Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]>CC#N>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:9])[N:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1nc(O)ncc1F
Solvent: CC#N
Product: Nc1nc(=O)n(C(=O)Oc2ccccc2)cc1F
Temperature: 65 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a suspension of 4-amino-5-fluoro-pyrimidin-2-ol (1.0 g, 7.74 mmol) in CH3CN (20 mL) was added BSA (2.84 mL, 11.61 mmol), and the mixture was heated to 65° C. for 1 h. The resulting solution was cooled to room temperature and to it was added phenyl chloroformate (2.4 mL, 19.35 mmol) causing a slight exotherm. The mixture was stirred at room temperature overnight. The suspension that formed was suction filtered, and the solid was washed with Et2O (3×10 mL). The solid was suspended in Et2O (10 mL) for 2 h, was collected via suction filtration and was air-dried overnight. Phenyl 4-amino-5-fluoro-2-oxopyrimidine-1(2H)-carboxylate (0.90 g, 47%) was isolated as a white solid: mp 175-180° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.25 (br s, 2H), 8.45 (d, J=7.25 Hz, 1H), 7.49-7.43 (m, 2H), 7.35-7.28 (m, 3H); ESIMS m/z 250 ([M+H]+).
Reaction SMILES: [CH:1](Br)=[CH2:2].[Mg].CN(C)[CH:7]=[CH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O1CCCC1.CCOCC>[CH2:1]=[CH:2][CH:7]=[CH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC(=O)C=CN(C)C
Reactant: C=CBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC=CC(=O)CCCCC
Temperature: 25 °C

Procedure:
To a solution of Grignard reagent prepared from vinyl bromide (10.7 g), and magnesium (2.43 g) in dry tetrahydrofuran (40 ml) is added gradually a solution of 1-(dimethylamino)-1-octen-3-one (16.9 g), described in Example 37, in dry tetrahydrofuran (20 ml). The mixture is stirred and heated to reflux for 1 hr. The reaction mixture is cooled to room temperature, diluted with ether, washed with hydrochloric acid (10 ml), followed by saturated ammonium chloride solution. The ether extract is dried, and the solvent is removed. The residue is chromatographed to yield the title compound, λmaxEtOH 260 nm (ε=17,050), γmaxfilm 1686, 1668 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>O1CCOCC1>[F:12][C:13]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:14]=1[C:15]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:16]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(F)cc1F
Yield: 84.4 %

Procedure:
Using a method similar to Preparation 13, using 4-fluoro-3-nitroaniline (1.0 g, 6.4 mmol), dioxane (20 mL), and 2,4-difluorobenzoyl chloride (1.46 g, 8.3 mmol) gives the title intermediate (1.6 g, 84% yield): mass spectrum (ion spray): m/z=297.0 (M+1).
Reaction SMILES: CC(C)(OC([N:7]1[CH2:11][C@@H:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=[C:20]([CH3:29])[CH:19]=3)[CH2:14][CH2:13]2)[CH2:9][C@H:8]1[C:30]([N:32]1[CH2:36][CH2:35][S:34][CH2:33]1)=[O:31])=O)C.FC(F)(F)C(O)=O>ClCCl>[CH3:29][C:20]1[CH:19]=[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C@@H:10]3[CH2:11][NH:7][C@H:8]([C:30]([N:32]4[CH2:36][CH2:35][S:34][CH2:33]4)=[O:31])[CH2:9]3)[CH2:13][CH2:14]2)[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:21]=1
Reactant: Cc1cc(N2CCN([C@H]3C[C@@H](C(=O)N4CCSC4)N(C(=O)OC(C)(C)C)C3)CC2)n(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)n(-c2ccccc2)n1
Reaction time: 19 h
Yield: 93 %

Procedure:
3-{(2S,4S)-1-(1,1-Dimethylethyloxycarbonyl)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine (25.45 g, synthesized according to the compound described in Example 222 of WO02/14271) was dissolved in dichloromethane (200 mL). Trifluoroacetic acid (50 mL) was added at room temperature, and the mixture was stirred for 19 hrs. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with chloroform. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a solid (19.28 g, yield 93%).
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21](O)=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:25][CH2:26][C:27]#[N:28].C(P(=O)([O-])OCC)#N>ClCCl.C(N(CC)CC)C>[C:26]([CH2:27][NH:28][C:21]([C:20]1[N:19]=[CH:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:9][C:10]=12)=[O:22])#[N:25]
Reactant: N#CCN
Reactant: O=C(O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Agent: CCOP(=O)([O-])C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCNC(=O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reaction time: 1.17 h

Procedure:
To a mixture of 4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylic acid (I, EXAMPLE 323, 0.203 g), 0.060 g of aminoacetonitrile hydrochloride, and 3 ml of dichloromethane are added 0.23 ml of triethylamine and 0.15 ml of ethyl cyanophosphonate. A slight exotherm ensued. After about 45 min a precipitate formed and an additional 5 ml of dichloromethane are added. When the reaction had stirred for a total of 70 min it is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel (125 ml) eluting with methanol/methylene chloride (2/98), the appropriate fractions are pooled and concentrated to give the title compound, mp 241°-242.5°; MS (m/z) at 350; IR (mineral off) 1641, 1506, 1658, 1409, 1417, 2237 (weak) cm-1 ; NMR (CDCl3) 1.83, 3.31, 4.36, 5.06, 7.12-7.30, 7.40, 7.49, 7.94 δ.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH2:14][CH:13]([CH3:17])[NH:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:10][CH:11]1[NH:12][CH:13]([CH3:17])[CH2:14][N:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: CC1CNCC(C)N1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(c2ccc(C=O)cc2)CC(C)N1
Temperature: 120 °C
Yield: 56.9 %

Procedure:
A mixture of 4-fluorobenzaldehyde (2.0 g, 16.1 mmol), 2,6-dimethylpiperazine (2.2 g, 19.3 mmol), and K2CO3 (2.7 g, 19.3 mmol) in DMF (10 mL) was heated at 120° C. for 4 hours. Then, the reaction was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 3% to 10% MeOH/CH2Cl2 afforded 4-(3,5-dimethylpiperazin-1-yl)benzaldehyde (2.0 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[C:14]([CH:16]1[CH2:18][CH2:17]1)#[CH:15]>C1(C)C=CC=CC=1.C(N(CC)CC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[C:4]([C:15]#[C:14][CH:16]2[CH2:18][CH2:17]2)[N:3]=1
Reactant: C#CC1CC1
Reactant: CCOC(=O)c1ccc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CC2CC2)nc1Cl
Yield: 31 %

Procedure:
Ethyl 2,6-dichloropyridine-3-carboxylate (2.0 g, 9.1 mmol), ethynylcyclopropane (1.6 mL of a 70% w/v solution in toluene, 13.63 mmol), copper(I) iodide (173 mg, 0.9 mmol), bis(triphenylphosphine) palladium(II) chloride (1.28 g, 1.82 mmol) were stirred in 40 mL triethylamine at room temperature for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography using 10-50% EtOAc/hexane to give the product (0.7 g, 31%) as a brown oil. m/z=250 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[Cl:14][CH2:15][Si:16]([CH3:19])([CH3:18])Cl.C(OCC)C>O1CCCC1>[Cl:14][CH2:15][Si:16]([CH3:19])([CH3:18])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: C[Si](C)(Cl)CCl
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(CCl)c1ccc(F)cc1
Temperature: -70 °C

Procedure:
250 ml of n-butyl lithium (1.6M in hexane) are added to 39 ml of 4-bromo-fluoro-benzene in 400 ml of tetrahydrofuran within a period of 45 minutes with stirring at −70° C. The mixture is stirred for a further 30 minutes and then 53 ml of chloromethyl-dimethyl-chlorosilane dissolved in 50 ml of tetrahydrofuran are added dropwise. The mixture is stirred at −70° C. for a further 30 minutes and the temperature of the reaction mixture is then allowed to rise to 0° C. The reaction mixture is poured onto 200 ml of ice, and 300 ml of diethyl ether are added; the mixture is washed with water and saturated sodium chloride solution and dried over sodium sulfate; the solvent is evaporated off in vacuo. Distillation of the residue at 97-105° C. (21 mbar) yields the title product.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25]O)[CH2:20][CH2:19]2)[CH:5]=1.C([N:35](CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.N>CO.C1COCC1>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH2:35])[CH2:20][CH2:19]2)[CH:5]=1
Reactant: CCN(CC)CC
Reactant: OCC(c1ccccc1)N1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NCC(c1ccccc1)N1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Yield: 55.9 %

Procedure:
In the same way as that described in Example 7, Step 1 using 1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]-4-[2-hydroxy-1-phenylethyl]piperazine (330 mg, 0.77 mmol), triethylamine (214 μL, 1.53 mmol), methanesulphonyl chloride (118 μL, 1.53 mmol) and THF (15 mL). The crude mesylate was then reacted with ammonia (7.7 mL of a 2.0M solution in MeOH, 15.3 mmol) in the same way as that described in Example 7, Step 1. The amine (185 mg, 56%) was isolated as a pale yellow foam. 1H NMR (250 MHz, CDCl3) δ1.88-2.00 (2H, m), 2.38-2.76 (12H, m), 2.79 (2H, t, J=7.5 Hz), 4.11 (1H, dd, J=10.4 and 3.6 Hz), 7.13-7.18 (2H, m), 7.22-7.39 (5H, m), 7.47 (1H, d, J=8.6 Hz), 7.59 (1H, s), 8.34 (1H, br s), 8.46 (2H, s). MS (430, M+1).
Reaction SMILES: C([Li])CCC.O1CCCC1.[Cl:11][C:12]1[CH:29]=[CH:28][C:15]2[S:16][CH:17]=[C:18]([CH2:19][N:20]([CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])[CH3:21])[C:14]=2[CH:13]=1.[C:30](=[O:32])=[O:31]>CO>[Cl:11][C:12]1[CH:29]=[CH:28][C:15]2[S:16][C:17]([C:30]([OH:32])=[O:31])=[C:18]([CH2:19][N:20]([CH2:22][CH:23]([O:24][CH3:25])[O:26][CH3:27])[CH3:21])[C:14]=2[CH:13]=1
Reactant: COC(CN(C)Cc1csc2ccc(Cl)cc12)OC
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: COC(CN(C)Cc1c(C(=O)O)sc2ccc(Cl)cc12)OC
Temperature: -30 °C
Yield: 54 %

Procedure:
Butyllithium in tetrahydrofuran (2.6M, 0.04 mol) was added slowly to a solution of 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]benzo[b]thiophene (10 g, 0.033 mol) in freshly distilled tetrahydrofuran (100 ml) stirred at -30° C. under argon. The mixture was stirred for 30 minutes, treated with dry carbon dioxide for 5 minutes and allowed to warm to 25° C. The mixture was treated with methanol, poured into ice water and extracted with ethyl ether. The aqueous phase was adjusted to pH 7.5 and extracted with methylene chloride. The organic phase was washed with water, dried with magnesium sulfate and concentrated to give 6.0 g (54%) of 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]benzo[b]thiophene-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][CH:3]1[C:5](O)=[O:6].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:31][C:32]1[C:33]([F:42])=[C:34]2[C:40]([NH2:41])=[CH:39][NH:38][C:35]2=[N:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:31][C:32]1[C:33]([F:42])=[C:34]2[C:40]([NH:41][C:5]([CH:3]3[CH2:4][C:2]3([CH3:8])[CH3:1])=[O:6])=[CH:39][NH:38][C:35]2=[N:36][CH:37]=1
Reactant: CC1(C)CC1C(=O)O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC1C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
2,2-Dimethylcyclopropanecarboxylic acid (0.992 g, 8.69 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (2.21 g, 8.69 mmol) and triethylamine (2.20 g, 21.7 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (1 g, 4.35 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 was added. The mixture was filtered, and the solid rinsed with water and dried to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylcyclopropanecarboxamide (672 mg, 47.4% yield) as a solid.
Reaction SMILES: [I:1][C:2]1[NH:3][C:4]([I:8])=[C:5]([I:7])[N:6]=1.[H-].[Na+].I[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.I>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[N:3]([CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:4]([I:8])=[C:5]([I:7])[N:6]=1
Reactant: ICCN1CCCC1
Reactant: Ic1nc(I)c(I)[nH]1
Agent: I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1nc(I)n(CCN2CCCC2)c1I
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of 2,4,5-triiodo-1H-imidazole (165) (4.08 g, 9.1 mmol) in DMF (28 mL) at 0° C., was added NaH (1.46 g, 36.4 mmol) portionwise over 30 mins. Then 1-(2-iodoethyl)pyrrolidine×HI 164 (4.85 g, 13.65 mmol) was added at 0° C., and the reaction mixture was allowed to warm to room temperature over a period of 4 hrs. EtOAc (50 mL) was added and the mixture was washed with NaHCO3 aqueous solution. The organic phase was separated and extracted with citric acid solution (3%), the acidic aqueous extract was basified with 2N NaOH solution to pH˜10, the resultant solid was collected by filtration to give the title compound 166 (1.75 g, 35%) as a light brown solid. MS (m/z): 543.5 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:33])=[O:32])[CH:28]=3)[CH2:24]2)[CH2:11][O:10]1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:32])=[O:33])[CH:28]=3)[CH2:24]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CC4)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CC4)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate from Step A above (93 mg, 0.16 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3 ml) at room temperature. After 1.5 h, the reaction mixture was concentrated to give the title compound. 1H NMR (500 MHz, CD3OD): δ 1.17-1.23 (m, 2H); 1.34-1.40 (m, 2H); 2.08 (q, 1H, J=12 Hz); 2.80 (d, 1H, J=12 Hz); 2.91-2.97 (m, 1H); 3.58-3.66 (m, 1H); 3.76 (t, 1H, J=12 Hz), 3.82-3.90 (m, 1H); 4.47-4.62 (m, 5H); 4.70 (d, 1H, J=10 Hz); 7.18-7.26 (m, 2H); 7.28-7.32 (m, 1H); 8.05 (s, 1H). LC-MS: 425.01 (M+1).
Reaction SMILES: C([O:8][C:9](=[O:37])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][N:24]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:13])[CH2:10][C:9]([OH:37])=[O:8])[CH:25]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(C#N)cc2)c1)C(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(C#N)cc2)c1)C(C)(C)C
Yield: 90 %

Procedure:
According to the procedure described in Example 1(a), 3(R)-(3-(4-cyanophenyl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester in MeOH and EtOAc was hydrogenolyzed to provide 1.2 g (90%) of 3(R)-[3-(4-cyanophenyl)-1H-pyrrol-1-yl ]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid as a yellow powder, mp 138-40° C. 1H NMR (CD3OD): δ 7.98 (bs, 1H), 7.82 (bd, 1H, J=8.4 Hz), 7.68 (d, 2H, J=8.7 Hz), 7.50 (d, 2H, J=8.4 Hz), 7.38 (t, 1H, J=1.6 Hz), 6.92 (t, 1H, J=2.5 Hz), 6.55 (t, 1H, J=2.2 Hz), 5.28 (t, 1H, J=7.5 Hz), 4.19 (d, 1H, J=9.0 Hz), 2.98 (dd, 1H, J=6.9, 16.5 Hz), 2.64 (d, 3H, J=4.7 Hz), 0.98 (s, 9H). IR (KBr): 3317, 2963, 2225, 1648, 1550, 1410, 1180 cm−1. HRFABMS: Calculated for C22H26N4O4Cs (M+Cs+): 543.1008. Found 543.1021. Anal. Calculated for C22H26N4O4. 0.4EtOAc: C, 63.60; H, 6.60; N, 12.57. Found: C, 63.80; H, 6.77; N, 12.57.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C:19]4([CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]4)[N:18]4[C@@H:13]([C:14](=[O:39])[O:15][C@@H:16]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C@H:17]4[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:12]3[C:40]3[CH:45]=[CH:44][N:43]=[C:42]([Cl:46])[C:41]=3[F:47])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-:49].[K+].[K+].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:12]([C:40]4[CH:45]=[CH:44][N:43]=[C:42]([Cl:46])[C:41]=4[F:47])[C@H:13]([C:14]([OH:49])=[O:39])[N:18]([C@H:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:16]([OH:15])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:19]43[CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1ccnc(Cl)c1F)[C@@]21C(=O)Nc2cc(Cl)ccc21
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: CC#N
Product: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)O)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
The compound (630 mg, 0.94 mmol) obtained in Step 1 of Example 16 was dissolved in acetonitrile (10 ml) and water (4 ml), potassium carbonate (130 mg, 0.94 mmol) was added and the resulting mixture was heated to reflux at 85° C. for 16 hours. After cooling, anhydrous magnesium sulfate (113 mg, 0.94 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. After extraction with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (4′S,5′R)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-1′-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylic acid (650 mg, 100%) as a pale orange amorphous solid [MS (ESI) m/z: 688 (M+H)+.]. The carboxylic acid (650 mg, 0.94 mmol) obtained was dissolved in methanol (30 ml) and water (8 ml), cerium (IV) diammonium nitrate (1.55 g, 2.82 mmol) was added under ice cooling and the resulting mixture was stirred at the same temperature for 30 minutes. Potassium carbonate (780 mg, 5.64 mmol) was added under ice cooling and the resulting mixture was stirred at the same temperature for 1 hour. Insoluble matter was removed by filtration through celite, then the filtrate was concentrated under reduced pressure and water was added to the residue obtained, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=20:1→4:1 (v/v)] to give 152 mg (33%) of the title compound as a colorless solid.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=O)C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:16]1([S:22]([C:14]2[S:15][C:9]3[CH2:8][CH2:7][NH:6][CH2:12][CH2:11][C:10]=3[CH:13]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)N1CCc2ccsc2CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=S(=O)(c1ccccc1)c1cc2c(s1)CCNCC2
Temperature: 80 °C

Procedure:
The product of Example 1, step (d) (75 mg, 0.33 mmol) was dissolved in 2 mL DCE and treated with phenyl sulfonyl chloride (83 uL, 0.66 mmol) followed by AlCl3 (88 mg, 0.66 mmol). After heating to 80° C. for ½ hour, the reaction was cooled and quenched carefully with 1M NaOH. The product was extracted into DCM (2×). The organic extracts were concentrated and the residue was dissolved in 3 mL each EtOH and 40% aqueous KOH. The reaction was heated to 100° C. for 14 hours, cooled, and diluted with water. The title compound was extracted into DCM (2×5 mL) and purified by preparative HPLC-MS. 1H NMR (CD3OD) δ 7.96 (d, J=8.1 Hz, 2H), 7.67-7.56 (m, 3H), 5.56 (s, 1H), 3.38-3.32 (m, 4H), 3.27-3.23 (m, 2H), 3.09 (t, J=5.4 Hz, 2H); MS: ESI (positive): 294 (M+H).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][C:28]([CH3:33])=[CH:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH:29]=[C:28]([CH3:33])[CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)=CC(=O)O
Agent: Cl
Product: CC(C)=CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (83 mg, 81%), MS (ISP) m/z=409.4 [(M+H)+], mp 147° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3-methyl-but-2-enoic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:11]([Cl:10])=[C:12]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2ccc(Cl)c(C(F)(F)F)c2)nc1Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-chloro-3-trifluoromethylaniline were reacted to yield N2,N4-bis(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.05 (bs, 1H), 7.89 (bd, 1H), 7.77 (dd, 1H, J=2.4 and 9 Hz), 7.65 (dd, 1H, J=2.4 and 8.7 Hz), 7.49 (d, J=8.1 Hz), 7.40 (d, 1H, J=6.2 Hz), 7.03 (s, 1H), 6.91 (s, 1H); 19F NMR (CDCl3): δ −17864 (s, 3F), −17894 (s, 3F), −46550 (s, 1F); LCMS: ret. time: 38.81 min.; purity: 75%; MS (m/e): 485 (MH+).