Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].Cl.[OH-].[NH4+]>C(O)C.[Pd].O>[O:12]1[C@@H:13]2[C@@:5]34[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:19]([C@@H:18]3[CH2:17][CH2:16][C:14]2=[O:15])[CH2:20][C:7]2=[C:6]4[C:11]1=[C:10]([O:21][CH3:22])[CH:9]=[CH:8]2
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: [Pd]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Yield: 87 %

Procedure:
A solution of 1 g of codeinone (prepared by the method of Gavard et al., Bull. Soc. Chim. Fr., 486 (1965)) in 25 ml of 95% ethanol was adjusted to about pH 1 with concentrated hydrochloric acid and was hydrogenated on a Paar apparatus at 50 psi using 200 mg of 10% Palladium on charcoal catalyst for about 1 hour. The catalyst was then removed by filtration and the filtrate was evaporated to give a solid residue. This residue was dissolved in water and the solution adjusted to about pH 11 with concentrated ammonium hydroxide solution. The basic solution was extracted with three portions of chloroform. The combined organic extracts were washed with water, dried over MgSO4 and evaporated to leave a solid residue. The residue was crystallized from absolute ethanol to give the product, which had a melting point of 191°-194° C., in 87% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([S:26]([NH:29][C@H:30](C#C)[CH2:31][C:32]([OH:34])=[O:33])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1.N1CCC[CH:39]([C:40](OCC)=O)[CH2:38]1>>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([S:26]([N:29]2[CH2:40][CH2:39][CH2:38][CH:31]([C:32]([OH:34])=[O:33])[CH2:30]2)(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: C#C[C@H](CC(=O)O)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CCCN(S(=O)(=O)c2cccc(OCCCCNc3ccccn3)c2)C1

Procedure:
The procedure for the preparation of the product of EXAMPLE 17 was repeated using ethyl nipecotate (Aldrich) in the place of ethyl (3S)-3-aminopent-4-ynoate hydrochloride to provide the title product. 1H (CD3OD): δ 7.88 (1H, t); 7.82 (1H, d); 7.52 (1H, t); 7.33 (1H, d); 7.24 (1H, s); 7.22 (1H, d); 7.06 (1H, d); 6.87 (1H, t); 4.13 (2H, t); 3.69 (1H, d); 3.47 (3H, m); 2.57 (2H, m); 2.45 (1H, t); 1.94 (5H, m); 1.80 (1H, br. d); 1.60 (1H, br. q); 1.41 (1H, br. q).
Reaction SMILES: [F:1][C:2]([C@:6]1([NH:18][C:19]#[N:20])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7]1)([F:5])[CH2:3][OH:4].[OH-].[NH4+]>CO>[F:1][C:2]1([F:5])[CH2:3][O:4][C:19]([NH2:20])=[N:18][C@@:6]21[C:14]1[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=1)[CH2:8][CH2:7]2
Reactant: N#CN[C@]1(C(F)(F)CO)CCc2ccc([N+](=O)[O-])cc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC1=N[C@@]2(CCc3ccc([N+](=O)[O-])cc32)C(F)(F)CO1
Temperature: 60 °C
Yield: 49.7 %

Procedure:
In a tube, a solution of (R)-1-(1,1-difluoro-2-hydroxy-ethyl)-6-nitro-indan-1-yl-cyanamide (1.0 g, 3.55 mmol) in methanol (10 ml) was treated with ammonium hydroxide (25% in water, 3 ml). The tube was sealed and heated at 60° C. for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure. The crude material was purified by column chromatography (NH-biotage) using a 95:5-mixture of dichloromethane and methanol as the eluent. The (R)-5′,5′-difluoro-6-nitro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (500 mg, 50% yield) was obtained as a white solid. MS (ISP): m/z=283.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:22])[N:13]([CH3:21])[CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:6]=1.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:22])[N:13]([CH3:21])[CH:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:6]=2)=[C:2]([F:1])[CH:26]=1
Reactant: [H][H]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reaction time: 3 h
Yield: 77.8 %

Procedure:
3-[4-(2-Fluoro-4-nitrophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (243 mg) was dissolved in tetrahydrofuran (6 ml)-methanol (6 ml), and then 10% palladium carbon (128 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the reaction system and stirring for 3 hrs. After replacing with nitrogen inside the system, the catalyst was filtered and washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) and concentrated under a reduced pressure to provide the titled compound (175 mg, 78.0%) as pale yellow powder.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:28])[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([CH3:27])=[CH:8][N:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][CH2:37]Cl.COCNC(C1C(N(COC)S(C2C=CC(Cl)=C(C(F)(F)F)C=2)(=O)=O)=CC(Cl)=CN=1)=O>C1COCC1>[CH3:1][O:2][N:3]([CH3:28])[C:4]([C:6]1[C:11]([N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)(=[O:15])=[O:14])[CH2:35][O:36][CH3:37])=[CH:10][C:9]([CH3:27])=[CH:8][N:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1ncc(C)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COCCl
Agent: COCNC(=O)c1ncc(Cl)cc1N(COC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Prepared from 223 mg (0.51 mmol) of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-5-methyl-pyridine-2-carboxylic acid methoxy-methyl-amide, 352 mg of potassium carbonate and 116 μL of methoxymethyl chloride in 1 mL THF using the procedure used to prepare Intermediate 12. Yield: 200 mg of a white solid. LC-MSD, m/z for C18H19ClF3N3O5S [M+H]+=482.0, 484.0; HPLC retention time: 2.5 minutes.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7](Br)[CH:8]=[CH2:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:8]=[CH2:7]
Reactant: C=CCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The piperidine from Example 114 (56 mg, 0.15 mmol) was dissolved in dimethylformamide (2 mL) and was treated with allyl bromide (17 μL, 0.18 mmol), and potassium carbonate (63 mg, 0.45 mmol) and the mixture was stirred at r.t. for 4 hrs. The mixture was diluted with water (2 mL) and the solution washed with ethyl acetate (3×10 mL). The organic phase was dried (MgSO4) and evaporated to give a pale oil which was purified by column chromatography on silica gel eluting with 80% ethyl acetate in hexanes to give the N-allylpiperidine. 1H NMR (CDCl3) 7.42-7.37 (4H, m), 7.13-7.02 (2H, m), 6.90-6.83 (1H, m), 5.83-5.71 (1H, m), 5.12-5.08 (2H, m), 2.99-2.95 (2H, m), 2.86 (2H, d, J=6.5 Hz), 2.84-2.38 (4H, m), and 1.91-1.85 (2H, m); MS MH+=412(414).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:24]([CH:25]2[CH2:27][CH2:26]2)=[N:23][NH:22][C:21]=1[C:28](O)=[O:29]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:21]3[NH:22][N:23]=[C:24]([CH:25]4[CH2:26][CH2:27]4)[C:20]=3[Cl:19])=[O:29])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1[nH]nc(C2CC2)c1Cl
Product: C[C@]1(c2cc(NC(=O)c3[nH]nc(C4CC4)c3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-chloro-5-cyclopropyl-2H-pyrazole-3-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=428.3 [M+H]+.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[O:11]1[CH2:12][C:13](=[O:15])[C:2]2[CH:3]=[CH:4][C:5]3[C:10]([C:1]1=2)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=C(O)COc1cccc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1COc2c1ccc1ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of 2-(1-naphthoxy)acetic acid (2.26 g, 11.2 mmol) in benzene (20 mL) was added oxalyl chloride (5 mL, 57.3 mmol). The resulting mixture was heated at reflux for 30 min, then allowed to cool and concentrated under reduced pressure. The residue was dissolved in benzene, and to this was added aluminium chloride (1.83 g, 13.9 mmol). The resulting mixture was stirred at room temperature for 1 h, then poured into ice. The organic phase was separated and washed with saturated aqueous NaCl. Removal of the solvent in vacuo provided the title compound (1.74 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:44][C@@H:45]1[C@@H:50]([OH:51])[C@H:49]([OH:52])[C@@H:48]([CH2:53][OH:54])[O:47][C@@H:46]1[OH:55]>>[ClH:1].[CH3:41][O:40][C:32]1[CH:33]=[C:34]([C:35](=[O:36])[NH:44][C@@H:45]2[C@@H:50]([OH:51])[C@H:49]([OH:52])[C@@H:48]([CH2:53][OH:54])[O:47][C@@H:46]2[OH:55])[CH:38]=[CH:39][C:31]=1[NH:30][C:28]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:42])[C@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]1)=[O:29]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O
Agent: Cl
Product: COc1cc(C(=O)N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with (2S,3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol hydrochloride to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-methoxy-4-((2S,3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-phenyl]-amide, hydrochloride. MS (ES+) m/z calcd. for C37H41Cl2F2N4O8: [(M+H)+]777. found: 777.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:26])[O:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([N:18]2[N:22]=[C:21]([CH2:23][CH3:24])[C:20]([CH3:25])=[N:19]2)[CH:12]=3)=[CH:4][CH:3]=1.CN([CH:30]=[N:31][N:32]=[CH:33]N(C)C)C>CN(C)C=O.CC1C=CC(S(O)(=O)=O)=CC=1>[N:31]1[N:32]=[CH:33][N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:9](=[O:26])[O:10][C:11]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[C:13]([N:18]3[N:22]=[C:21]([CH2:23][CH3:24])[C:20]([CH3:25])=[N:19]3)[CH:12]=4)=[CH:4][CH:3]=2)[CH:30]=1
Reactant: CN(C)C=NN=CN(C)C
Reactant: CCc1nn(-c2ccc3cc(-c4ccc(N)cc4)c(=O)oc3c2)nc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CCc1nn(-c2ccc3cc(-c4ccc(-n5cnnc5)cc4)c(=O)oc3c2)nc1C
Yield: 71.8 %

Procedure:
17.3 g (50.0 mmols) of 3-(4-aminophenyl)-7-(4-ethyl-5-methyl-2H-1,2,3-triazol-2-yl)-coumarin, 10.5 g (75.0 mmols) of 1,2-bis-(dimethylaminomethylene)-hydrazine and 200 mg of 4-methylbenzenesulphonic acid are refluxed in 40 ml of anhydrous dimethylformamide for 10 hours under an N2 atmosphere. A further 3.50 g (25.0 mmols) of 1,2-bis-(dimethylaminomethylene)-hydrazine are then added, and the mixture is refluxed for a further 10 hours. 16.1 g (81%) of pale yellow crystals are precipitated on cooling the mixture. Recrystallisation from dimethylformamide yields 14.3 g (72%) of 3-(4-(1,2,4-triazol-4-yl)-phenyl)-7-(4-ethyl-5-methyl-2H-1,2,3-triazol-2-yl)-coumarin in the form of small pale yellow crystals of melting point 321°-323° C.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])=[CH:17][CH:18]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(C(=O)NCC(=O)c2ccco2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(C)cc1)C(=O)c1ccco1
Yield: 85.6 %

Procedure:
12.0 g of N-(4-methylbenzoyl)-(2-furylcarbonyl)methylamine, 2.3 g of 61% sodium hydride and 9.1 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 13.9 g of ethyl 3-(4-methylbenzoylamino)-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 85.5%
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:7][CH2:6]1)=[O:4].[OH-].[K+].Cl>CO.O>[F:25][C:22]([F:23])([F:24])[C:19]1[CH:18]=[CH:17][C:16]([S:13]([NH:12][CH2:11][C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)(=[O:14])=[O:15])=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 1.09 g (2.87 mmol) of trans-4-[(4-trifluoromethyl-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid methyl ester and 569 mg (85%, 8.62 mmol, 3 eq) of KOH in 20 mL of MeOH and 1 mL of H2O were refluxed for 3 h. After cooling to RT, 4.5 mL of 2M aqueous HCl were added and extracted with 3 portions of 20 mL of CH2Cl2. The combined organic phases were washed with H2O, then with brine, dried over anhydrous Na2SO4 and finally evaporated, leaving 1 g (95%) of trans-4-[(4-trifluoromethyl-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid as white solid, MS: 364 ((M−H)−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[F:20])(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(F)cc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2,4-difluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH:12]=[C:13]([CH3:15])[CH3:14])=[N:7][CH:6]=1)[CH3:2]>C1COCC1.CO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(C=C(C)C)c(C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cnc(CC(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.4 %

Procedure:
5-Methyl-6-(2-methyl-propenyl)-nicotinic acid ethyl ester (3.98 g, 18.2 mmol) is dissolved in THF (100 mL) and MeOH (100 mL), Pd/C (500 mg, 10% Pd) is added and the mixture is stirred under 1 atm H2 at rt for 15 h. The catalyst is filtered off and the filtrate is evaporated to give 6-isobutyl-5-methyl-nicotinic acid ethyl ester (3.76 g) as a colourless oil; LC-MS: tR=0.75 min; [M+1]+=222.15; 1H NMR (CDCl3) δ 0.97 (d, J=6.8 Hz, 6H), 1.42 (t, J=7.3 Hz, 3H), 2.20 (hept, J=6.8 Hz, 1H), 2.38 (s, 3H), 2.75 (d, J=7.0 Hz, 2H), 4.41 (q, J=7.3 Hz, 2H), 8.03 (d, J=1.8 Hz, 1H), 9.00 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:5](C(O)=O)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[CH3:21].N1CCCCC1.Cl>N1C=CC=CC=1>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([OH:8])=[O:7])=[CH:15][C:14]=1[CH3:21]
Reactant: CCCCC(C(=O)O)C(=O)O
Reactant: Cc1cc(C=O)ccc1F
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCCCC(=Cc1ccc(F)c(C)c1)C(=O)O
Temperature: 100 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
A mixture of 2-butyl-malonic acid (2.319 g, 14.482 mmol), 4-fluoro-3-methylbenzaldehyde (1.000 g, 7.241 mmol), and piperidine (1.232 g, 14.482 mmol) in 10 mL of pyridine was heated to 100° C. and stirred at this temperature for 16 h. After cooling to room temperature, the reaction mixture was poured into 25 mL of concentrated HCl containing 50 g of ice, and then extracted with ethyl acetate. The organic extracts were combined and dried over anhydrous Na2SO4, concentrated under reduced pressure, the product isolated by Flash chromatography (silica gel) eluting with 0-30% ethyl acetate/hexanes to give the title compound as yellow liquid (1.370 g, 80% yield). LC-MS: tR=9.5 min; m/z 237 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:32]=[CH:31][C:20]([CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:19][CH:18]=1.C(O)(C(F)(F)F)=O>>[NH2:23][CH2:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:4]2[C:5]3[C:6]4[CH:16]=[CH:15][S:14][C:7]=4[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])=[CH:32][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN)cc1
Yield: 91 %

Procedure:
Following General Procedure C, tert-butyl 4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (310 mg, 0.69 mmol) was reacted with TFA (2 mL) to afford the desired product (220 mg, 90%) as an off-white solid: 1H NMR (500 MHz, DMSO-d) δ 7.91 (s, 1H), 7.91 (br s, 2H), 7.71 (d, J=5.4 Hz, 1H), 7.52 (d, J=9.1 Hz, 1H), 7.40 (m, 3H), 7.22 (d, J=8.1 Hz, 2H), 5.80 (d, J=5.4 Hz, 1H), 3.68 (s, 3H), 3.20-3.17 (m, 2H), 3.02-2.99 (m, 2H); ESI MS m/z 351 [C20H18N2O2S+H]+; HPLC 98.8% (AUC), tR=8.32 min.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:9][CH:6]([CH:7]=[CH:8]1)[CH2:5][CH:4]2[CH2:10][OH:11].[F:12][C:13]([F:22])([F:21])[C:14]1([C:17]([F:20])([F:19])[F:18])[O:16][CH2:15]1>CN(C=O)C>[CH:3]12[CH2:9][CH:6]([CH:7]=[CH:8]1)[CH2:5][CH:4]2[CH2:10][O:11][CH2:15][C:14]([C:13]([F:12])([F:21])[F:22])([OH:16])[C:17]([F:20])([F:19])[F:18]
Reactant: OCC1CC2C=CC1C2
Reactant: FC(F)(F)C1(C(F)(F)F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(COCC1CC2C=CC1C2)(C(F)(F)F)C(F)(F)F
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A dry round bottom flask with mechanical stirrer and condenser was charged under nitrogen with 28.8 g (1.2 mol) of 95% sodium hydride and 400 ml of anhydrous DMF (N,N′-dimethylformamide). 5-Norbornene-2-methanol (108.6 g, 0.875 mol) was added dropwise at room temperature over 0.5 hr. The resulting mixture was stirred for 3 hr. 1,1-Bis(trifluoromethyl)ethylene oxide (1, Hexafluoroisobutylene epoxide) (173.2 g, 0.96 mol) from Example 1 was added dropwise over 2 hr. The resulting mixture was stirred for 72 hr at room temperature. DMF was evaporated on a rotary evaporator at 45° C. and 1 mm. The residue was diluted with 300 ml of ice water containing 30 ml of glacial acetic acid. A lower layer was separated and the aqueous layer was extracted with 2×25 ml of methylene chloride. The combined organic layers were washed with 3×100 ml of water, dried over anhydrous magnesium chloride, filtered and distilled under vacuum in a Kugelrohr apparatus at 65-87° C. and 0.1 mm. An NMR spectrum revealed that the product was contaminated with small amounts of DMF so it was dissolved in 100 ml of hexane, washed with 4×200 ml water, dried over anhydrous magnesium sulfate, filtered and distilled in a Kugelrohr apparatus at 70-80° C. and 0.1 mm giving 233.9 g (88%) of the title product (3-[(bicyclo[2.2.1]hept-5-en-2-yl)methoxy]-1,1,1-trifluoro-2-(trifluoromethyl)-2-propanol, comonomer 2). In another preparation, the product was distilled through a 12″ Vigreux column indicating a bp of 52-53° C. at 0.1 mm. 1H NMR (δ, CD2Cl2) 0.5 to 4.3 (complex multiplets, 12 H), 5.90, 6.19 and 6.26 (m, 2H). 19F NMR (δ, CD2Cl2) −77.4 (s).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]>C(Cl)Cl>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:1]([O-:4])=[O:2])[C:7]=1[OH:12]
Reactant: Oc1ccccc1F
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(F)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Concentrated HNO3 (95%, 44 g, 0.62 mol) was added dropwise at 0-5° C. to the solution of 2-fluorophenol (64.6 g, 0.58 mol) in 1 L of DCM. The mixture was stirred at 0° C. for 1 hour before filtration. The filtrate was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (DCM:PE=1:2) to afford 2-fluoro-6-nitrophenol.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].[N:24]([CH2:27][CH2:28][OH:29])=[N+:25]=[N-:26]>CN(C)C=O.CO.[Cu]I>[C:19]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:26]=[N:25][N:24]([CH2:27][CH2:28][OH:29])[CH:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:23])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:22])(=[O:21])[CH3:20]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: [N-]=[N+]=NCCO
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (100 mg, 0.318 mmol) in a mixture of N,N-dimethylformamide (DMF) (1.8 mL) and methanol (0.200 mL) were successively added 2-azidoethanol (55.4 mg, 0.636 mmol) and copper(I) iodide (3.03 mg, 0.016 mmol). The resulting mixture was stirred at 100° C. under microwave irradiation for 2 h then cooled to room temperature. The reaction mixture was partitioned between EtOAc and brine and the layers were separated. The aqueous phase was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over a Na2SO4 cartridge and concentrated in vacuo. Purification of the residue on SP4 using a 10 G silica cartridge (gradient: 2 to 10% MeOH in DCM) gave 1-methylethyl {(2S,4R)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (83 mg, 0.198 mmol, 62%) as an off white solid.