Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=3)=[CH:31][C:30]=2[N:43]2[CH:47]=[CH:46][C:45]([CH3:48])=[N:44]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=3)=[CH:31][C:30]=2[N:43]2[CH:47]=[CH:46][C:45]([CH3:48])=[N:44]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(C)c5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HCl and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided the title compound as an off-white solid as the zwitterionic form.
Reaction SMILES: CO[C:3](=[O:32])[CH:4]([C:15]1[N:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]2=[N:17][C:16]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[CH2:5][CH2:6][CH2:7][NH:8]S(C(C)(C)C)=O.Cl>CO.CO.CCOC(C)=O>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([C:15]([CH:4]3[CH2:5][CH2:6][CH2:7][NH:8][C:3]3=[O:32])=[C:16]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[N:17]=2)[CH:20]=1
Reactant: COC(=O)C(CCCNS(=O)C(C)(C)C)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3ccc(C)cn3c2C2CCCNC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To a magnetically stirred solution of (+/−)-5-(2-methyl-propane-2-sulfinylamino)-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-pentanoic acid methyl ester 44b (0.039 g, 0.0824 mmol) in methanol (3 mL) at room temperature under Ar atmosphere was 5N HCl (1.71 mL). The reaction mixture was stirred for 3 h at room temperature, then concentrated in vacuo. The reaction mixture was treated with 10% aq NaOH solution until basic. After 30 mm, water (30 mL) was added, and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic layers were dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel (EtOAc, then 4:96 MeOH/EtOAc as eluent) which gave the title compound (0.0202 g, 77%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.92 (m, 1H), 2.04 (m, 2H), 2.16 (m, 1H), 2.32 (s, 3H), 2.39 (s, 3H), 3.50 (m, 2H), 4.28 (dd, J=6.2, 12.4 Hz, 1H), 6.37 (s, 1H), 7.00 (d, J=10.2 Hz, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.56 (m, 3H). Mass spectrum (m/e) 320 (M+).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][C@H:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[C@H:21]1([NH:20][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 20 h
Yield: 59.7 %

Procedure:
For 20 hours, 1.83 g 6-chloropurine riboside, 0.95 g (R)(-)-1-aminoindane and 0.862 g triethylamine are refluxed in 50 ml absolute ethanol under nitrogen atmosphere. The solvent is evaporated to dryness and residue is treated with 50 ml cold water. The solid material is filtered, dissolved in excess ethanol, and volatiles are evaporated under reduced pressure to remove water. Residue upon treatment with ethanol affords solid material. It is filtered and dried. One more crop of the same material is obtained from the mother liquor yielding 1.46 g (60% of theory) of N(6) [1-(R)-indanyl]adenosine having a melting point of 185°-187° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(=O)C)[N:6]=[CH:5]2>CO.Cl.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CCc1c(Br)ccc2c1cnn2C(C)=O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1c(Br)ccc2[nH]ncc12

Procedure:
A mixture of 3.78 g of the compound prepared in Example 212c in 7.3 ml methanol and 26.3 ml of 37% hydrochloric acid was heated under reflux for 2 hours. This was then diluted with 400 ml ethyl acetate. The organic phase was washed three times with 50 ml portions of sodium hydrogen carbonate solution and once with 50 ml saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The crude product thus obtained was purified by column chromatography on silica gel with hexane/0-50% ethyl acetate. Yield: 2.97 g of the title compound.
Reaction SMILES: [CH3:1]C1C=CC=C(C)C=1C(O)=O.BrBr.[Br:14][C:15]1[C:16]([CH3:25])=[C:17]([C:21]([CH3:24])=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].CI>C(O)(=O)C>[Br:14][C:15]1[C:16]([CH3:25])=[C:17]([C:21]([CH3:24])=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].[Br:14][C:15]1[C:16]([CH3:25])=[C:17]([C:21]([CH3:24])=[CH:22][CH:23]=1)[C:18]([O:20][CH3:1])=[O:19]
Reactant: Cc1cccc(C)c1C(=O)O
Agent: BrBr
Agent: Cc1ccc(Br)c(C)c1C(=O)O
Solvent: CI
Solvent: CC(=O)O
Product: COC(=O)c1c(C)ccc(Br)c1C

Procedure:
3-Bromo-2,6-dimethylbenzoic acid was prepared from 2,6-dimethylbenzoic acid by treatment with bromine in acetic acid; see Org. Synth. Coll., Vol. 3, 138 (1944). 3-Bromo-2,6-dimethylbenzoic acid was esterified with methyl iodide as described in Tet. Letters, 689 (1973) to give methyl 3-bromo-2,6-dimethylbenzoate.
Reaction SMILES: C(O[C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1OC(=O)C)(=O)C.[O:17]=[C:18]1[CH:27]=[CH:26][C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][C:20]3([S:36][CH2:35][CH2:34][S:33]3)[C:19]1=2>C1(C)C(C)=CC=CC=1>[O:17]=[C:18]1[C:27]2[C:26](=[CH:6][C:7]3[C:8]([CH:5]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][C:20]3([S:33][CH2:34][CH2:35][S:36]3)[C:19]1=2
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Reactant: COC(=O)C1CC2=C(C(=O)C=CC2=O)C2(C1)SCCS2
Solvent: Cc1ccccc1C
Product: COC(=O)C1CC2=C(C(=O)c3cc4ccccc4cc3C2=O)C2(C1)SCCS2
Yield: 60.3 %

Procedure:
A mixture of 70 mg (0.32 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 66 mg (0.21 mmol) of methyl rac-1',2',3',4',5',8'-hexahydro-5',8'-dioxospiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylate [prepared as described in Example 2(A)] in 5 ml of xylene was stirred and heated under reflux under an atmosphere of nitrogen for 23 hours. The mixture was evaporated to dryness and the residue was stirred with 5 ml of diethyl ether and then filtered to give 52 mg (60%) of methyl rac-1',2',3',4',5',12'-hexahydro-5',12'-dioxospiro[1,3-dithiolane-2,4'-naphthacene]-2'-carboxylate in the form of a bright yellow solid of melting point 216° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2([C:15]([O:17]CC)=[O:16])[CH2:14][CH2:13][CH2:12]2)=[C:5]([CH3:20])[C:4]=1[CH3:21].[OH-].[K+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12]2)=[C:5]([CH3:20])[C:4]=1[CH3:21]
Reactant: CCOC(=O)C1(CNc2ccc(OC)c(C)c2C)CCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(NCC2(C(=O)O)CCC2)c(C)c1C
Temperature: 85 °C
Yield: 122.3 %

Procedure:
To a solution of ethyl 1-((4-methoxy-2,3-dimethylphenylamino)methyl)-cyclobutanecarboxylate (19 g) in ethanol (120 mL) was added KOH (9 g in 50 mL of water). The solution was then heated up in an 85° C. bath for 2 hours. The solution was then evaporated to dryness, HCl (3 M) was then added while the flask cooled in ice bath to reach a pH of less than 1, and the solution was extracted with ethylacetate. The combined organic phases were then dried and evaporated to give 1-((4-methoxy-2,3-dimethylphenylamino)methyl)cyclobutanecarboxylic acid (21.0 g), which was used in the next step without further purification. 1H-NMR (300 MHz, CDCl3) δ=8.78-7.95 (s, 1H), 6.81-6.74 (d, 1H), 6.73-6.66 (d, 1H), 3.77 (s, 3H), 3.44 (s, 2H), 2.68-2.41 (m, 2H), 2.17 (s, 3H); 2.14 (s, 3H), 2.09-1.93 (m, 4H) ppm. 13C-NMR (75 MHz, CDCl3) δ=181.21, 15.251, 137.65, 126.32, 125.78, 112.31, 108.99, 56.21, 52.84, 46.64, 28.46, 15.93, 13.36, 12.27 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[C:4]([F:23])[CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[C:4]([F:23])[CH:3]=1
Reactant: CCCC(CC(=O)c1ccc(OC)nc1)c1ccc(Br)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: CCCC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1F

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-2-fluoro-phenyl)-1-(6-methoxy-pyridin-3-yl)-hexan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless foam, MS (ESI+): m/z=366.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[C:11](Cl)(Cl)=[S:12]>C(OCC)(=O)C>[Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]([N:6]=[C:11]=[S:12])=[C:4]([F:10])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(O)c(Cl)cc1F
Solvent: CCOC(C)=O
Product: Oc1cc(N=C=S)c(F)cc1Cl
Temperature: 25 °C

Procedure:
1.00 g of 4-chloro-2-fluoro-5-hydroxyaniline was dissolved in 10 ml of ethyl acetate, and 0.61 ml of thiophosgene was dropwise added at 0° C. After the dropwise addition, the temperature was raised to room temperature, and the mixture was refluxed. After refluxing for 6 hours, ethyl acetate was distilled off to obtain a crude product of crystals. This crude product was washed with hexane to obtain 0.70 g of the above-identified compound as gray crystals.
Reaction SMILES: C(NCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3[CH:22]2[CH2:27]C[N:25](S(CC)(=O)=O)[CH2:24][CH2:23]2)=CC=1)C.[CH:33]([C:35]1[S:39][C:38]([B:40]([OH:42])[OH:41])=[CH:37][CH:36]=1)=O.C1(CN)CC1.[BH3-]C#N.[Na+]>>[CH:23]1([CH2:24][NH:25][CH2:33][C:35]2[S:39][C:38]([B:40]([OH:42])[OH:41])=[CH:37][CH:36]=2)[CH2:22][CH2:27]1
Reactant: CCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: NCC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: OB(O)c1ccc(CNCC2CC2)s1

Procedure:
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (cyclopropylmethyl)amine (0.027 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 73 mg of crude (5-{[(cyclopropylmethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(cyclopropylmethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 19.1 mg of the title compound (20%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:31])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)=[C:13]([C:15]([OH:17])=O)[N:14]=[C:7]3[C:6]=2[CH:30]=1.[Cl-].[NH4+:33]>>[Br:1][C:2]1[C:3]([F:31])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=4)=[C:13]([C:15]([NH2:33])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:30]=1
Reactant: O=C(O)c1nc2n(c1C(O)c1cccc(C(F)(F)F)c1)CCOc1cc(F)c(Br)cc1-2
Reactant: [NH4+]
Agent: [Cl-]
Product: NC(=O)c1nc2n(c1C(O)c1cccc(C(F)(F)F)c1)CCOc1cc(F)c(Br)cc1-2

Procedure:
The title compound was prepared similarly according to the procedure described in Example 2. 10-bromo-9-fluoro-3-(hydroxy(3-(trifluoromethyl)phenyl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid was reacted with ammonium chloride to give the titled compound which was used in subsequent steps without purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1CCCC1)([O:16][C:17](C)(C)[CH3:18])=O.CN1C[C@@H]2[C@H]3N(C[C@@H](C2)C1)CCCC3>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[CH2:18][CH2:17][OH:16])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Agent: CN1C[C@@H]2C[C@H](C1)[C@@H]1CCCCN1C2
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CCO

Procedure:
This compound is prepared in a manner analogous to that described in Example 3, but 1-Boc-piperidine is used insead of 1-Boc-pyrrolidine, and (+)-sparteine surrogate is used instead of (−)-sparteine.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13]S(C(C)(C)C)=O)[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[ClH:20].O1CCOCC1>CO>[ClH:20].[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH2:13])[CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(C)CC(NS(=O)C(C)(C)C)c1ccc(I)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)CC(N)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
N-(1-(4-iodophenyl)-3-methylbutyl)-2-methylpropane-2-sulfinamide (1.36 g, 3.45 mmol) was dissolved in methanol (17.2 mL). 4M HCl in dioxane (4.31 mL, 17.2 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated and the resulting solid was triturated with ether and dried under vacuum to provide 1-(4-iodophenyl)-3-methylbutan-1-amine hydrochloride (1.1 g, 100%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 7.80-7.84 (m, 2H), 7.20-7.24 (m, 2H), 4.25-4.31 (m, 1H), 1.83-1.92 (m, 1H), 1.71-1.79 (m, 1H), 1.34-1.42 (m, 1H), 0.92 (dd, J=12.19, 6.54 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:41])[CH2:31][CH2:30][CH2:29][C:28]2[CH:27]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=[CH:24][C:23]1=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:26]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:41])([CH3:21])[CH2:31][CH2:30][CH2:29][C:28]=4[CH:27]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(-c3ccc4c(c3)CCCC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(4-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (US 2005/59668) and 2-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [OH:1]O.[C:3]([CH2:6][S:7][C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([F:19])=[CH:14][CH:15]=2)[N:10]([CH3:20])[CH:9]=1)([OH:5])=[O:4]>C(O)(=O)C.O>[C:3]([CH2:6][S:7]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([F:19])=[CH:14][CH:15]=2)[N:10]([CH3:20])[CH:9]=1)=[O:1])([OH:5])=[O:4]
Reactant: Cn1cc(SCC(=O)O)c(=O)c2ccc(F)cc21
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(S(=O)CC(=O)O)c(=O)c2ccc(F)cc21
Temperature: 55 °C
Reaction time: 4 h

Procedure:
50% hydrogen peroxide (57 ml, 33.6 mg, 0.988 mmol) was added to a solution of 3-carboxymethylthio-7-fluoro-1-methyl-4-quinolone (4) in acetic acid (3.6 ml) at 60° C. and the mixture was stirred at 55° C. for 4 h. The hot mixture was diluted with water (12 ml) and cooled to 0° C. A white solid that precipitated was filtered off and dried under high vacuum. The yield of 3-Carboxymethylsulfinyl-7-fluoro-1-methyl-4-quinolone was 185 mg (72.7%) (5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[N:11]=[N:12][C:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:14][CH:15]=3)[NH:7][C:6]=2[CH:22]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[N:11]=[N:12][C:13]([N:16]4[CH2:17][CH2:18][N:19]([C:27]([C:26]5[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=5[C:24]([F:23])([F:34])[F:35])=[O:28])[CH2:20][CH2:21]4)=[CH:14][CH:15]=3)[NH:7][C:6]=2[CH:22]=1
Reactant: Clc1ccc2nc(-c3ccc(N4CCNCC4)nn3)[nH]c2c1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3nc4ccc(Cl)cc4[nH]3)nn2)CC1
Yield: 24 %

Procedure:
Following the procedure as described in Example 6, making variations only as required to use 6-chloro-2-(6-piperazin-1-yl-pyridazin-3-yl)-1H-benzoimidazole in place of 2-(6-piperazin-1-ylpyridin-3-yl)-1H-benzoimidazole to react with 2-trifluoromethyl-benzoyl chloride, the title compound was obtained as a white powder in 24% yield (0.118 g). 1H NMR (300 MHz, CDCl3) δ 13.4 (m, 1H), 8.15 (d, J=9.5 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.76 (t, J=7.5 Hz, 1H), 7.70-7.63 (m, 2H), 7.54 (d, J=7.5 Hz, 1H), 7.48-7.45 (m, 1H), 7.42 (d, J=9.6 Hz, 1H), 7.24-7.16 (m, 1H), 3.83-3.59 (m, 6H), 3.30-3.20 (m, 2H). MS (ES+) m/z 487.4 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Br:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].[CH2:24](Br)[CH:25]=[CH2:26].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([O:21][CH2:26][CH:25]=[CH2:24])[C:18]([Br:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1)[CH3:2]
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Br)cc1F
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(-n2c(OCC)nc(C(F)(F)F)cc2=O)c(F)cc1Br

Procedure:
using 2-ethoxy-1-(4-bromo-2-fluoro-5-hydroxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone and allyl bromide with sodium hydride in dimethylformamide there is obtained 2-ethoxy-1-[4-bromo-2-fluoro-5-(2-propenyloxy)-phenyl]-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 68°-70° C.;
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=2)[CH:13]=1)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([Cl:36])[CH:30]=1>>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([Cl:36])[CH:30]=3)[N:19]=2)[CH:13]=1)[CH:8]([CH3:9])[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: CC(C)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(=O)OC(C)(C)C
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)OC(C)(C)C

Procedure:
Intermediate 70 was coupled with Intermediate 71 following procedure F. LC-MS showed the product had the expected M+H+ of 497. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (d, 1H) 7.9 (m, 2H) 7.4 (m, 2H) 7.2 (m, 2H) 7.0 (m, 3H) 4.4 (s, 2H) 3.7 (m, 2H) 2.8 (m, 2H) 1.4 (s, br, 10H) 1.0 (d, 6H).
Reaction SMILES: CS[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:24][CH3:25])([O:22][CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5]>C(O)C.[Ni]>[CH3:23][O:22][C:15]([C:11]1[CH:10]=[C:9]([CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[CH:14]=[CH:13][CH:12]=1)([O:24][CH3:25])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C(C)(SC)c1cccc(C(OC)(OC)c2ccccc2)c1
Agent: [Ni]
Solvent: CCO
Product: COC(=O)C(C)c1cccc(C(OC)(OC)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Methyl α-methylthio-α-[m-(α,α-dimethoxybenzyl)phenyl]-propionate (211 mg) was dissolved in 1 ml of ethanol, and 5 ml of an ethanol suspension of 2 cc of Raney nickel (W-II) was added. The mixture was stirred at room temperature for 1 hour. The insoluble matter was separated by filtration, and washed with 40 ml of ethanol. The filtrate and the washing were combined and concentrated under reduced pressure, and 30 ml of methylene chloride was added to the residue. The insoluble matter was separated by filtration, and the solvent was evaporated off under reduced pressure to afford 159 mg of methyl α-[m-(α,α-dimethoxybenzyl)phenyl]propionate as an oil in a yield of 86%.
Reaction SMILES: I[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][O:5][C:6]=1[CH3:7].C(N(CC)CC)C.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:21][C:22]([OH:26])([C:24]#[C:25][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][O:5][C:6]=1[CH3:7])[CH3:23]
Reactant: C#CC(C)(C)O
Reactant: Cc1onc(-c2ccccc2)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1C#CC(C)(C)O
Temperature: 90 °C
Reaction time: 1.75 h
Yield: 77.7 %

Procedure:
A mixture of 4-iodo-5-methyl-3-phenylisoxazole (5.73 g, 20.1 mmol), palladium(II) acetate (135 mg, 0.60 mmol), 1,3-bis(diphenylphosphino)propane (249 mg, 0.60 mmol), triethylamine (7.0 mL, 50.2 mmol) and 2-methyl-3-butyn-2-ol (3.0 mL, 30.7 mmol) in N,N-dimethylformamide (40 mL) was evaporated and flushed with argon. Cuprous iodide (77 mg, 0.40 mmol) was added and the reaction mixture was stirred for 23 h at 90° C. (after 1.75 h and 4.5 h, respectively, further palladium(II) acetate (135 mg, 0.60 mmol), 1,3-bis(diphenylphosphino)propane (249 mg, 0.60 mmol), triethylamine (7.0 mL, 50.2 mmol), 2-methyl-3-butyn-2-ol (3.0 mL, 30.7 mmol) and cuprous iodide (77 mg, 0.40 mmol) were added) before cooled to ambient temperature and separated between aqueous sodium hydroxide (1 M, 600 mL) and ethyl acetate (1000 mL). The aqueous layer was extracted with ethyl acetate (1000 mL) and washed with aqueous sodium hydroxide (1 M, 600 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=67:33) afforded the title compound (3.77 g, 78%) as a yellow oil. MS: m/e=242.2 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[C:18]([Br:26])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[BH4-]>C1COCC1.CCOCC.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:25]=[CH:24][C:19]([CH2:20][OH:21])=[C:18]([Br:26])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccc(CO)c(Br)c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
Methyl 4-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-bromobenzoate (4.12 g, 9.9 mmol) was added to a solution of LiBH4 (429 mg, 19.8 mmol) in THF/ether/H2O (20/20/1 mL) and was allowed to stir at 25° C. After 16 hours, the reaction was quenched with H2O (10 mL). The reaction mixture was diluted with dichloromethane (25 mL) and was extracted with 1N HCl (30 mL×3) and brine (30 mL). The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by chromatography on silica gel (eluting with 0-100% ethyl acetate in hexanes) to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)phenyl)cyclopropanecarboxamide (2.84 g, 74%); ESI-MS m/z calc. 389.0, found 390.1 (M+1)+; retention time 2.91 minutes.