 mg, 5 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.05 g, 2.7 mmol) were added. After 5 minutes of stirring at room temperature cis-1,2-diaminocyclohexane (570 mg, 5 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0->140:10:1) yielded cis-N-(2-amino-cyclohexyl)-2-methylsulfanyl-4-trifluoromethyl-benzamide as a light yellow solid (282 mg, 34%), MS: m/e=3331.1 [(M+H)+].
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=O.O=S(Cl)Cl>CN(C=O)C>[I:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: CCCOc1ccc(I)c(C(N)=O)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCOc1ccc(I)c(C#N)c1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
To 1.40 g (4.59 mmol) 2-iodo-5-propoxy-benzamide in 40 mL DMF are added 1.67 mL (22.9 mmol) SOCl2 and the reaction mixture is stirred at 115° C. for 1 h. The reaction is quenched by the addition of water and extracted with EtOAc (3×). The combined organic layers are washed with water and brine, dried with Na2SO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, heptane/EtOAc 100/0→60/40).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28](O)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:14][CH:13]=3)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Product: O=C(Nc1ccc(OCCN2CCCC2)cc1)c1cc(-c2ccc(Cl)cc2)c[nH]1
Yield: 56.2 %

Procedure:
4-(2-(Pyrrolidin-1-yl)ethoxy)benzenamine (35 mg) from step A was converted to the title compound (26 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (25 mg) following the procedure described in step C of Example 1. Step C. MS (ESI) 410 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Cl[CH2:9][CH2:10][C:11]([N:13]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:19][CH:18]=1)[CH2:14][CH:15]=[CH2:16])=[O:12]>>[CH2:1]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:9][CH2:10][C:11]([N:13]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:19][CH:18]=1)[CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:2][CH3:3]
Reactant: C=CCN(C(=O)CCCl)c1ccc(-n2ccnc2)cc1
Reactant: CCCNCCC
Product: C=CCN(C(=O)CCN(CCC)CCC)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 4, react dipropylamine with 3-chloro-N-[4-(1H-imidazol-yl)phenyl]-N-(2-propenyl)propanamide to obtain the title compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:24][CH:23]([CH2:25][C:26]([O:28]CC)=[O:27])[C:22]4[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=4[CH2:20][C:19]=3[CH:35]=2)[CH:5]=1>CCO>[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:24][CH:23]([CH2:25][C:26]([OH:28])=[O:27])[C:22]4[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=4[CH2:20][C:19]=3[CH:35]=2)[CH:5]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3cc(C)ccn3)cc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc(NCCCOc2ccc3c(c2)Cc2ccccc2C(CC(=O)O)C3)c1

Procedure:
1.0 N NaOH (0.144 mL, 0.144 mmole) was added to a solution of ethyl (±)-10,11-dihydro-3-[3-(4-methyl-2-pyridylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (35 mg, 0.08 mmole) in EtOH(5 mL) at RT. The mixture was warmed overnight in an oil bath set at 32° C., then was concentrated. The residue was dissolved in H2O (3 mL), and the solution was acidified with 20% TFA. ODS chromatography (5-10% CH3CN/H2O containing 0.1% TFA) followed by concentration and lyophilization gave the title compound as a white powder: MS (ES) m/e 417.3(M+H)+. Anal. Calcd for C26H2N2O3 . 2.0 TFA . 1.0 H2O: C, 54.38; H,4.87; N, 4.23. Found: C, 54.66; H, 6.4.53; N, 4.32.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)[CH:6]=1.Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=O>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[S:15][C:26]4[CH2:27][CH2:28][CH2:29][CH:24]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=5)[C:25]=4[N:16]=3)=[CH:11][CH:12]=2)[CH:6]=1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2)cn1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2)cn1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A suspension of [4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (29.2 mg, 0.13 mmol) and of 2-bromo-6-phenyl-cyclohexanone (65.5 mg, 0.26 mmol) in ethanol (2 mL) was stirred at room temperature for 30 minutes and then heated for two days to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified on silica gel using dichloromethane then dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (50 mg, 100%) as an colourless oil. MS ISP (m/e): 387.4 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.12 (s, 1H), 7.95 (s, 1H), 7.52 (d, 2H), 7.39 (d, 2H), 7.29 (m, 3H), 7.11-7.20 (m, 3H), 4.02 (m, 1H), 2.71 (m, 2H), 2.13 (s, 3H), 2.12 (m, 1H), 1.70-1.94 (m, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:8])[CH3:7].[Cl-].[Cl-].[Cl-].[Al+3].[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16].Cl>ClCCl>[C:6]([C:2]1[NH:1][CH:5]=[C:4]([C:15](=[O:16])[C:14]([Cl:19])([Cl:18])[Cl:13])[CH:3]=1)(=[O:8])[CH3:7]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(=O)c1ccc[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)c[nH]1
Reaction time: 0.25 h
Yield: 46 %

Procedure:
To a solution of 1-(1H-Pyrrol-2-yl)-ethanone (0.980 g, 8.98 mmol) in dichloromethane (10 mL), anhydrous aluminum trichloride (3.05 g, 22.9 mmol) were added and the suspension was vigorously stirred for 15 minutes. Trichloro-acetyl chloride (1.53 mL, 13.74 mmol) in 7 mL of dichloromethane was slowly added and the mixture was then refluxed for 3 hours. The reaction mixture was cooled and poured into an iced solution of 75 mL of HCl 2N and vigorously stirred for 2 hours. Organic layer was separated and then washed with a saturated solution of NaHCO3 (2×100 mL) and water (80 mL), dried over sodium sulfate, filtered, and concentered in vacuo to give 1.061 g of (46%) of the title compound as a pale brown solid.
Reaction SMILES: Cl.CO[C:4](=O)[C@@H:5]([CH2:11][OH:12])[NH:6][CH2:7][CH:8]([CH3:10])[CH3:9].O=S(Cl)Cl.[CH3:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[N:28]=[C:29]=[S:30]>>[CH2:7]([N:6]1[C:5](=[CH2:4])[C:11](=[O:12])[S:30][C:29]1=[N:28][C:20]1[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=1[CH3:18])[CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](CO)NCC(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: Cl
Solvent: O=S(Cl)Cl
Product: C=C1C(=O)SC(=Nc2ccc([N+](=O)[O-])cc2C)N1CC(C)C
Yield: 10 %

Procedure:
(R)-N-Isobutylserine methyl ester HCl salt (Method B3a; 2.28 g, 10.8 mmol) was treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a. The resulting material was purified by column chromatography (SiO2, gradient from hexane to 10% EtOAc/hex) to give 3-isobutyl-4-methylene-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidin-5-one (0.028 g, 10%) followed by (S)-3-isobutyl-4-carbomethoxy-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine HCl salt (0.192 g, 56%). 3-Isobutyl-4-methylene-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidin-5-one: TLC (25% EtOAc/hex) Rf 0.40. (S)-3-isobutyl-4-carbomethoxy-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine HCl salt: TLC (free base, 25% EtOAc/hex) Rf0.50.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1.[CH2:28](O)[CH:29]([CH3:31])[CH3:30].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:28][CH:29]([CH3:31])[CH2:30][O:26][C:25]([C:22]1([C:20]2[N:21]=[C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[C:6]([C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[C:14](=[O:18])[O:13][CH2:12]5)[N:5]3[N:19]=2)[CH2:23][CH2:24]1)=[O:27]
Reactant: CC(C)CO
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)O)CC3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)OCC(C)C)CC3)nc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A mixture of 1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylic acid (250 mg, 685 μmol), isobutanol (100 μL, 1.37 mmol), DMAP (250 mg, 2.05 mmol) and EDCI.HCl (262 mg, 1.37 mmol) in DCM (14 mL) was stirred at 50° C. for 2 hours in a sealed vial, before it was diluted with DCM (80 mL), washed with an aqueous 1 M solution of HCl (40 mL) and evaporated to dryness. The crude mixture was redissolved in MeCN (˜2 mL) and the crude product was crystallized upon addition of water (˜2 mL). Column chromatography (gradient EtOAc 20 to 100% in pet. ether) and subsequent recrystallization in MeCN and water afforded the title compound as colorless crystals (178 mg, 62%). HPLC-Retention time (XE Metode 7 CM): 2.34 minutes. Detected “M+1”-mass: 422.16. Calculated “M+1”-mass: 422.17. 1H NMR (DMSO, 600 MHz): δ=8.22 (br s, 1H), 8.13 (dd, 1H, J=8.1 Hz, 1.5 Hz), 8.00 (d, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.2 Hz), 7.24 (d, 1H, J=8.2 Hz), 5.51 (s, 2H), 4.04 (s, 3H), 3.84 (d, 2H, J=6.5 Hz), 1.79 (m, 1H), 1.61-1.54 (m, 2H), 1.54-1.46 (m, 2H), 0.78 (d, 6H, J=6.7 Hz) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8]/[C:9](/[CH3:15])=[CH:10]\[C:11]([O:13][CH3:14])=[O:12].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH3:15][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9]([CH3:15])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)/C=C(/C)Nc1ccccc1C
Solvent: c1ccccc1
Product: COC(=O)C1=C(C)N(c2ccccc2C)C(C)=C(C(=O)OC)C1c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 4.1 grams (20 millimoles) of methyl 3-(2-methylphenyl)aminocrotonate in 5 milliliters of dry benzene is added to the titanamine complex followed by 1.1 grams (10 millimoles) of benzaldehyde and the mixture stirred at ambient temperature for several hours to obtain the desired dimethyl 2,6-dimethyl-4-phenyl-1-(2-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate which may be recovered in a manner similar to that previously described.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7](O)=[O:8])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:10])[CH2:7][OH:8])=[CH:11][CH:12]=1
Reactant: O=C(O)C(O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(O)c1ccc(F)cc1
Temperature: 0 °C
Yield: 94.8 %

Procedure:
To a stirred solution of 4-fluoromandelic acid (1.0 g, 5.88 mmol) in tetrahydrofuran was added lithium aluminum hydride (0.47 g, 12.34 mmol). The reaction mixture was refluxed for 1.5 hours. The reaction mixture was cooled (0° C.), quenched with sat. ammonium chloride solution, filtered, concentrated to yield 0.87 g of 1-(4-fluorophenyl)ethane-1,2-diol.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]#[N:18])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[C:17]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2)#[N:18]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C#N)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)CNC2

Procedure:
A solution of N-t-butoxycarbonyl-5-cyanoisoindoline (D15) (130 mg) in DCM (3 ml) at rt was treated with TFA (1 ml) and after 1 h it was evaporated. The residue was re-evaporated from MeOH/toluene to give the title compound (D16) (140 mg). 1H NMR δ (CDCl3): 7.70 (2H, m), 7.50 (1H, m), 4.75 (4H, m).
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[OH:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:12][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in ethyl acetate. (20 ml) were added 3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (471 mg, 84%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.[CH2:9]([C:16]1[S:20][C:19]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C@H:29]([NH:34][CH2:35][C@H:36]1[C@@H:40]([F:41])[CH2:39][N:38]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:37]1)[C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O>[CH2:9]([C:16]1[S:20][C:19]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C@H:29]([N:34]([CH2:35][C@H:36]1[C@@H:40]([F:41])[CH2:39][N:38]([C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[CH2:37]1)[C:6]([C@@H:2]1[CH2:3][CH2:4][CH2:5][O:1]1)=[O:8])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: CC(C)(C)[C@@H](NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(C)[C@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)C(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
The solution of (S)-(−)-2-tetrahydrofuroic acid (50 mg, 0.43 mmol) in thionyl chloride (0.5 mL) was refluxed for 30 min, and the volatile materials were completely concentrated in vacuo. The crude product was then dissolved in dichloromethane (0.3 mL), which was then added to a solution of (3R,4R)-benzyl 3-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (40 mg, 0.066 mmol) and N,N-diisopropylethylamine (34 μL, 0.197 mmol). After the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield the desired (3R,4R)-benzyl 3-(((S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)tetrahydrofuran-2-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (30 mg, 64.6%). LC/MS (uplc): MH+ 706.0, 1.40 min.
Reaction SMILES: [C:1]1([PH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[P:16]([CH2:29][CH2:30][CH2:31]Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Li]>C1COCC1.O>[P:16]([CH2:29][CH2:30][CH2:31][PH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Pc1ccccc1
Reactant: ClCCCP(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(PCCCP(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
In a Schlenk flask were placed phenylphosphine (3.3806 g, 30.71 mmol) with THF (60 ml) and chilled to −30° C. in a freezer over 30 minutes. To this solution was added lithium diisopropylamide (16 ml, 32.16 mmol) and the resulting solution was allowed to warm to room temperature while stirring. In a 250 ml Schlenk flask was placed (C6H5)2P(CH2)3Cl (7.9089 g, 30.1 mmol) in 100 ml THF and the solution was cooled to −78° C. The lithium phenylphosphide solution was added to the (C6H5)2P(CH2)3Cl solution at such a rate that the temperature of the solution remained constant at −78° C. After addition, the solution was slowly warmed to room temperature. Degassed DI water (0.2 ml) was added to the dark orange solution. The color changed to yellow-orange. The solvents were removed in vacuo. The resulting gel was dissolved in toluene and filtered through Celite. Toluene was then removed in vacuo, leaving an orange-yellow oil. Yield: 10.0 g (99.1%). 31P{1H} NMR (CDCl3, 122 MHz, δppm: −16.30 and −52.86 (>99% pure). 1H NMR (CDCl3, 400 MHz, δ: 1.58–2.15 (3 complex peaks integrated to ˜7Hs), 4.12 (d of t, H—P) and 7.26–7.43 (complex pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:31][C@@H:29]([C:26]4[CH:25]=[N:24][C:23]([O:22][CH3:21])=[N:28][CH:27]=4)[CH3:30])[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COc1ncc([C@@H](C)N)cn1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc([C@@H](C)Nc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (130 mg, 0.41 mmol) and (R)-1-(2-methoxypyrimidin-5-yl)ethanamine (85 mg, 0.55 mmol) (prepared similarly according to the method for Intermediate 16) in acetonitrile (3 mL) and N,N-diisopropylethylamine (140 μL, 0.83 mmol) was subjected to microwave irradiation at 180° C. for 3 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to yield a white solid.
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([NH:12][C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])=[S:14])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.Br[CH2:21][C:22](=O)[C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:22]1[N:15]([CH2:16][CH2:17][O:18][CH3:19])/[C:13](=[N:12]/[C:10]([C:4]23[CH2:5][CH:6]4[CH2:9][CH:2]([CH2:1][CH:8]2[CH2:7]4)[CH2:3]3)=[O:11])/[S:14][CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COCCNC(=S)NC(=O)C12CC3CC(CC1C3)C2
Reactant: CC(C)(C)C(=O)CBr
Product: COCCn1c(C(C)(C)C)cs/c1=N\C(=O)C12CC3CC(CC1C3)C2

Procedure:
A mixture of Example 14B (57 mg, 0.20 mmol) and 1-bromo-3,3-dimethylbutan-2-one (36 mg, 0.027 mL, 0.20 mmol, Aldrich) was processed according to the method described in Example 14C. Purification by column chromatography (SiO2, 30-45% ethyl acetate/hexanes gradient) afforded title compound. 1H NMR (dimethylsulfoxide-d6, 300 MHz) δ 1.37 (s, 9H), 1.56-1.63 (m, 4H), 1.69-1.79 (m, 4H), 2.07-2.18 (m, 2H), 2.24-2.30 (m, 2H), 2.53-2.60 (m, 1H), 3.26 (s, 3H), 3.75 (t, J=6.78 Hz, 2H), 4.40 (t, J=6.95 Hz, 2H), 6.57 (s, 1H); MS (DCI/NH3) m/z 363 (M+H)+.