Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][N:14]=[C:10]3[CH2:9][CH:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:6]=2[CH:22]=1.[Br:23]Br>C(Cl)(Cl)Cl.N1C=CC=CC=1>[Br:23][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[CH:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: BrBr
Reactant: Fc1ccccc1C1=CCc2nncn2-c2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Fc1ccccc1C1=CCc2nnc(Br)n2-c2ccc(Cl)cc21

Procedure:
8.5 g of 8-chloro-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine are dissolved in 135 ml of chloroform and 3.3 ml of pyridine. 2.0 ml of bromine are added dropwise at room temperature while stirring. The mixture is then heated to 55°-60° for 50 minutes and evaporated in vacuo. The residue is chromatographed on 550 g of silica gel. By elution with chloroform which contains 0.3% or 0.4% methanol and crystallization of the obtained material from benzene there is obtained 1-bromo-8-chloro-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine of melting point 222°.
Reaction SMILES: B.C1COCC1.[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].CO.Cl>C1COCC1>[ClH:7].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
BH3/THF (279 mL; 279 mmol) was added to a solution of 4-chloro-3-nitrobenzonitrile (30 g; 164 mmol) in THF (100 mL) over 30 min at 0° C. and the resulting mixture was stirred over night and allowed to reach rt. MeOH (150 mL) and conc. HCl (60 mL) was added and the resulting mixture was refluxed for 4 h and thereafter concentrated. The residue was treated with water (500 mL) and the resulting precipitate was filtered off. The filtrate was treated with NaCl (120 g) and heated and the resulting precipitate was filtered off to give the sub-title compound. Yield: 24.059 g (65%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C:20]([CH3:24])([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[CH3:22][N:21]1[C:14]2[N:15]([C:16](=[O:18])[N:17]=[C:12]([O:1][CH2:2][C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=3)[C:6]#[N:7])[CH:13]=2)[CH2:19][C:20]1([CH3:24])[CH3:23]
Reactant: N#Cc1cccc(CO)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cccc(C#N)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 3-(hydroxymethyl)benzonitrile and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH3:48][P:49]([C:54]1[CH:59]=[CH:58][C:57]([CH:60]([NH2:67])[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:56][CH:55]=1)(=[O:53])[O:50][CH2:51][CH3:52]>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:67][CH:60]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:57]2[CH:56]=[CH:55][C:54]([P:49]([CH3:48])(=[O:53])[O:50][CH2:51][CH3:52])=[CH:59][CH:58]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1O
Reactant: CCOP(C)(=O)c1ccc(C(N)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid, 1-1-h (325.5 mg, 1.5 mmol) in MeCN (10 ml) were added HATU (599 mg, 1.51 mmol), Et3N (159 mg, 1.51 mmol) and ethyl methyl(4-(amino(phenyl)methyl)phenyl)phosphinate (2-d′, 433 mg, 1.5 mmol). The resulting mixture was stirred at room temperature for 2 hour. Then it was concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with saturated NH4Cl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC to provide the product, 2-4, (159 mg, 22%). 1H NMR (CD3OD, 300 MHz,): δ 8.67 (m, 2H), 8.39 (m, 2H), 7.94 (m, 1H), 7.46 (m, 5H), 7.26 (m, 5H), 6.29 (s, 1H), 3.76 (m, 2H), 1.57 (d, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.CCOCC>O1CCCC1>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: COCCOCCl
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCOCOc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-iodophenol (10 g, 45.45 mmoles) in 200 mL of anhydrous tetrahydrofuran was treated at 0° C. with sodium hydride (2.36 g, 60% dispersion, 59.09 mmoles) for 5 minutes. To the resulting mixture was slowly added over a 5 minute period methoxyethoxymethyl chloride (8.3 mL, 72.73 mmoles). The mixture was stirred at 0° C. for 30 minutes, warmed to room temperature, and stirred under nitrogen for 24 hours. The solvent was removed under reduced pressure. The residue was taken into 500 mL of ether, washed with 200 mL of 5% sodium hydroxide (4×200 mL), water (4×200 mL), saturated sodium chloride (1×200 mL), and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave an oily product in 14.1 g. TLC (silica gel, ether): Rf 0.5.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:15].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[N:6][CH:7]=[N+:8]([O-:15])[CH:9]=1)[CH3:2]
Reactant: CCOc1cncnc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1cnc[n+]([O-])c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of 5-ethoxypyrimidine (2.00 g, 16.1 mmol) in CH2Cl2 (100 mL) was added 3-chloroperoxybenzoic acid, 50-60% tech. grade, (6.13 g, 17.7 mmol) and the reaction stirred at 23° C. for 18 h. The reaction was extracted with water (2 mL) containing Na2CO3 (1.71 g, 16.1 mmol). The organic phase was dried with anhydrous K2CO3, filtered, and concentrated under reduced pressure to afford the N-oxide (1.75 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:5])[NH2:4].[Cl:6][C:7]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:8]=1[CH:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12]>>[NH2:14][CH2:13][C:10]1[C:11]([NH2:12])=[N:5][C:3]([O:2][CH3:1])=[N:4][C:9]=1[C:8]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:7]=1[Cl:6]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: COC(=N)N
Product: COc1nc(N)c(CN)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
The title compound, MS: m/e=337.8 (M+), was prepared from 2-methyl-isourea and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 a solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:16])[CH:6]=[C:7]([CH3:15])[CH:8]=2)[N:3]=1.[NH2:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[C:26]([C@@H:18]([NH:17][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:16])[CH:6]=[C:7]([CH3:15])[CH:8]=2)[N:3]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:28])=[O:27]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1cc(C)c2nc(Cl)c(C(=O)O)cc2c1
Solvent: CS(C)=O
Product: Cc1cc(C)c2nc(N[C@@H](Cc3ccccc3)C(=O)O)c(C(=O)O)cc2c1

Procedure:
In close analogy to the procedure described in Example 1, 2-chloro-6,8-dimethyl-quinoline-3-carboxylic acid is reacted with L-phenylalanine in DMSO to provide the title compound in good yield. LCMS m/z 364 (M+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1.[C:22]1([CH2:28][S:29](Cl)(=[O:31])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(CC)CC>ClCCl>[O:20]=[C:6]1[N:5]2[CH2:21][C@H:2]([NH:1][S:29]([CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:31])=[O:30])[CH2:3][C@H:4]2[CH2:8][N:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](NS(=O)(=O)Cc3ccccc3)CN12
Reaction time: 12 h
Yield: 66.5 %

Procedure:
(6R,7aS)-6-Amino-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step h) (100 mg, 0.33 mmol), phenylmethanesulfonyl chloride (125 mg, 0.66 mmol) and Et3N (0.1 g, 0.99 mmol) were added to dichloromethane (3 mL), and the mixture was stirred for 12 hours. The mixture was directly purified by prep-TLC (DCM/MeOH=30:1) to yield 100 mg (67%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.58-7.55 (m, 2H), 7.43-7.40 (m, 5H), 7.20-7.17 (m, 2H), 4.40-4.37 (m, 1H), 4.29 (s, 2H), 4.05-3.97 (m, 4H), 3.68-3.62 (m, 1H), 2.85-2.81 (m, 1H), 2.11-2.07 (m, 1H), 1.78-1.72 (m, 1H); LC-MS: 456.1 [M+1]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:12][S:13](=[S:16])([O-:15])=[O:14].[Na+].CN(C=O)C>O>[CH3:12][S:13](=[S:16])([O:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:14]
Reactant: CCCCCCCCCCBr
Reactant: CS(=O)([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCOS(C)(=O)=S
Temperature: 60 °C
Yield: 94 %

Procedure:
The mixture of 1-bromodecane (2.095 g, 0.00947 mol), sodium methanethiosulfonate and dry DMF (6 mL) was heated at 60° C. for 2 hr. At room temperature, water (15 mL) was added and the mixture was extracted with ether (3×30 mL). The ether extracts were washed with brine, dried, concentrated and the residue was subjected to flash column chromatography on silica gel with EtOAc-hexanes (1:4) to afford a white solid (2.063 g, 94%). It was recrystallized from 95% EtOH. mp: 28.0-29.5° C. IR (CDCl3 cast): 2954 (m), 2921 (st), 2852 (st), 1469 (m), 1305 (st), 1128 (st), 965 (m), 758 (m) and 720 cm−1 (m); 1H NMR (200 MHz, CDCl3): δ 3.32 (s, 3H, CH3SO2S), 3.17 (t, J=7.4 Hz, 2H, SCH2CH2), 1.77 (m, 2H, SCH2CH2), 1.50-1.20 (m, 14H, —(CH2)7—), 0.88 (m, 3H, CH2CH3); 13C NMR (50 MHz, CDCl3): δ 50.64, 36.49, 31.84, 29.45 (two carbons), 29.37, 29.23, 28.94, 28.57, 22.64, 14.08.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccc(Cl)c(Cl)c2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(Cl)c(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of 2-amino-4-(3,4-dichlorophenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 6 & 7, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) was heated at reflux overnight. After cooling to room temperature, the acetic acid was removed in vacuo and the residue triturated with petroleum ether. The crude product was collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue was dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization from petroleum ether afforded the desired product as a yellow solid in 74% yield.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[C:22]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=[C:19]([CH2:29][NH2:30])[CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH2:29][C:19]3[CH:18]=[C:17]([CH3:16])[C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[CH:21][N:20]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)ncc1OCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)(F)F
Yield: 22 %

Procedure:
The title compound is prepared in 22% yield (42 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (170 mg, 0.61 mmol, Step-1 of Intermediate-1) and (4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine hydrochloride (230 mg, 0.51 mmol, Amine-57) in a similar manner to Step-2 of Intermediate-1.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][N:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>O1CCOCC1>[N:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=4[Cl:26])=[CH:23][CH:22]=3)=[O:7])[CH2:9][C:10]=12
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A slurry of 0.330 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 15 ml of dioxane is stirred and warmed slightly to obtain a nearly complete solution. The reaction mixture is cooled to room temperature and 43 mg of sodium hydride in oil added. The mixture is warmed slightly. Gas evolution stops in a few minutes. The reaction mixture is cooled to room temperature and 153 μl of 2,4-dichlorobenzoyl chloride in 2.5 ml of dioxane added. An additional 3.5 ml of dioxane is added and the reaction mixture stirred at room temperature for 2 days. The volatiles are evaporated in vacuo to a residue which is partitioned between water and chloroform. The organic layer is separated and the aqueous phase extracted with chloroform two more times. The combined organic layers are trated with activated carbon and filtered through MgSO4. The filtrate is evaporated in vacuo to a tan foam which is purified by flash chromatography on silica gel by elution with CHCl3 and 3-7% CH3 OH in chloroform to give 310 mg of tan foam.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1>C1C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of aluminum chloride (1.27 g, 9.52 mmol) in 30 ml dry benzene under nitrogen was added at room temperature 4-chlorophenylacetyl chloride (1.80 g, 9.52 mmol) over a period of 30 minutes as a solution in 10 ml benzene. The resulting clear, pale yellow solution was refluxed for six hours. After cooling to room temperature, the resulting grey-brown solution was poured into 100 ml ice water. The layers were separated and the aqueous portion extracted with benzene (1×20 ml). The combined organic portions were washed with water (2×30 ml), 10% NaOH (1×30 ml), water (1×30 ml), and brine (1×30 ml), and dried over magnesium sulfate. Filtration through Celite afforded, after concentration in vacuo, 2.18 g of the ketone as a white crystalline solid (99% crude yield): Rf 0.46 (benzene); 1H NMR (CDCl3) 8.03 (d, J=7.2 Hz, 2H), 7.63-7.21 (m, 7H), 4.29 (s, 2H). A portion (ca. 1 g) of the ketone was recrystallized from 75 ml boiling pet. ether/ethanol (5:1) to give a fluffy white crystalline solid: m.p. 132.5-134.0° C. (lit. m.p. 135-136° C.; Loeshorn, C. H. et al., J. Org. Chem. 48:4409 (1983)).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.O[C@@H:32]1[C@@H:37]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:36][C@H:35]2[C@@H:33]1[CH2:34]2.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.CO>[O:25]=[C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:30])[N:24]1[C@H:36]1[C@@H:37]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:32][C@H:33]2[C@@H:35]1[CH2:34]2
Reactant: O=C(N[C@H]1C[C@@H]2C[C@@H]2[C@@H]1O)OCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(N[C@H]1C[C@@H]2C[C@@H]2[C@H]1N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A solution of triphenylphosphine (6.4 g, 24.292 mmol), phthalimide (6.2 g, 42.511 mmol) and benzyl (1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hexan-3-ylcarbamate (3.0 g, 12.146 mmol) in toluene (250 mL) was stirred at −78° C. for 30 minutes under nitrogen protection, followed by the addition of diisopropyl azodicarboxylate (8.6 mL, 42.511 mmol) dropwise. The resulting mixture was stirred at −78° C. for another 1 hour and then at room temperature overnight. The reaction mixture was treated with 10 mL of methanol, and the solvents were removed under reduced pressure. The crude material was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:2) to afford the title compound (3.0 g, 65%) as a light yellow oil. MS (ES+) C22H20N2O4 requires: 376, found: 399 [M+23]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=2)[N:32]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[C:30]=1[CH3:47]>CCOC(C)=O>[F:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:30]([CH3:47])[C:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[F:46])=[N:32]2)=[CH:37][CH:36]=1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 140 °C

Procedure:
Under a N2 atmosphere, 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.19 g, 0.69 mmol) was dissolved in DMF (2.00 mL, 26 mmol) and sodium hydride (0.018 g, 0.76 mmol) was added and the reaction was treated with 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (0.100 g, 0.35 mmol) and heated to 140° C. for 6 h. The reaction was then diluted with EtOAc and washed with 2% sodium bicarbonate then brine. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The reaction was then purified by flash column chromatography eluting with 40% to 60% EtOAc in hexane and then purified by preparative reverse phase HPLC to afford 1-(7-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. Mass Spectrum (ESI) m/e=528.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.99 (1H, m), 7.83 (1H, dd, J=10.2, 2.3 Hz), 7.50-7.62 (3H, m), 7.35-7.42 (2H, m), 7.10 (1H, d, J=8.2 Hz), 6.29 (1H, dd, J=8.2, 2.3 Hz), 5.56 (1H, d, J=2.3 Hz), 4.07 (1H, d, J=9.8 Hz), 3.80-3.91 (3H, m), 3.56-3.63 (4H, m), 3.41-3.54 (2H, m), 2.82-2.89 (4H, m), 2.05 (3H, d, J=1.2 Hz), 1.90-2.02 (2H, m), 1.81-1.88 (1H, m), 1.62-1.72 (1H, m)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]1[CH2:18][NH:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1.C(N(CC)CC)C>ClCCl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]1[CH2:18][N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (40 μL, 0.51 mmol, 1.00 equiv) was added to a solution of 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (2-4, 130 mg, 0.505 mmol, 1 equiv) and triethylamine (350 μL, 2.52 mmol, 5.00 equiv) in dichloromethane (30 mL) at 23° C., and the resulting reaction mixture was stirred for 16 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 4-(2,5-difluorophenyl)-1-(methylsulfonyl)-2-phenyl-2,5-dihydro-1H-pyrrole (6-1) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.39-7.30 (m, 5H), 7.09 (td, 1H, J=9.8, 4.6 Hz), 7.01 (m, 2H), 6.36 (br s, 1H), 5.76 (m, 1H), 4.84 (br d, 1H, J=13.2 Hz), 4.64 (ddd, 1H, J=13.2, 5.6, 2.0 Hz), 2.55 (s, 3H). LRMS m/z (M+H) 336.0 found, 336.1 required.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.C1(C)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][O:25][CH2:24][CH2:23][O:22][C:3]1[C:2]([C:37]2[N:33]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][O:27]3)[N:34]=[CH:35][CH:36]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: COCCOc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COCCOc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1ccnn1C1CCCCO1
Reaction time: 0.25 h

Procedure:
A mixture of 5-bromo-6-(2-methoxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 51.1, 50 mg, 0.115 mmol), 1-(tetrahydro-2h-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (49 mg, 0.172 mmol), Pd(Ph3P)4 (13 mg, 0.011 mmol) and toluene (0.5 mL) was stirred for 15 min under an argon atmosphere. K3PO4 (73 mg, 0.345 mmol) was added and the RM was stirred at 110° C. for 6 h. The RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure to afford 6-(2-methoxyethoxy)-5-(1-(tetrahydro-2h-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, of which (50 mg, 0.099 mmol), TFA (0.25 mL, 3.24 mmol) and DCM (0.4 mL) was stirred at RT for 2 h. The mixture was treated with a solution of Na2CO3 (2 M) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative SFC (Column Diol; gradient 13% to 18% in 6 min.) and lyophilized to afford an off-white powder. UPLC-MS (Condition 2) tR=1.04 min, m/z=423.3 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.34 (s, 3H) 3.73-3.82 (m, 2H) 4.58 (br. s, 2H) 6.90 (d, J=1.88 Hz, 1H) 7.37 (d, J=8.47 Hz, 2H) 7.83-7.87 (m, 1H) 7.89 (d, J=9.03 Hz, 2H) 8.70 (d, J=2.26 Hz, 1H) 8.77-8.90 (m, 1H) 10.55 (br. s, 1H) 13.06-13.22 (m, 1H).