Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.C([Li])CCC.CCCCCC.Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CCOCC>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1)[CH3:40]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(Br)ccc3c2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
A solution of 2-bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalene (2 g, 5.5 mmol) in ether (10 mL) under nitrogen was added 1.6 M n-butyllithium in hexane (4 mL, 6.4 mmol) at 0° C. The solution was stirred for 30 min at 0° C., then treated with copper(I) bromide-dimethyl sulfide complex (0.8 g, 3.9 mmol). After 2 hrs stirring, a solution of ethyl bromoacetate (0.7 mL, 6 mmol) in ether (4 mL) was added. The solution was stirred at 0° C. for 2 hrs, then warmed to room temperature for 3 hrs. The reaction was quenched with 10% HCl aqueous then the insoluble was filtered off. The organic layer was washed with water, sodium bicarbonate aqueous, dried over MgSO4, filtered and concentrated. The crude was purified via silica gel column eluted with EtOAc in hexanes from 0 to 10% to give light yellow solid (0.45 g, yield: 22% yield). ESI-MS: 369.20 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([CH2:22][OH:23])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([CH:22]=[O:23])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(C=O)C1
Temperature: -78 °C
Yield: 37.5 %

Procedure:
Oxalyl chloride (2.1 mL; 24.0 mmol) was dissolved in methylene chloride (30 mL) and cooled to -78° C. Dimethyl sulfoxide (2.3 mL; 32.0 mmol) was added. A solution of 3-hydroxymethylazetidine-1-carboxylic acid tert-butyl ester (3.0 g; 16.0 mmol) in methylene chloride (20 mL) was added dropwise to the reaction mixture. Triethyl amine (11.1 mL; 80.1 mmol) was added and the reaction mixture was heated to room temperature. Methylene chloride (200 mL) and hydrochloric acid (200 mL; 1 N) was added. The aqueous phase was extracted with methylene chloride (100 mL). The combined organic phases were washed with saturated sodium hydrogen carbonate (100 mL), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (3×30 cm) using ethyl acetate/heptane (4:1) as eluent to afford 1.11 g of 3-formylazetidine-1-carboxylic acid tert-butylester.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:22][C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=2[Cl:30])=[N:12][N:11]=1.O>CN(C=O)C>[Cl:30][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:29])[C:23]=1[CH2:22][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:10]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[NH:11][N:12]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(N1CCCC1=O)NN=C2Cc1c(Cl)cncc1Cl
Temperature: 40 °C
Yield: 53.5 %

Procedure:
A solution of 2-pyrrolidinone (0.14 ml, 1.83 mmoles) in dry DMF (10 ml) under N2 was added with NaH (0.068 g, 1.7 mmoles; 60% in oil) and the mixture was heated to 40° C. for 1 hour, cooled and added with 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.5 g, 1.41 mmoles), prepared as described in example 45. The mixture was heated to 80° C. overnight, then poured into water (10 volumes) and extracted three times with ethyl acetate. The organic phase was discoloured with charcoal, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: ethyl acetate/petrolatum 9:1). The resultant solid was triturated in ethyl ether and 0.306 g of the title compound were yielded (yield: 53%). m.p.: 223-225° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH:18]([N:13]1[C:12]([C:35]2[CH:34]=[CH:33][C:32]([O:31][C:30]([F:29])([F:41])[F:42])=[CH:37][CH:36]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)n1nc2c(c1-c1ccc(OC(F)(F)F)cc1)CCNCC2
Yield: 88.8 %

Procedure:
The title compound (196 mg) was prepared according to Example 189 using 278 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 402 mg of 4-trifluoromethoxyphenylboronic acid. MS (ESI): exact mass calculated for C17H20F3N3O, 339.36. found, m/z 340.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.53-7.45 (m, 4H), 4.66 (br s, 1H), 4.40 (J=6.68 Hz, 1H), 3.45-3.43 (m, 1H), 3.23-3.21 (m, 1H), 2.88-2.79 (m, 2H), 1.42 (d, J=6.7 Hz, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].[NH:22]1[C:30]2[C:25](=CC=C[CH:29]=2)[C:24]2(COC3C=C4C(=[CH:41][C:31]2=3)CCO4)C1=O.ClCC1C=NC(OC)=NC=1>>[N:22]1[CH:41]=[CH:31][CH:24]=[CH:25][C:30]=1[CH2:29][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: COc1ncc(CCl)cn1
Product: O=C1N(Cc2ccccn2)c2ccccc2[C@]12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using (3S)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (2-bromomethyl)pyridine hydrobromide to replace 5-(chloromethyl)-2-methoxypyrimidine, (3S)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (77%) as a colorless solid: mp 154-156° C. (diethyl ether); mp 84-85° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ8.53-8.51 (m, 1H), 7.82-7.77 (m, 1H), 7.38-7.13 (m, 4H), 7.05-6.99 (m, 1H), 6.98-6.92 (m, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 5.10 (d, J=16.4 Hz, 1H), 5.00 (d, J=16.4 Hz, 1H), 4.86 (d, J=9.3 Hz, 1H), 4.75 (d, J=9.3 Hz, 1H), 4.49 (t, J=8.7 Hz, 2H), 2.98 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.0, 161.0, 160.4, 155.2, 149.2, 142.4, 137.0, 132.2, 128.5, 123.4, 122.8, 122.6, 121.5, 120.6, 119.7, 119.2, 109.2, 92.3, 79.7, 72.0, 56.8, 44.7, 28.2; MS (ES+) m/z 371.0 (M+1).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:26]([O:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[O:34][C:35](=[O:37])[CH3:36])=[O:27]>ClCCl>[C:35]([O:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[O:28][C:26]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:27])(=[O:37])[CH3:36]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
In a separate reaction flask, to a stirred solution of gabapentin (1.8 g, 10 mmol) and triethylamine (4.3 mL, 31 mmol) in dichloromethane (100 mL) at 0° C. under nitrogen atmosphere, was added dropwise a solution of chlorotrimethylsilane (2.6 mL, 21 mmol) in dichloromethane (10 mL). After stirring for 30 min at 0° C., 2(R)-acetoxycyclopent-1(R)-yl chloroformate was added dropwise into the reaction mixture. The resulting mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h (monitored by TLC). The reaction mixture was then concentrated in vacuo and the resulting residue was poured into cold water (50 mL), acidified to about pH 5.0 using 0.1 N HCl, then extracted using ethyl acetate (2×50 mL). The combined extracts were washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified using flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluant to afford 2.0 g (84%) of compound 48 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ1.31–1.78 (14H, m); 2.03–2.04 (5H, m); 2.31 (2H, s); 3.20 (2H, t, J=6.4 Hz); 5.07–4.97 (2H, m), 5.20 (1H, broad s). MS (ESI): m/z=340.25 (M−H−).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:12]([OH:13])[CH2:11][CH2:10][C:9]=2[C:14]([O:16]C)=[O:15])=[CH:4][CH:3]=1.C1COCC1.COCCO[AlH2-]OCCOC.[Na+].OS([O-])(=O)=O.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@@H:12]([OH:13])[CH2:11][CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(c2ccc(F)cc2)[C@@H](O)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CC[C@H](O)[C@H]1c1ccc(F)cc1
Temperature: -48 °C
Reaction time: 0.5 h

Procedure:
To a toluene stream containing methyl (3S)-2-(4-fluorophenyl)-3-hydroxycyclopent-1-enecarboxylate in 21 L toluene was added 12 Liters of dry THF and the reaction mixture was cooled to −48° C. To the cooled solution was added drop-wise over 45 min 3.8 Liters (13.46 mol) of 70% Red-Al in toluene. The reaction mixture was allowed to warm to −25° C. over 2.5 h and was added to a solution of 21 L of 2M NaHSO4. The mixture was stirred for 30 min and the layers separated. The toluene layer was then washed with 15 L of water. The toluene layer was then azeotropically dried (50° C., 25 inHg) to a final volume of 21 L (KF 130 ug/mL) and used in the next step. To the toluene solution was added 820 mL (3.6 mol) of 25 wt % NaOMe in MeOH at 50° C. and the mixture heated to 75° C. for 1 h. The mixture was then cooled to 50° C. and 17 L of water, 1 L of MeOH, and 4.5 L of 6N NaOH was added. The mixture was stirred at 20-25° C. overnight. The layers were separated, and the toluene layer discarded. The aqueous layer was then washed with 15 L of MTBE and the MTBE layer discarded. The aqueous layer was then made acidic with conc. HCl (2.1 L, pH 1). The mixture was extracted with 40 L of IPAC. The IPAC layer containing the product (1.35 kg, 69% assay) was then treated with 500 g of Darco for 30 min at 25° C. and filtered over a pad of solka floc, rinsing the pad with and additional 5 L of IPAC. The IPAC solution was then azeotropically dried (45° C., 25 inHg) to a final volume of 15 L (KF<200) and cooled to 20° C. To the IPAC solution was added 3.04 L of n-heptane and the mixture seeded with 5 g of (1R,2R,3S)-2-(4-fluorophenyl)-3-hydroxycyclopentane-1-carboxylic acid. After a good seed bed had been formed (30 min) the rest of the n-heptane (40.4 L) was added drop-wise over 1 hour. The slurry was cooled to 10° C. and filtered. The cake was washed with 2 L of 5:1 n-heptane/IPAC and then with 1 L of heptane. The cake was then dried under vacuum/N2 sweep at 20-25° C. overnight to provide (1R,2R,3S)-2-(4-fluorophenyl)-3-hydroxycyclopentane-1-carboxylic acid as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12](Cl)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.C[NH:17]C.[CH:19]([N:22]([CH:25]([CH3:27])C)CC)([CH3:21])C.C(=O)(O)[O-].[Na+]>ClCCl>[N:22]1([C:11]2[C:2]([OH:1])=[N:3][C:4]3[C:9]([C:10]=2[C:12]([NH2:17])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:19][CH2:21][CH2:27][CH2:25]1
Reactant: CNC
Reactant: O=C(Cl)c1cc(O)nc2ccccc12
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1c(N2CCCC2)c(O)nc2ccccc12

Procedure:
To 2-hydroxyquinolin-4-oyl chloride (V-A, 0.90 g) in dichloromethane (20 ml) are added dimethylamine hydrochloride (0.52 g), followed by diisopropylethylamine (1.12 ml). After stirring for 5 hr aqueous sodium bicarbonate is added and the mixture is extracted several times with dichloromethane. The organic layers are dried over sodium sulfate and concentrated. The crude product was chromatographed (silica gel; methanol/dichloromethane (2/98 to 4/96)), to give dimethylamino 2-hydroxyquinoline-4-carboxamide (VI, 0.73 g), mp 219-220°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][C:21]=1[CH3:22].C(N(CC)CC)C>CCCCCCC>[Br:15][C:16]1[CH:17]=[C:18]([C:23](=[O:25])[CH2:24][C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)([OH:14])[C:10]([F:11])([F:12])[F:13])[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: CC(=O)c1ccc(C)c(Br)c1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: Cc1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 3.42 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone and 3.00 g of 3′-bromo-4′-methylacetophenone in 5 mL of heptane, 0.71 g of triethylamine was added and the resultant reaction mixture was stirred at 60° C. for 8 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature. A deposited solid was separated off and was washed with 3 mL of hexane to obtain 6.16 g of the objective substance as a white crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.[N:11]([O-])=O.[Na+].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>Cl>[N:1]1[N:11]([C:18]2[CH:19]=[CH:20][C:15]([OH:21])=[CH:16][CH:17]=2)[N:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=12
Reactant: Oc1ccccc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc(-n2nc3ccccc3n2)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
o-Nitroaniline (0.5 mole) was diazotized in the usual manner with concentrated hydrochloric acid (200 ml.) and sodium nitrite (0.5 mole). The clear diazonium solution was added slowly to a cold solution (0-5° C.) of phenol (0.5 mole) in 450 ml. of 10% sodium hydroxide. The mixture was stirred for 1 hour and compound A filtered out (60% yield). One-tenth mole of compound A was dissolved in 100 ml. of 2N NaOH. Zinc dust (30 g.) and sodium hydroxide (50 ml. of a 25% solution) were added slowly to the well-stirred solution to keep the temperature below 45° C. The mixture was then cooled to <30° C. and acidified with concentrated hydrochloric acid. After stirring for 2 hours, the precipitate was filtered. Recrystallization from ethanol-water gave p-(2H-benzotriazol-2-yl)phenol (B) in 90% yield (mp 216°-18° ). ##STR18##
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=O)(C)(C)C.Cl.[NH2:14][CH2:15]C(N)=O.C1([N:25]=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CN(C)C1C=CN=CC=1>[NH2:14][CH2:15][C:6]([NH:8][CH2:9][C:10]([NH2:25])=[O:12])=[O:5]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCC(N)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: NCC(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2 g (11.4 mmole) of N-(tert-butoxycarbonyl)-glycine (Boc-glycine) and 1.26 g (22.8 mmole) of glycinamide hydrochloride in 100 mL of DMF at neutral pH, 3.54 g (17.1 mmole) of dicyclohexylcarbodiimide (DCC) was added and 0.28 g (2.3 mmole) of 4-dimethylaminopyridine (DMAP) was added as a catalyst. The reaction mixture was stirred for 24 hours at room temperature, the insoluble materials were filtered and the filtrate was evaporated to dryness in vacuum.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH2:23])[CH:17]=[C:18]([F:20])[CH:19]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:16]2[CH:17]=[C:18]([F:20])[CH:19]=[C:14]([F:13])[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1cc(F)cc(F)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
0.67 ml of 4-tert-butylbenzaldehyde (3.87 mmol) and 500 mg 2-(3,5-difluoro-phenyl)-ethylamine (2.58 mmol) were dissolved in 7.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 4 h. After cooling down to rt, 147 mg (3.87 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 10 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 653 mg light yellow oil (83%). MS (ISP) 304.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:6][CH:7]=1.C1C(=O)N([Br:30])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:12]([O:11][C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][Br:30])=[CH:7][N:6]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)cn1
Temperature: 80 °C
Yield: 65.4 %

Procedure:
A mixture of di-tert-butyl (5-methylpyridin-2-yl)imidodicarbonate (Compound 309C, 5.66 g, 18.4 mmol), NBS (3.92 g, 22 mmol), and benzoyl peroxide (0.444 g, 1.84 mmol) in CCl4 (30 mL) was heated at 80° C. for 6 h. The mixture was cooled to room temperature, the solids were filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography (EtOAc/heptane: 1:1) to give 4.66 g of di-tert-butyl[5-(bromomethyl)pyridin-2-yl]imidodicarbonate (yield: 65%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C3CCCCO3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[OH:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])=[CH:15][CH:14]=1
Reactant: Ic1ccc(NCc2ccc(OC3CCCCO3)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N(Cc1ccc(O)cc1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
To a solution of (4-iodo-phenyl)-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (3.43 g, 8.38 mmol) in 10 mL methylene chloride was added triethylamine (2.0 mL, 14.35 mmol) and benzenesulfonyl chloride (1.2 mL, 9.40 mmol). The reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was quenched with water, was acidified with 1N HCl, and the aqueous solution was washed three times with methylene chloride. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated. The residue was dissolved in methanol and the solution was treated with a catalytic amount of 1N HCl. The reaction mixture was stirred at room temperature for 20 hr. The reaction mixture was made basic with saturated aqueous sodium bicarbonate and the aqueous solution was washed two times with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 3.21 g (82%) of the title compound of Step B.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:19]1[C:38]([C:39]2[NH:43][N:42]=[CH:41][CH:40]=2)=[CH:37][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([Cl:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[O:24])=[CH:21][N:20]=1.O>CC(O)C>[Cl:36][C:33]([F:34])([F:35])[O:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:37]=[C:38]([C:39]3[NH:43][N:42]=[CH:41][CH:40]=3)[C:19]([N:5]3[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]3)=[N:20][CH:21]=2)=[CH:31][CH:30]=1
Reactant: FC1(F)CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCC(F)(F)C2)c(-c2ccn[nH]2)c1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
3,3-Difluoropyrrolidine hydrochloride (69.8 mg, 0.486 mmol) and DIPEA (0.170 mL, 0.972 mmol) were added to 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 100 mg, 0.243 mmol) in iPrOH (0.5 mL) and stirred at 140° C. for 3 h. The RM was treated with water, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude material which was purified by crystallization from DCM/EtOAc to give the title product as a white solid. HPLC (Condition 7) tR=6.746 min, UPLC-MS (Condition 3) tR=1.11 min, m/z=470.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.32-2.45 (m, 2H) 3.42-3.51 (m, 2H) 3.56 (t, J=13.29 Hz, 2H) 6.48 (s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.73-7.88 (m, 3H) 8.13 (d, J=2.35 Hz, 1H) 8.79 (s, 1H) 10.30 (s, 1H) 13.01 (br.s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:30][CH:31]=[CH2:32])[C:11]1[C:16](=[O:17])[N:15]2[C@H:18]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:20][C:14]2=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:44](I)[CH3:45].[CH2:47]1COC[CH2:48]1>>[CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:30][CH:31]=[CH2:32])[C:11]1[C:16](=[O:17])[N:15]2[C@H:18]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][C:20]([CH2:44][CH3:45])([CH2:47][CH3:48])[C:14]2=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)Nc1ccccc1)CC2
Reactant: C1CCOC1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)Nc1ccccc1)CC2(CC)CC
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of phenyl amide 18b (100 mg, 0.225 mmol) in 1 mL THF at −78° C., was added LiHMDS (IM in THF, 0.720 mL, 0.720 mmol). The orange solution was stirred at −78° C. for 5 min, then EtI (0.045 mL, 0.563 mmol) was added. The reaction was stirred and allowed to slowly warm to −30° C. over 45 min. Additional LiHMDS (IM in THF, 0.250 mL, 0.250 mmol) and EtI (0.025 mL) were added and the mixture was allowed to warm to −20° C. over 30 min. The reaction was quenched with the addition of sat. NH4Cl. The mixture was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (40 to 45% EtOAc/hexanes) to afford 81.1 mg (72%) of 37a as a colorless foam. MS (ESI) 501.3 (M+H+), 523.3 (M+Na+), 499.4 (M−H+), 535.3 (M+Cl−).